stem cell treatment alzheimer's disease - asci - asian stem cell institute

7/30/2019 Stem Cell Treatment Alzheimer's Disease - ASCI - Asian Stem Cell Institute

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Stem Cell Treatments for

Alzheimer's Disease are now

available at ASCI

Alzheimer's disease (AD) is the most

common form of dementia; it worsens as it

progresses, and eventually leads to death. It

was first described by German psychiatrist and

neuropathologist Alois Alzheimer in 1906 and

was named after him.

Most often, AD is diagnosed in people over

65 years of age, although the less-prevalent

early-onset Alzheimer's can occur much

earlier. In 2006, there were 26.6 millionsufferers worldwide. Alzheimer's is predicted to affect 1 in 85 people globally by 2050.

Although Alzheimer's disease develops differently for every individual, there are many common symptoms.

Early symptoms are often mistakenly thought to be 'age-related' concerns, or manifestations of stress. In the

early stages, the most common symptom is difficulty in remembering recent events. When AD is suspected,

the diagnosis is usually confirmed with tests that evaluate behaviour and thinking abilities, often followed by

a brain scan if available.

Causation

The cause for most Alzheimer's cases is still

essentially unknown (except for 1% to 5% ofcases where genetic differences have been

identified). Several competing hypotheses

exist trying to explain the cause of the disease.

The oldest, on which most currently available

drug therapies are based, is the cholinergic

hypothesis, which proposes that AD is caused

by reduced synthesis of the neurotransmitter

acetylcholine. The cholinergic hypothesis has

not maintained widespread support, largely

because medications intended to treat

acetylcholine deficiency have not been veryeffective. Other cholinergic effects have also

been proposed, for example, initiation of

large-scale aggregation of amyloid, leading to

generalised neuroinflammation.

A 2004 study found that deposition of

amyloid plaques does not correlate well with

tem Cell Treatment Alzheimer's Disease - ASCI - Asian Stem ... http://www.stem-cell-regeneration.com/alzheimers-disease?t

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neuron loss. This observation supports the tau

hypothesis, the idea that tau protein

abnormalities initiate the disease cascade. In

this model, hyperphosphorylated tau begins to

pair with other threads of tau. Eventually, they

form neurofibrillary tangles inside nerve cell

bodies. When this occurs, the microtubules

disintegrate, collapsing the neuron's transportsystem. This may result first in malfunctions

in biochemical communication between

neurons and later in the death of the cells.

Another hypothesis asserts that the disease may be caused by age-related myelin breakdown in the brain.

Demyelination leads to axonal transport disruptions. Iron released during myelin breakdown is hypothesized

to cause further damage. Homeostatic myelin repair processes contribute to the development of proteinaceous

deposits such as amyloid-beta and tau.

Oxidative stress may be significant in the formation of the pathology.

Alzheimers Stem Cell Treatment and stem cell therapy. Alzheimers treatment studies and stem cell

protocols:

Valproic acid as a promising agent to combat Alzheimer's disease.

Related Articles Valproic acid as a promising agent to combat Alzheimer's disease. Brain Res Bull. 2010 Jan

15;81(1):3-6 Authors: Zhang XZ, Li XJ, Zhang HY Abstract Alzheimer's disease (AD) is one of the most threatening

diseases to the elderly population at present. However, there is no yet efficient therapeutic method to AD. Recently,

accumulating evidence indicates that valproic acid (VPA), a widely used mood stabilizer and antiepileptic drug, has

neuroprotective potential relevant to AD. Moreover, VPA can induce neurogenesis of neural progenitor/stem cells both

in vitro and in vivo via multiple signaling pathways. Therefore, it is suggested that VPA is a promising agent to combat

AD. PMID: 19748552 [PubMed - indexed for MEDLINE]

Neuroscience: Alzheimer's disease.

Related Articles Neuroscience: Alzheimer's disease. Nature. 2009 Oct 15;461(7266):895-7 Authors: Mucke L PMID:

19829367 [PubMed - indexed for MEDLINE]

Neurogenesis and Alzheimer's disease: Biology and pathophysiology in mice and men.

Related Articles Neurogenesis and Alzheimer's disease: Biology and pathophysiology in mice and men. Curr Alzheimer

Res. 2010 Mar;7(2):113-25 Authors: Marlatt MW, Lucassen PJ Abstract The hippocampus is critical for learning and

memory and heavily affected in dementia. The presence of stem cells in this structure has led to an increased interest

in the phenomenon of adult neurogenesis and its role in hippocampal functioning. Not surprising, investigators of

Alzheimer's disease have also evaluated adult neurogenesis due to its responsiveness to hippocampal damage.

Although causal relationships have not been established, many factors known to impact neurogenesis in the

hippocampus, are implicated in the pathogenesis of AD. Also, adult neurogenesis has been proposed to reflect a"neurogenic reserve" that may determine vulnerability to hippocampal dysfunction and neurodegeneration. Since

neurogenesis is modifiable, stimulation of this process, or the potential use of stem cells, recruited endogenously or

implanted by transplantation, has been speculated as a possible treatment of neurodegenerative disorders. As the

structural and molecular mechanisms governing adult neurogenesis are important for evaluating therapeutic strategies,

we will here review collective literature findings and speculate about the future of this field with a focus on findings from

Alzheimer's mouse models. Continued research in this area and use of these models is critical for evaluating if

neurogenesis based therapeutic strategies will indeed have the potential to aid those with degenerative conditions.

PMID: 19860727 [PubMed - indexed for MEDLINE]


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Intracerebral transplantation of bone marrow-derived mesenchymal stem cells reduces amyloid-beta

deposition and rescues memory deficits in Alzheimer's disease mice by modulation of immune responses.

Related Articles Intracerebral transplantation of bone marrow-derived mesenchymal stem cells reduces amyloid-beta

deposition and rescues memory deficits in Alzheimer's disease mice by modulation of immune responses. Stem Cells.

2010 Feb;28(2):329-43 Authors: Lee JK, Jin HK, Endo S, Schuchman EH, Carter JE, Bae JS Abstract Alzheimer's

disease (AD) is characterized by the deposition of amyloid-beta peptide (Abeta) and the formation of neurofibrillary

tangles. Transplantation of bone marrow-derived mesenchymal stem cells (BM-MSCs) has been suggested as apotential therapeutic approach to prevent various neurodegenerative disorders, including AD. However, the actual

therapeutic impact of BM-MSCs and their mechanism of action in AD have not yet been ascertained. The aim of this

study was therefore to evaluate the therapeutic effect of BM-MSC transplantation on the neuropathology and memory

deficits in amyloid precursor protein (APP) and presenilin one (PS1) double-transgenic mice. Here we show that

intracerebral transplantation of BM-MSCs into APP/PS1 mice significantly reduced amyloid beta-peptide (Abeta)

deposition. Interestingly, these effects were associated with restoration of defective microglial function, as evidenced by

increased Abeta-degrading factors, decreased inflammatory responses, and elevation of alternatively activated

microglial markers. Furthermore, APP/PS1 mice treated with BM-MSCs had decreased tau hyperphosphorylation and

improved cognitive function. In conclusion, BM-MSCs can modulate immune/inflammatory responses in AD mice,

ameliorate their pathophysiology, and improve the cognitive decline associated with Abeta deposits. These results

demonstrate that BM-MSCs are a potential new therapeutic agent for AD. PMID: 20014009 [PubMed - indexed for

MEDLINE]

Are circulating monocytes as microglia orthologues appropriate biomarker targets for neuronal diseases?

Related Articles Are circulating monocytes as microglia orthologues appropriate biomarker targets for neuronal

diseases? Cent Nerv Syst Agents Med Chem. 2009 Dec;9(4):307-30 Authors: Schmitz G, Leuthuser-Jaschinski K,

Ors E Abstract Microglial cells, in contrast to other central nervous system cell types such as neurons and macroglia,

are of myeloid origin. They constitute the immune cells of the brain and are involved in neuroinflammatory and

neurodegenerative processes. Moreover, diseases of the central nervous system with an inflammatory component are

characterized by the migration of bone marrow-derived monocytes into the brain where they differentiate into microglia,

the "tissue macrophages" of the nervous system, bearing a therapeutic potential for certain diseases by transplantation

of bone marrow-derived hematopoietic stem and progenitor cells. Due to their common origin, microglial cells and

monocytes/macrophages share expression of many surface receptors and signalling proteins. Moreover, there is

overlap in the expression of many genes related to Alzheimer s disease. Activation of resident and blood-derived

microglia in diseases of the central nervous system can be both beneficial, e.g. by degradation of protein aggregates,

and detrimental, e.g. by secretion of neurotoxic factors. This review summarizes the current knowledge about the role

of microglia in neurodegenerative diseases with a focus on Alzheimer s disease. Moreover, we present data how

neuroinflammation is reflected by cellular changes in peripheral blood enabling the use of blood

monocytes/macrophages for diagnosis, therapeutic target finding and outcome monitoring of neurodegenerative

disorders. In summary, blood monocytes as microglia orthologues are an important model system to study the role of

microglia in the pathogenesis of neurodegenerative diseases. They are suitable biomarker targets for diagnosis and

prognosis and maybe also therapy of central nervous system disease. PMID: 20021364 [PubMed - indexed for

MEDLINE]

Neural progenitor cells attenuate inflammatory reactivity and neuronal loss in an animal model of inflamed AD

brain.

Related Articles Neural progenitor cells attenuate inflammatory reactivity and neuronal loss in an animal model of

inflamed AD brain. J Neuroinflammation. 2009;6:39 Authors: Ryu JK, Cho T, Wang YT, McLarnon JG AbstractBACKGROUND: Transplantation of neural progenitor cells (NPC) constitutes a putative therapeutic maneuver for use

in treatment of neurodegenerative diseases. At present, effects of NPC transplantation in Alzheimer's disease (AD)

brain are largely unknown and a primary objective of this work was to demonstrate possible efficacy of NPC

administration in an animal model of AD. The benefits of transplantation could involve a spectrum of effects including

replacement of endogenous neurons or by conferring neuroprotection with enhancement of neurotrophic factors or

diminishing levels of neurotoxic agents. Since chronic inflammation is a characteristic property of AD brain, we

considered that transplantation of NPC could have particular utility in inhibiting ongoing inflammatory reactivity. We


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have tested intrahippocampal transplantation of NPC for efficacy in attenuating inflammatory responses and for

neuroprotection in beta-amyloid (Abeta1-42) peptide-injected rat hippocampus. METHODS: Spheres of neural

progenitor cells were grown from dissociated telencephalon tissue of rat embryos. NPC were infected with lentiviral

vector green fluorescent protein (GFP) with subsequent cell transplantation into rat hippocampus previously injected (3

d prior) with Abeta1-42 peptide or PBS control. Immunohistochemical analysis was carried out (7 d post-NPC

transplantation, 10 d post-peptide/PBS injection) for GFP, microgliosis (Iba-1 marker), astrogliosis (GFAP marker),

neuron viability (MAP-2 marker) and levels of the proinflammatory cytokine, TNF-alpha. RESULTS: Successful infection

of cultured NPC with lentiviral vector green fluorescent protein (GFP) was demonstrated prior to cell transplantation into

rat hippocampus. In vivo, immunohistochemical staining showed migration of GFP-positive cells, in a region of dentate

gyrus between Abeta1-42/PBS injection site and NPC transplantation site, was increased x2.8-fold with Abeta1-42

compared to PBS injection. Double immunostaining in peptide-injected brain indicated GFP association with nestin and

GFAP, but not MAP-2. Cell-specific immunostaining showed marked increases in microgliosis and astrogliosis in

Abeta1-42-injected brain (respective increases of x4.3- and x4.6-fold compared with PBS injection). NPC

transplantation significantly reduced microgliosis (by 38%) but not astrogliosis in peptide-injected hippocampus. The

proinflammatory cytokine TNF-alpha was elevated by 6.7-fold (peptide vs PBS injection) with NPC administration

attenuating levels of TNF-alpha (by 40%). Peptide-injected brain demonstrated neuronal loss (MAP-2 staining reduced

by 45% vs PBS injection) with NPC transplantation effective in conferring neuroprotection (26% recovery of neurons).

CONCLUSIONS: These findings indicate efficacy for NPC transplantation in an animal model of AD with effects

consistent with cellular actions to attenuate inflammatory reactivity induced by intrahippocampal peptide injection.


Neurotransmitter phenotype differentiation and synapse formation of neural precursors engrafting in amyloid-

(1-40) injured rat hippocampus.

Related Articles Neurotransmitter phenotype differentiation and synapse formation of neural precursors engrafting in

amyloid-(1-40) injured rat hippocampus. J Alzheimers Dis. 2010;21(4):1233-47 Authors: Li Z, Gao C, Huang H, SunW, Yi H, Fan X, Xu H Abstract Alzheimer's disease (AD) is characterized by the dysfunction or loss of a vulnerable

group of neurons. At present, only a few options exist for treating neurodegenerative diseases effectively. Advances in

stem cell research have raised the hope and possibility for therapy in neurodegenerative diseases. In AD transgenic

animal models, stem cell transplantation has been demonstrated to reverse behavioral deficits. Our recent study

demonstrates that neural precursor cells, derived from embryonic stem (ES) cells, improve memory dysfunction in rats

caused by injections of amyloid- peptide (1-40) (A) in the dorsal hippocampus. However, the underlyingmechanisms remain unknown. The present study tests a murine ES cell-based transplantation approach in rats

subjected to A injection into the hippocampus dentate gyrus. Efficacy of cell therapy with regard to graft survival,neuronal yield and diversity, synapse formation of the grafted cells, and the behavioral improvements was determined

after transplanting ES cell-derived neural precursors into the hippocampus of adult rats. Here, we show that grafted

cells can survive, and differentiate with high yield into immunohistochemically mature glial cells and neurons of diverse

neurotransmitter-subtypes. More importantly, transplanted cells demonstrate characteristics of proper synapse

formation between host and grafted neural cells. Thus, our observations show that an ES cell-based transplantation

approach may be promising in the treatment of AD. PMID: 21504128 [PubMed - indexed for MEDLINE]

Stem cells in human neurodegenerative disorders--time for clinical translation?

Related Articles Stem cells in human neurodegenerative disorders--time for clinical translation? J Clin Invest. 2010

Jan;120(1):29-40 Authors: Lindvall O, Kokaia Z Abstract Stem cell-based approaches have received much hype as

potential treatments for neurodegenerative disorders. Indeed, transplantation of stem cells or their derivatives in animal

models of neurodegenerative diseases can improve function by replacing the lost neurons and glial cells and by

mediating remyelination, trophic actions, and modulation of inflammation. Endogenous neural stem cells are alsopotential therapeutic targets because they produce neurons and glial cells in response to injury and could be affected

by the degenerative process. As we discuss here, however, significant hurdles remain before these findings can be

responsibly translated to novel therapies. In particular, we need to better understand the mechanisms of action of stem

cells after transplantation and learn how to control stem cell proliferation, survival, migration, and differentiation in the

pathological environment. PMID: 20051634 [PubMed - indexed for MEDLINE]


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Adult neurogenesis: a potential tool for early diagnosis in Alzheimer's disease?

Related Articles Adult neurogenesis: a potential tool for early diagnosis in Alzheimer's disease? J Alzheimers Dis.

2010;20(2):395-408 Authors: Lopez-Toledano MA, Ali Faghihi M, Patel NS, Wahlestedt C Abstract Alzheimer's disease

(AD) is a devastating age-related neurodegenerative disorder characterized by progressive impairment of cognition and

short-term memory loss. The deposition of amyloid-beta (Abeta) 1-42 into senile plaques is an established feature of

AD neuropathology. Controversy still exists about the amyloid pathway as the initiating mechanism or a mere

consequence of the events leading to AD. Nevertheless, Abeta toxicity has been probed in vitro and in vivo and

increased production or decreased clearance of Abeta peptides are reported to play a major role in the development of

AD. Treatment of neural stem cells with Abeta in vitro induces neuronal differentiation. Increased neurogenesis has

been also described in AD patients as well as in amyloid-beta protein precursor (AbetaPP) transgenic mice. Adult

neurogenesis is greatly enhanced in young AbetaPP transgenic mice, before other AD-liked pathologies, and reduced

in older animals. This increased neurogenesis at young ages might be the first pathology related to AD, which is

detectable long before other harmful manifestation of the disease. Therefore, understanding the mechanisms of Abeta-

induced neurogenesis will reveal insights into the pathogenesis of AD and may prove useful as an early AD biomarker.


Mechanisms of mononuclear phagocyte recruitment in Alzheimer's disease.

Related Articles Mechanisms of mononuclear phagocyte recruitment in Alzheimer's disease. CNS Neurol Disord Drug

Targets. 2010 Apr;9(2):168-73 Authors: Hickman SE, El Khoury J Abstract Alzheimer's disease (AD) is associated with

a significant neuroinflammatory component. Mononuclear phagocytes including monocytes and microglia are the

principal cells involved, and they accumulate at perivascular sites of beta-amyloid (Abeta) deposition and in senileplaques. Recent evidence suggests that mononuclear phagocyte accumulation in the AD brain is dependent on

chemokines. CCL2, a major monocyte chemokine, is upregulated in the AD brain. Interaction of CCL2 with its receptor

CCR2 regulates mononuclear phagocyte accumulation in a mouse model of AD. CCR2 deficiency leads to lower

mononuclear phagocyte accumulation and is associated with higher brain Abeta levels, specifically around blood

vessels, suggesting that monocytes accumulate at sites of Abeta deposition in an initial attempt to clear these deposits

and stop or delay their neurotoxic effects. Indeed, enhancing mononuclear phagocyte accumulation delays progression

of AD. Here we review the mechanisms of mononuclear phagocyte accumulation in AD and discuss the potential roles

of additional chemokines and their receptors in this process. We also propose a multi-step model for recruitment of

mononuclear phagocytes into the brain. The first step involves egress of monocyte/microglial precursors from the bone

marrow into the blood. The second step is crossing the blood-brain barrier to the perivascular areas and into the brain

parenchyma. The final step includes movement of monocytes/microglia from areas of the brain that lack any amyloid

deposition to senile plaques. Understanding the mechanism of recruitment of mononuclear phagocytes to the AD brain

is necessary to further understand the role of these cells in the pathogenesis of AD and to identify any potentialtherapeutic use of these cells for the treatment of this disease. PMID: 20205643 [PubMed - indexed for MEDLINE]

Impact of the CD40-CD40L dyad in Alzheimer's disease.

Related Articles Impact of the CD40-CD40L dyad in Alzheimer's disease. CNS Neurol Disord Drug Targets. 2010

Apr;9(2):149-55 Authors: Giunta B, Rezai-Zadeh K, Tan J Abstract As the number of elderly individuals rises,

Alzheimer's disease (AD), marked by amyloid-beta deposition, neurofibrillary tangle formation, and low-level

neuroinflammation, is expected to lead to an ever-worsening socioeconomic burden. AD pathoetiologic mechanisms

are believed to involve chronic microglial activation. This phenomenon is associated with increased expression of

membrane-bound CD40 with its cognate ligand, CD40 ligand (CD40L), as well as increased circulating levels of soluble

forms of CD40 (sCD40) and CD40L (sCD40L). Here, we review the role of this inflammatory dyad in the pathogenesis

of AD. In addition, we examine potential therapeutic strategies such as statins, flavonoids, and human umbilical cord

blood transplantation, all of which have been shown to modulate CD40-CD40L interaction in mouse models of AD.Importantly, therapeutic approaches focusing on CD40-CD40L dyad regulation, either alone or in combination with

amyloid-beta immunotherapy, may provide for a safe and effective AD prophylaxis or treatment in the near future.


Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease.

Related Articles Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease.

Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6498-503 Authors: Wang JM, Singh C, Liu L, Irwin RW, Chen S, Chung


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EJ, Thompson RF, Brinton RD Abstract Our previous analyses showed that allopregnanolone (APalpha) significantly

increased proliferation of rodent and human neural progenitor cells in vitro. In this study, we investigated the efficacy of

APalpha to promote neurogenesis in the hippocampal subgranular zone (SGZ), to reverse learning and memory

deficits in 3-month-old male triple transgenic mouse model of Alzheimer's (3xTgAD) and the correlation between

APalpha-induced neural progenitor cell survival and memory function in 3xTgAD mice. Neural progenitor cell

proliferation was determined by unbiased stereological analysis of BrdU incorporation and survival determined by

FACS for BrdU+ cells. Learning and memory function was assessed using the hippocampal-dependent trace eye-blink

conditioning paradigm. At 3 months, basal level of BrdU+ cells in the SGZ of 3xTgAD mice was significantly lower

relative to non-Tg mice, despite the lack of evident AD pathology. APalpha significantly increased, in a dose-dependent

manner, BrdU+ cells in SGZ in 3xTgAD mice and restored SGZ proliferation to normal magnitude. As with the deficit in

proliferation, 3xTgAD mice exhibited deficits in learning and memory. APalpha reversed the cognitive deficits to restore

learning and memory performance to the level of normal non-Tg mice. In 3xTgAD mice, APalpha-induced survival of

neural progenitors was significantly correlated with APalpha-induced memory performance. These findings suggest

that early neurogenic deficits, which were evident before immunodetectable Abeta, may contribute to the cognitive

phenotype of AD, and that APalpha could serve as a regenerative therapeutic to prevent or delay neurogenic and

cognitive deficits associated with mild cognitive impairment and Alzheimer's disease. PMID: 20231471 [PubMed -

indexed for MEDLINE]

Incretin analogues that have been developed to treat type 2 diabetes hold promise as a novel treatment

strategy for Alzheimer's disease.

Related Articles Incretin analogues that have been developed to treat type 2 diabetes hold promise as a noveltreatment strategy for Alzheimer's disease. Recent Pat CNS Drug Discov. 2010 Jun;5(2):109-17 Authors: Holscher C

Abstract Analogues of the incretins Glucagon-like peptide 1 (GLP-1) and Glucose-dependent insulinotropic peptide

(GIP) have been developed to treat type 2 diabetes mellitus. They are protease resistant and have a longer biological

half life than the native peptides. Some of these novel analogues can cross the blood-brain barrier, have

neuroprotective effects, activate neuronal stem cells in the brain, and can improve cognition. The receptors for GIP and

GLP-1 are expressed in neurons, and both GIP and GLP-1 are expressed and released as transmitters by neurons.

GIP analogues such as DAla(2)GIP and GLP-1 analogues such as liraglutide enhance synaptic plasticity in the brain

and also reverse the betaamyloid induced impairment of synaptic plasticity. In mouse models of Alzheimer's disease,

GLP-1 analogues Val(8)GLP-1 and liraglutide prevent memory impairment and the block of synaptic plasticity in the

brain. Since two GLP- 1 analogues exendin-4 (Exenatide, Byetta) and liraglutide (Victoza) are already on the market as

treatments for Type 2 diabetes, and others are in late stage clinical trials, these drugs show promise as treatments for

neurodegenerative diseases such as Alzheimer's disease. Currently, there are three patents covering native GLP-1 and

different GLP-1 analogues and one patent for the use of GIP and different GIP analogues for the treatment ofneurodegenerative diseases. PMID: 20337586 [PubMed - indexed for MEDLINE]

[Positron emission tomography imaging of cell transplantation in a rat model of Alzheimer's disease].

Related Articles [Positron emission tomography imaging of cell transplantation in a rat model of Alzheimer's disease].

Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2010 Apr;32(2):210-4 Authors: He TT, Zhang JM, Shen L, Yao SL, Tian JH

Abstract OBJECTIVE: To explore the value of positron emission tomography (PET) in the Alzheimer's disease (AD) rat

model verification and in monitoring the therapeutic effectiveness of cell transplantation. METHODS: A beta(1-40)

hippocampus injected rat model was successfully established and neural stem cells were injected into hippocampus.

Results of behavior tests and histological examinations were compared between model group and graft group, and

then the N-methyl-[(11)C]2-(4 methylaminophenyl)-6-hydroxybenzothiazole ((11)C-PIB) and (18)F-fluorodeoxyglucose

((18)F-FDG) imaging were performed to observe whether the result of imaging was matched with behavior test and

histological examination. RESULTS: The Morris water maze showed that the latent period of the escape wassignificantly longer in model group than in control group (P

Gene- and cell-based approaches for neurodegenerative disease.

Related Articles Gene- and cell-based approaches for neurodegenerative disease. Adv Exp Med Biol. 2010;671:117-30

Authors: Urbaniak Hunter K, Yarbrough C, Ciacci J Abstract Neurodegenerative diseases comprise an important group

ofchronic diseases that increase in incidence with rising age. In particular, the two most common neurodegenerative

diseases are Alzheimer's disease and Parkinson's disease, both of which will be discussed below. A third, Huntington's


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disease, occurs infrequently, but has been studied intensely. Each of these diseases shares characteristics which are

also generalizeable to other neurodegenerative diseases: accumulation ofproteinaceous substances that leads

inexorably to selective neuronal death and decline in neural function. Treatments for these diseases have historically

focused on symptomatic relief, but recent advances in molecular research have identified more specific targets.

Additionally, stem cell therapy, immunotherapy and trophic-factor delivery provide avenues for neuronal protection that

may alter the natural progression of these devastating illnesses. Upcoming clinical trials will evaluate treatment

strategies and provide hope that translational research will decrease the onset of debilitating disability associated with

neurodegenerative disease. PMID: 20455500 [PubMed - indexed for MEDLINE]

Bone marrow-derived mesenchymal stem cells attenuate amyloid -induced memory impairment and

apoptosis by inhibiting neuronal cell death.

Related Articles Bone marrow-derived mesenchymal stem cells attenuate amyloid -induced memory impairment andapoptosis by inhibiting neuronal cell death. Curr Alzheimer Res. 2010 Sep;7(6):540-8 Authors: Lee JK, Jin HK, Bae JS

Abstract Amyloid (A) peptide plays a central role in neuronal apoptosis, promoting oxidative stress, lipidperoxidation, caspase pathway activation and neuronal loss. Our previous study has shown that bone marrow-derived

mesenchymal stem cells (BM-MSCs) reduce A deposition when transplanted into acutely-induced Alzheimer'sdisease (AD) mice brain. However, the impact of reduced A deposition on memory impairment and apoptosis byBM-MSCs has not yet been investigated. Therefore, the aim of the present study was to investigate the neuroprotective

mechanism of BM-MSCs in vitro and in vivo. We found that BM-MSCs attenuated A-induced apoptotic cell death inprimary cultured hippocampal neurons by activation of the cell survival signaling pathway. These anti-apoptotic effects

of BM-MSCs were also observed in an acutely-induced AD mice model produced by injecting A intrahippocampally. Inaddition, BM-MSCs diminished A -induced oxidative stress and spatial memory impairment in the in vivo model.These findings lead us to hypothesize that BM-MSCs ameliorate A -induced neurotoxicity and cognitive decline byinhibiting apoptotic cell death and oxidative stress in the hippocampus. These findings provide support for a potentially

beneficial role for BM-MSCs in the treatment of AD. PMID: 20455866 [PubMed - indexed for MEDLINE]

Human umbilical cord blood-derived mesenchymal stem cells improve neuropathology and cognitive

impairment in an Alzheimer's disease mouse model through modulation of neuroinflammation.

Related Articles Human umbilical cord blood-derived mesenchymal stem cells improve neuropathology and cognitive

impairment in an Alzheimer's disease mouse model through modulation of neuroinflammation. Neurobiol Aging. 2012

Mar;33(3):588-602 Authors: Lee HJ, Lee JK, Lee H, Carter JE, Chang JW, Oh W, Yang YS, Suh JG, Lee BH, Jin HK,

Bae JS Abstract Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSC) have a potential

therapeutic role in the treatment of neurological disorders, but their current clinical usage and mechanism of action has

yet to be ascertained in Alzheimer's disease (AD). Here we report that hUCB-MSC transplantation into amyloid

precursor protein (APP) and presenilin1 (PS1) double-transgenic mice significantly improved spatial learning and

memory decline. Furthermore, amyloid- peptide (A) deposition, -secretase 1 (BACE-1) levels, and tauhyperphosphorylation were dramatically reduced in hUCB-MSC transplanted APP/PS1 mice. Interestingly, these effects

were associated with reversal of disease-associated microglial neuroinflammation, as evidenced by decreased

microglia-induced proinflammatory cytokines, elevated alternatively activated microglia, and increased

anti-inflammatory cytokines. These findings lead us to suggest that hUCB-MSC produced their sustained

neuroprotective effect by inducing a feed-forward loop involving alternative activation of microglial neuroinflammation,

thereby ameliorating disease pathophysiology and reversing the cognitive decline associated with A deposition in ADmice. PMID: 20471717 [PubMed - indexed for MEDLINE]

Suppressed accumulation of cerebral amyloid {beta} peptides in aged transgenic Alzheimer's disease mice by

transplantation with wild-type or prostaglandin E2 receptor subtype 2-null bone marrow.Related Articles Suppressed accumulation of cerebral amyloid {beta} peptides in aged transgenic Alzheimer's disease

mice by transplantation with wild-type or prostaglandin E2 receptor subtype 2-null bone marrow. Am J Pathol. 2010

Jul;177(1):346-54 Authors: Keene CD, Chang RC, Lopez-Yglesias AH, Shalloway BR, Sokal I, Li X, Reed PJ, Keene

LM, Montine KS, Breyer RM, Rockhill JK, Montine TJ Abstract A complex therapeutic challenge for Alzheimer's disease

(AD) is minimizing deleterious aspects of microglial activation while maximizing beneficial actions, including

phagocytosis/clearance of amyloid beta (Abeta) peptides. One potential target is selective suppression of microglial

prostaglandin E(2) receptor subtype 2 (EP2) function, which influences microglial phagocytosis and elaboration of


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neurotoxic cytokines. To test this hypothesis, we transplanted bone marrow cells derived from wild-type mice or mice

homozygous deficient for EP2 (EP2(-/-)) into lethally irradiated 5-month-old wild-type or APPswe-PS1DeltaE9 double

transgenic AD mouse model recipients. We found that cerebral engraftment by bone marrow transplant (BMT)-derived

wild-type or EP2(-/-) microglia was more efficient in APPswe-PS1DeltaE9 than in wild-type mice, and APPswe-

PS1DeltaE9 mice that received EP2(-/-) BMT had increased cortical microglia compared with APPswe-PS1DeltaE9

mice that received wild-type BMT. We found that myeloablative irradiation followed by bone marrow transplant-derived

microglia engraftment, rather than cranial irradiation or BMT alone, was responsible for the approximate one-third

reduction in both Abeta plaques and potentially more neurotoxic soluble Abeta species. An additional 25% reduction in

cerebral cortical Abeta burden was achieved in mice that received EP2(-/-) BMT compared with mice that received

wild-type BMT. Our results provide a foundation for an adult stem cell-based therapy to suppress soluble Abeta peptide

and plaque accumulation in the cerebrum of patients with AD. PMID: 20522650 [PubMed - indexed for MEDLINE]

Why scientific details are important when novel technologies encounter law, politics, and ethics.

Related Articles Why scientific details are important when novel technologies encounter law, politics, and ethics. J Law

Med Ethics. 2010;38(2):204-11 Authors: Goldstein L Abstract This paper focuses on the issue of what to do if a couple

who generates embryos chooses to lawfully, and in their (and my) view, ethnically discard those embryos. Specifically,

is it appropriate to use the cells that come from "excess" embryos in medical research instead of discarding them when

a couple has ceased trying to have any additional children? PMID: 20579243 [PubMed - indexed for MEDLINE]

The therapeutic potential of human umbilical cord blood-derived mesenchymal stem cells in Alzheimer's

disease.

Related Articles The therapeutic potential of human umbilical cord blood-derived mesenchymal stem cells in

Alzheimer's disease. Neurosci Lett. 2010 Aug 30;481(1):30-5 Authors: Lee HJ, Lee JK, Lee H, Shin JW, Carter JE,

Sakamoto T, Jin HK, Bae JS Abstract The neuropathological hallmarks of Alzheimer's disease (AD) include the

presence of extracellular amyloid-beta peptide (Abeta) in the form of amyloid plaques in the brain parenchyma and

neuronal loss. The mechanism associated with neuronal death by amyloid plaques is unclear but oxidative stress and

glial activation has been implicated. Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) are

being scrutinized as a potential therapeutic tool to prevent various neurodegenerative diseases including AD. However,

the therapeutic impact of hUCB-MSCs in AD has not yet been reported. Here we undertook in vitro work to examine

the potential impact of hUCB-MSCs treatment on neuronal loss using a paradigm of cultured hippocampal neurons

treated with Abeta. We confirmed that hUCB-MSCs co-culture reduced the hippocampal apoptosis induced by Abeta

treatment. Moreover, in an acute AD mouse model to directly test the efficacy of hUCB-MSCs treatment on AD-related

cognitive and neuropathological outcomes, we demonstrated that markers of glial activation, oxidative stress and

apoptosis levels were decreased in AD mouse brain. Interestingly, hUCB-MSCs treated AD mice demonstrated

cognitive rescue with restoration of learning/memory function. These data suggest that hUCB-MSCs warrant further

investigation as a potential therapeutic agent in AD. PMID: 20600610 [PubMed - indexed for MEDLINE]

The novel protein MANI modulates neurogenesis and neurite-cone growth.

Related Articles The novel protein MANI modulates neurogenesis and neurite-cone growth. J Cell Mol Med. 2011

Aug;15(8):1713-25 Authors: Mishra M, Akatsu H, Heese K Abstract Neuronal regeneration and axonal re-growth in the

injured mammalian central nervous system remains an unsolved field. To date, three myelin-associated proteins [Nogo

or reticulon 4 (RTN4), myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMG)] are

known to inhibit axonal regeneration via activation of the neuronal glycosylphosphatidylinositol-anchored Nogo receptor

[NgR, together with p75 neurotrophin receptor (p75NTR) and Lingo-1]. In the present study we describe the novel

protein MANI (myelin-associated neurite-outgrowth inhibitor) that localizes to neural membranes. Functional

characterization of MANI overexpressing neural stem cells (NSCs) revealed that the protein promotes differentiationinto catecholaminergic neurons. Yeast two-hybrid screening and co-immunoprecipitation experiments confirmed the cell

division cycle protein 27 (Cdc27) as an interacting partner of Mani. The analyses of Mani-overexpressing PC12 cells

demonstrated that Mani retards neuronal axonal growth as a positive effector of Cdc27 expression and activity. We

show that knockdown of Cdc27, a component of the anaphase-promoting complex (APC), leads to enhanced neurite

outgrowth. Our finding describes the novel MANI-Cdc27-APC pathway as an important cascade that prevents neurons

from extending axons, thus providing implications for the potential treatment of neurodegenerative diseases. PMID:



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Amyloid Precursor Protein Binding Protein-1 Is Up-regulated in Brains of Tg2576 Mice.

Related Articles Amyloid Precursor Protein Binding Protein-1 Is Up-regulated in Brains of Tg2576 Mice. Korean J

Physiol Pharmacol. 2010 Aug;14(4):229-33 Authors: Yang HJ, Joo Y, Hong BH, Ha SJ, Woo RS, Lee SH, Suh YH, Kim

HS Abstract Amyloid precursor protein binding protein-1 (APP-BP1) binds to the carboxyl terminus of amyloid

precursor protein and serves as a bipartite activation enzyme for the ubiquitin-like protein, NEDD8. Previously, it has

been reported that APP-BP1 rescues the cell cycle S-M checkpoint defect in Ts41 hamster cells, that this rescue is

dependent on the interaction of APP-BP1 with hUba3. The exogenous expression of APP-BP1 in neurons has beenreported to cause DNA synthesis and apoptosis via a signaling pathway that is dependent on APP-BP1 binding to APP.

These results suggest that APP-BP1 overexpression contributes to neurodegeneration. In the present study, we

explored whether APP-BP1 expression was altered in the brains of Tg2576 mice, which is an animal model of

Alzheimer's disease. APP-BP1 was found to be up-regulated in the hippocampus and cortex of 12 month-old Tg2576

mice compared to age-matched wild-type mice. In addition, APP-BP1 knockdown by siRNA treatment reduced cullin-1

neddylation in fetal neural stem cells, suggesting that APP-BP1 plays a role in cell cycle progression in the cells.

Collectively, these results suggest that increased expression of APP-BP1, which has a role in cell cycle progression in

neuronal cells, contributes to the pathogenesis of Alzheimer's disease. PMID: 20827337 [PubMed]

Neural stem cells reduce hippocampal tau and reelin accumulation in aged Ts65Dn Down syndrome mice.

Related Articles Neural stem cells reduce hippocampal tau and reelin accumulation in aged Ts65Dn Down syndrome

mice. Cell Transplant. 2011;20(3):371-9 Authors: Kern DS, Maclean KN, Jiang H, Synder EY, Sladek JR, Bjugstad KB

Abstract Tau accumulation, in the form of neurofibrillary tangles (NFT), is an early neuropathological characteristic of

Alzheimer's disease (AD) and early onset AD frequently seen in Down syndrome (DS). We investigated the presence

of tau accumulation in the brains of aging DS mice using the Ts65Dn mouse model. All aged mice appeared to have

substantial clusters of extracellular granules that were positive for tau and reelin, but not for amyloid- or APP. Theseclusters were found primarily in CA1 of the hippocampus. In addition, the aged trisomic DS mice had a significantly

greater accumulation of extracellular tau/reelin granular deposits compared to disomic littermates. These granules were

similar to those described by others who also found extracellular proteinous granules in the brains of non-DS mice

engineered to model aging and/or AD. When neural stem cells (NSC) were implanted unilaterally into the hippocampus

of the Ts65Dn mice, the tau/reelin-positive granules were significantly reduced in both trisomic and disomic mice. Our

findings indicate that changes in tau/reelin-positive granules could be used as an index for neuropathological

assessment in aging DS and AD. Furthermore, changes in granule density could be used to test the efficacy of novel

treatments, such as NSC implantation. Lastly, it is speculated that the unique abilities of NSC to migrate and express

growth factors might be a contributing factor to reducing tau/reelin accumulation in aging DS and AD. PMID: 20875225

[PubMed - indexed for MEDLINE]

[The feasibility of synthetic enhancer substances for preventive nanotherapy].

Related Articles [The feasibility of synthetic enhancer substances for preventive nanotherapy]. Neuropsychopharmacol

Hung. 2010 Sep;12(3):395-403 Authors: Miklya I Abstract Nanotechnology, the great promise of the 21st century, may

revolutionize also the art of healing. Previously unexpected broadening of diagnostic procedures and methods to

deliver specific drugs acting in lower than nanomolecular concentrations right to the target cells may play a crucial role

in the rapid development of preventive medicine. In this context, (-)-deprenyl/selegiline, a drug developed 40 years ago

and still world-wide used to treat Parkinson's disease, Alzheimer's disease and depression, by enhancing the activity of

catecholaminergic neurons in the brain stem via a previously unknown mechanism [catecholaminergic activity

enhancer (CAE) effect], is a highly promising experimental tool for further research in this direction. The same fits for

(-)-BPAP, the newly developed enhancer substance, 100 times more potent than (-)-deprenyl, which in contrast to the

latter is not only an enhancer of the catecholaminergic neurons but also of the serotonergic neurons in the brain stem.Tiny amounts of enhancer substances are closed in liposomes and marked with a specific signal to help identify the

exact location of the target cells, through the activation of which the drug exerts its specific enhancer effect. The

method also offers an approach to better understand the up-to-the-present unknown mechanism of the enhancer effect.



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Phosphatidylinositol 3-kinase (PI3K) signaling via glycogen synthase kinase-3 (Gsk-3) regulates DNA

methylation of imprinted loci.

Related Articles Phosphatidylinositol 3-kinase (PI3K) signaling via glycogen synthase kinase-3 (Gsk-3) regulates DNA

methylation of imprinted loci. J Biol Chem. 2010 Dec 31;285(53):41337-47 Authors: Popkie AP, Zeidner LC, Albrecht

AM, D'Ippolito A, Eckardt S, Newsom DE, Groden J, Doble BW, Aronow B, McLaughlin KJ, White P, Phiel CJ Abstract

Glycogen synthase kinase-3 (Gsk-3) isoforms, Gsk-3 and Gsk-3, are constitutively active, largely inhibitory kinasesinvolved in signal transduction. Underscoring their biological significance, altered Gsk-3 activity has been implicated in

diabetes, Alzheimer disease, schizophrenia, and bipolar disorder. Here, we demonstrate that deletion of both Gsk-3 and Gsk-3 in mouse embryonic stem cells results in reduced expression of the de novo DNA methyltransferaseDnmt3a2, causing misexpression of the imprinted genes Igf2, H19, and Igf2r and hypomethylation of their

corresponding imprinted control regions. Treatment of wild-type embryonic stem cells and neural stem cells with the

Gsk-3 inhibitor, lithium, phenocopies the DNA hypomethylation at these imprinted loci. We show that inhibition of Gsk-3

by phosphatidylinositol 3-kinase (PI3K)-mediated activation of Akt also results in reduced DNA methylation at these

imprinted loci. Finally, we find that N-Myc is a potent Gsk-3-dependent regulator of Dnmt3a2 expression. In summary,

we have identified a signal transduction pathway that is capable of altering the DNA methylation of imprinted loci.


Leaf and stem of Vitis amurensis and its active components protect against amyloid protein (25-35)-induced

neurotoxicity.

Related Articles Leaf and stem of Vitis amurensis and its active components protect against amyloid protein

(25-35)-induced neurotoxicity. Arch Pharm Res. 2010 Oct;33(10):1655-64 Authors: Jeong HY, Kim JY, Lee HK, Ha doT, Song KS, Bae K, Seong YH Abstract This study investigated a methanol extract from the leaf and stem of Vitis

amurensis (Vitaceae) for possible neuroprotective effects on neurotoxicity induced by amyloid protein (A) (25-35) incultured rat cortical neurons and also for antidementia activity in mice. Exposure of cultured cortical neurons to 10 M

A (25-35) for 36 h induced neuronal apoptotic death. At concentrations of 1-10 g/mL, V. amurensis inhibited neuronaldeath, the elevation of intracellular calcium ([Ca(2+)](i)) and the generation of reactive oxygen species (ROS), all of

which were induced by A (25-35) in primary cultures of rat cortical neurons. Memory loss induced byintracerebroventricular injection of ICR mice with 16 nmol A (25-35) was inhibited by chronic treatment with V.amurensis extract (50 and 100 mg/kg, p.o. for 7 days), as measured by a passive avoidance test. Amurensin G,

r-2-viniferin and trans--viniferin isolated from V. amurensis also inhibited neuronal death, the elevation of [Ca(2+)](i)and the generation of ROS induced by A (25-35) in cultured rat cortical neurons. These results suggest that theneuroprotective effect of V. amurensis may be partially attributable to these compounds. These results suggest that the

antidementia effect of V. amurensis is due to its neuroprotective effect against A (25-35)-induced neurotoxicity and

that the leaf and stem of V. amurensis have possible therapeutic roles for preventing the progression of Alzheimer'sdisease. PMID: 21052941 [PubMed - indexed for MEDLINE]

The purinergic receptor P2X7 triggers alpha-secretase-dependent processing of the amyloid precursor protein.

Related Articles The purinergic receptor P2X7 triggers alpha-secretase-dependent processing of the amyloid precursor

protein. J Biol Chem. 2011 Jan 28;286(4):2596-606 Authors: Delarasse C, Auger R, Gonnord P, Fontaine B,

Kanellopoulos JM Abstract The amyloid precursor protein (APP) is cleaved by - and -secretases to generate the-amyloid (A) peptides, which are present in large amounts in the amyloid plaques of Alzheimer disease (AD) patientbrains. Non-amyloidogenic processing of APP by -secretases leads to proteolytic cleavage within the A peptidesequence and shedding of the soluble APP ectodomain (sAPP), which has been reported to be endowed withneuroprotective properties. In this work, we have shown that activation of the purinergic receptor P2X7 (P2X7R)

stimulates sAPP release from mouse neuroblastoma cells expressing human APP, from human neuroblastoma cells

and from mouse primary astrocytes or neural progenitor cells. sAPP

shedding is inhibited by P2X7R antagonists orknockdown of P2X7R with specific small interfering RNA (siRNA) and is not observed in neural cells from P2X7R-

deficient mice. P2X7R-dependent APP-cleavage is independent of extracellular calcium and strongly inhibited by

hydroxamate-based metalloprotease inhibitors, TAPI-2 and GM6001. However, knockdown of a disintegrin and

metalloproteinase-9 (ADAM9), ADAM10 and ADAM17 by specific siRNA, known to have -secretase activity, does notblock the P2X7R-dependent non-amyloidogenic pathway. Using several specific pharmacological inhibitors, we

demonstrate that the mitogen-activated protein kinase modules Erk1/2 and JNK are involved in P2X7R-dependent

-secretase activity. Our study suggests that P2X7R, which is expressed in hippocampal neurons and glial cells, is apotential therapeutic target in AD. PMID: 21081501 [PubMed - indexed for MEDLINE]


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Wnt signaling pathway overcomes the disruption of neuronal differentiation of neural progenitor cells induced

by oligomeric amyloid -peptide.

Related Articles Wnt signaling pathway overcomes the disruption of neuronal differentiation of neural progenitor cells

induced by oligomeric amyloid -peptide. J Neurochem. 2011 Feb;116(4):522-9 Authors: Shruster A, Eldar-FinkelmanH, Melamed E, Offen D Abstract Neural stem cells give rise to new hippocampal neurons throughout adulthood.

Defects in neurogenesis are associated with cognitive dysfunctions, such as Alzheimer disease (AD). Our

understanding of the signals controlling this process is limited. The present in vitro study explored the manner in whichthe Wnt signaling pathway regulates the differentiation of hippocampal progenitors (HPs) into neurons under the

influence of amyloid (42) (A(42) ). The results showed that oligomeric A(42) reduced neuronal differentiation. Thisprocess was accompanied by a reduction in active -catenin levels and proneural gene expression. The addition ofWnt3a increased the neuronal differentiation of A(42) -treated HPs, at the expense of astrocyte differentiation. Theeffect of Wnt signaling was attributable to progenitor cell differentiation to the neuronal lineage, and not to increased

proliferation or rescue of neurons. The interruption of Wnt signaling by oligomeric A(42) may have clinical implicationsfor the treatment of impaired neurogenesis in AD. PMID: 21138436 [PubMed - indexed for MEDLINE]

Stem cells for the treatment of neurodegenerative diseases.

Related Articles Stem cells for the treatment of neurodegenerative diseases. Stem Cell Res Ther. 2010;1(5):37

Authors: Dantuma E, Merchant S, Sugaya K Abstract Stem cells offer an enormous pool of resources for the

understanding of the human body. One proposed use of stem cells has been as an autologous therapy. The use of

stem cells for neurodegenerative diseases has become of interest. Clinical applications of stem cells for Alzheimer

disease, Parkinson disease, amyotrophic lateral sclerosis, and multiple sclerosis will increase in the coming years, and

although great care will need to be taken when moving forward with prospective treatments, the application of stem

cells is highly promising. PMID: 21144012 [PubMed - in process]

[Treatment of Alzheimer's disease and future approaches].

Related Articles [Treatment of Alzheimer's disease and future approaches]. Therapie. 2010 Sep-Oct;65(5):429-37

Authors: Forette F, Hauw JJ Abstract The progressive neuronal loss in Alzheimer's disease leads to neurochemical

abnormalities which provide the basis for symptomatic treatments. Four cholinesterase inhibitors were released in this

indication. Meta-analyses have confirmed a beneficial effect on cognitive functioning and activities of daily living. The

NMDA receptor antagonist, memantine, was also approved for the treatment of moderate to severe and may be

associated. Progress in the patho-physiology of the disease offers some hope of new treatments acting on the cerebral

lesions. The amyloid hypothesis allowed the emergence of active or passive immunotherapies, and of secretaseinhibitors or modulators. Recent studies have targeted the P tau protein. The brain plasticity and the uses of stem cells

offer more distant hope. PMID: 21144478 [PubMed - indexed for MEDLINE]

Alzheimer's Disease Drug Discovery--11th International Conference--Promising New Therapeutic Approaches.

27-28 September 2010, Jersey City, NJ, USA.

Related Articles Alzheimer's Disease Drug Discovery--11th International Conference--Promising New Therapeutic

Approaches. 27-28 September 2010, Jersey City, NJ, USA. IDrugs. 2010 Dec;13(12):825-7 Authors: Wolfe MS

Abstract The 11th Alzheimer's Disease Drug Discovery International Conference, held in Jersey City, NJ, USA, included

topics covering new therapeutic developments in the field of Alzheimer's disease. This conference report highlights

selected presentations on the use of patient-specific stem cells, and neuroprotection, regeneration and cognitive

enhancement strategies for the prevention or treatment of Alzheimer's disease. Investigational approaches discussed

include allopregnanolone for neuron protection and regeneration, PDE5 inhibitors as therapeutics, upregulating theprotein Klotho to prevent cognitive decline, targeting memory deficits induced by A42 oligomers, inhibiting striatal-enriched protein tyrosine phosphatase (STEP) for treating neuropsychiatric disorders, and agonism of GABA-A

receptors to treat age-related cognitive deficits. PMID: 21154134 [PubMed - indexed for MEDLINE]

-amyloid 1-42 oligomers impair function of human embryonic stem cell-derived forebrain cholinergic

neurons.

Related Articles -amyloid 1-42 oligomers impair function of human embryonic stem cell-derived forebrain cholinergic


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neurons. PLoS One. 2010;5(12):e15600 Authors: Wicklund L, Leo RN, Strmberg AM, Mousavi M, Hovatta O,

Nordberg A, Marutle A Abstract Cognitive impairment in Alzheimer's disease (AD) patients is associated with a decline

in the levels of growth factors, impairment of axonal transport and marked degeneration of basal forebrain cholinergic

neurons (BFCNs). Neurogenesis persists in the adult human brain, and the stimulation of regenerative processes in the

CNS is an attractive prospect for neuroreplacement therapy in neurodegenerative diseases such as AD. Currently, it is

still not clear how the pathophysiological environment in the AD brain affects stem cell biology. Previous studies

investigating the effects of the -amyloid (A) peptide on neurogenesis have been inconclusive, since both neurogenicand neurotoxic effects on progenitor cell populations have been reported. In this study, we treated pluripotent human

embryonic stem (hES) cells with nerve growth factor (NGF) as well as with fibrillar and oligomeric A1-40 and A1-42(nM-M concentrations) and thereafter studied the differentiation in vitro during 28-35 days. The process applied realtime quantitative PCR, immunocytochemistry as well as functional studies of intracellular calcium signaling. Treatment

with NGF promoted the differentiation into functionally mature BFCNs. In comparison to untreated cells, oligomeric

A1-40 increased the number of functional neurons, whereas oligomeric A1-42 suppressed the number of functionalneurons. Interestingly, oligomeric A exposure did not influence the number of hES cell-derived neurons compared withuntreated cells, while in contrast fibrillar A1-40 and A1-42 induced gliogenesis. These findings indicate that A1-42oligomers may impair the function of stem cell-derived neurons. We propose that it may be possible for future AD

therapies to promote the maturation of functional stem cell-derived neurons by altering the brain microenvironment with

trophic support and by targeting different aggregation forms of A. PMID: 21179413 [PubMed - indexed for MEDLINE]

Neurogenesis, NSCs, pathogenesis and therapies for Alzheimer's disease.

Related Articles Neurogenesis, NSCs, pathogenesis and therapies for Alzheimer's disease. Front Biosci (Schol Ed).2011;3:178-90 Authors: Taupin P Abstract Neurogenesis occurs in the adult brain and neural stem cells (NSCs) reside

in the adult central nervous system (CNS) of mammals. Adult NSCs offer tremendous potential for cellular therapy for

the treatment of neurological diseases and injuries, particularly of Alzheimer's disease (AD). The contribution of newly

generated neuronal cells of the adult brain to the functioning of the nervous system remains to be elucidated.

Neurogenesis is enhanced in the brain of patients with AD. Enhanced neurogenesis would contribute to regenerative

attempts in AD, to compensate for the neuronal loss. Adult neurogenesis holds the potential to generate aneuploid

cells, a landmark of AD pathology. Aneuploid newly generated neuronal cells in the adult brain would contribute to the

pathogenesis of AD. Adult neurogenesis would not only be beneficial, but also detrimental for patients with AD. We will

review and discuss the potential of adult NSCs for the treatment of AD and their contribution to the pathogenesis of the

disease, as well as the development of novel drugs and therapies for treating AD. PMID: 21196368 [PubMed - indexed

for MEDLINE]

P60TRP interferes with the GPCR/secretase pathway to mediate neuronal survival and synaptogenesis.

Related Articles P60TRP interferes with the GPCR/secretase pathway to mediate neuronal survival and

synaptogenesis. J Cell Mol Med. 2011 Nov;15(11):2462-77 Authors: Mishra M, Heese K Abstract In the present study,

we show that overexpression of the G-protein-coupled receptor (GPCR)-associated sorting protein p60TRP

(transcription regulator protein) in neural stem cells (NSCs) and in a transgenic mouse model modulates the

phosphorylation and proteolytic processing of amyloid precursor protein (App), N-cadherin (Cdh2), presenilin (Psen)

and protein (Mapt). Our results suggest that p60TRP is an inhibitor of Bace1 (-site App cleaving enzyme) and Psen.We performed several apoptosis assays [Annexin-V, TdT-mediated dUTP Nick-End Labeling (TUNEL), caspase-3/7]

using NSCs and PC12 cells (overexpressing p60TRP and knockdown of p60TRP) to substantiate the neuroprotective

role of p60TRP. Functional analyses, both in vitro and in vivo, revealed that p60TRP promotes neurosynaptogenesis.

Characterization of the cognitive function of p60TRP transgenic mice using the radial arm water maze test

demonstrated that p60TRP improved memory and learning abilities. The improved cognitive functions could be

attributed to increased synaptic connections and plasticity, which was confirmed by the modulation of the-aminobutyric acid receptor system and the elevated expression of microtubule-associated protein 2, synaptophysinand Slc17a7 (vesicle glutamate transporter, Vglut1), as well as by the inhibition of Cdh2 cleavage. In conclusion,

interference with the p60TRP/ GPCR/secretase signalling pathway might be a new therapeutic target for the treatment

of Alzheimer's disease (AD). PMID: 21199326 [PubMed - indexed for MEDLINE]

Impact of induced pluripotent stem cells on the study of central nervous system disease.

Related Articles Impact of induced pluripotent stem cells on the study of central nervous system disease. Curr Opin


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Genet Dev. 2011 Jun;21(3):354-61 Authors: Cundiff PE, Anderson SA Abstract The derivation of pluripotent stem cells

from somatic tissues has provided researchers with a source of patient-specific stem cells. The potential applications of

this technology are truly momentous, and include cellular modeling of disease processes, drug discovery, and

cell-based therapy. Here, we review the use of induced pluripotent stem cells (iPSCs) to study CNS disease. Since the

iPSC field is still in its infancy, we also discuss some of the challenges that will need to be overcome before the

potential of this technology to study and to treat neurological and psychiatric disorders can be fully harnessed. PMID:


Effects of Chinese herbal medicine Fuzhisan on autologous neural stem cells in the brain of SAMP-8 mice.

Related Articles Effects of Chinese herbal medicine Fuzhisan on autologous neural stem cells in the brain of SAMP-8

mice. Exp Gerontol. 2011 Aug;46(8):628-36 Authors: Yang H, Wen SR, Zhang GW, Wang TG, Hu FX, Li XL, Wang DS

Abstract Fuzhisan (FZS), a Chinese herbal complex prescription, has been used in the treatment of Alzheimer's

disease (AD) for more than 16 years. However the underlying mechanism remains to be explored. The effects of the

aqueous extract of FZS on the cognitive functions of the aged mice and the pharmacological basis for its therapeutic

efficacy were investigated. The results showed that FZS improved impaired cognitive ability of aged SAMP-8 mice. FZS

(2.4, 4.8 g/kg/d) increased hippocampal neurogenesis and the long-term survival of BrdU-labeled cells without affecting

the proportion of BrdU-positive neurons and glial cells. FZS also increased the number of BrdU-positive cells in the

subventricular zone (SVZ) of the lateral ventricles of 8-month-old SAMP-8 mice. These studies suggest that FZS

upregulates neurogenesis by increasing proliferation of neural progenitor cells and prolonging survival of the newborn

cells in the hippocampal DG. FZS may be beneficial for the treatment of senile dementia, especially Alzheimer's

disease. PMID: 21277365 [PubMed - indexed for MEDLINE]

Leptin induces proliferation of neuronal progenitors and neuroprotection in a mouse model of Alzheimer's

disease.

Related Articles Leptin induces proliferation of neuronal progenitors and neuroprotection in a mouse model of

Alzheimer's disease. J Alzheimers Dis. 2011;24 Suppl 2:17-25 Authors: Prez-Gonzlez R, Antequera D, Vargas T,

Spuch C, Bols M, Carro E Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disease associated

with senile amyloid- (A) plaques, neuronal death, and cognitive decline. Neurogenesis in the adult hippocampus,which is notably affected by progressive neurodegeneration and A pathology, is implicated in learning and memoryregulation. Human postmortem brains of AD patients and APP/PS1 double transgenic mice show increasedneurodegeneration. Leptin, an adipose-derived hormone, promotes neurogenesis in the adult hippocampus, but the

way in which this process occurs in the AD brain is still unknown. Thus, we sought to determine if leptin stimulated the

proliferation of neuronal precursors in APP/PS1 mice. We estimated the number proliferating hippocampal cells afterintracerebroventricular administration of a lentiviral vector encoding leptin. After 3 months of treatment with leptin we

observed an increase in the number of BrdU-positive cells in the subgranular zone of the dentate gyrus, as shown by

morphometric analysis. This increase resulted mainly from an increased proliferation of neuronal precursors.

Additionally, leptin led to an attenuation of A-induced neurodegeneration, as revealed by Fluoro-Jade staining. Ourresults suggest that in APP/PS1 mice, leptin exerts changes resembling acute neurotrophic and neuroprotectiveeffects. These effects could serve as the basis for the design of future treatment strategies in AD. PMID: 21335656


Stem cell factor and granulocyte colony-stimulating factor reduce -amyloid deposits in the brains of APP/PS1

transgenic mice.

Related Articles Stem cell factor and granulocyte colony-stimulating factor reduce -amyloid deposits in the brains ofAPP/PS1 transgenic mice. Alzheimers Res Ther. 2011;3(2):8 Authors: Li B, Gonzalez-Toledo ME, Piao CS, Gu A,

Kelley RE, Zhao LR Abstract INTRODUCTION: Alzheimer's disease (AD) is widely recognized as a serious publichealth problem and heavy financial burden. Currently, there is no treatment that can delay or stop the progressive brain

damage in AD. Recently, we demonstrated that stem cell factor (SCF) in combination with granulocyte colony-

stimulating factor (G-CSF) (SCF+G-CSF) has therapeutic effects on chronic stroke. The purpose of the present study is

to determine whether SCF+G-CSF can reduce the burden of-amyloid deposits in a mouse model of AD. METHODS:APP/PS1 transgenic mice were used as the model of AD. To track bone marrow-derived cells in the brain, the bone

marrow of the APP/PS1 mice was replaced with the bone marrow from mice expressing green fluorescent protein

(GFP). Six weeks after bone marrow transplantation, mice were randomly divided into a saline control group and a


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SCF+G-CSF-treated group. SCF in combination with G-CSF was administered subcutaneously for 12 days. Circulating

bone marrow stem cells (CD117+ cells) were quantified 1 day after the final injection. Nine months after treatment, at

the age of 18 months, mice were sacrificed. Brain sections were processed for immunohistochemistry to identify

-amyloid deposits and GFP expressing bone marrow-derived microglia in the brain. RESULTS: Systemicadministration of SCF+G-CSF to APP/PS1 transgenic mice leads to long-term reduction of-amyloid deposition in thebrain. In addition, we have also observed that the SCF+G-CSF treatment increases circulating bone marrow stem cells

and augments bone marrow-derived microglial cells in the brains of APP/PS1 mice. Moreover, SCF+G-CSF treatment

results in enhancement of the co-localization of bone marrow-derived microglia and -amyloid deposits in the brain.CONCLUSIONS: These data suggest that bone marrow-derived microglia play a role in SCF+G-CSF-induced

long-term effects to reduce -amyloid deposits. This study provides insights into the contribution of the hematopoeiticgrowth factors, SCF and G-CSF, to limit -amyloid accumulation in AD and may offer a new therapeutic approach forAD. PMID: 21406112 [PubMed]

Genetic therapy for the nervous system.

Related Articles Genetic therapy for the nervous system. Hum Mol Genet. 2011 Apr 15;20(R1):R28-41 Authors: Bowers

WJ, Breakefield XO, Sena-Esteves M Abstract Genetic therapy is undergoing a renaissance with expansion of viral and

synthetic vectors, use of oligonucleotides (RNA and DNA) and sequence-targeted regulatory molecules, as well as

genetically modified cells, including induced pluripotent stem cells from the patients themselves. Several clinical trials

for neurologic syndromes appear quite promising. This review covers genetic strategies to ameliorate neurologic

syndromes of different etiologies, including lysosomal storage diseases, Alzheimer's disease and other

amyloidopathies, Parkinson's disease, spinal muscular atrophy, amyotrophic lateral sclerosis and brain tumors. Thisfield has been propelled by genetic technologies, including identifying disease genes and disruptive mutations, design

of genomic interacting elements to regulate transcription and splicing of specific precursor mRNAs and use of novel

non-coding regulatory RNAs. These versatile new tools for manipulation of genetic elements provide the ability to tailor

the mode of genetic intervention to specific aspects of a disease state. PMID: 21429918 [PubMed - indexed for

MEDLINE]

Human embryonic stem cell therapies for neurodegenerative diseases.

Related Articles Human embryonic stem cell therapies for neurodegenerative diseases. CNS Neurol Disord Drug

Targets. 2011 Jun;10(4):440-8 Authors: Tomaskovic-Crook E, Crook JM Abstract There is a renewed enthusiasm for

the clinical translation of human embryonic stem (hES) cells. This is abetted by putative clinically-compliant strategies

for hES cell maintenance and directed differentiation, greater understanding of and accessibility to cells through formal

cell registries and centralized cell banking for distribution, the revised US government policy on funding hES cell

research, and paradoxically the discovery of induced pluripotent stem (iPS) cells. Additionally, as we consider the

constraints (practical and fiscal) of delivering cell therapies for global healthcare, the more efficient and economical

application of allogeneic vs autologous treatments will bolster the clinical entry of hES cell derivatives.

Neurodegenerative disorders such as Parkinson's disease are primary candidates for hES cell therapy, although there

are significant hurdles to be overcome. The present review considers key advances and challenges to translating hES

cells into novel therapies for neurodegenerative diseases, with special consideration given to Parkinson's disease and

Alzheimer's disease. Importantly, despite the focus on degenerative brain disorders and hES cells, many of the issues

canvassed by this review are relevant to systemic application of hES cells and other pluripotent stem cells such as iPS

cells. PMID: 21495960 [PubMed - indexed for MEDLINE]

Stem cell therapy for Alzheimer's disease.

Related Articles Stem cell therapy for Alzheimer's disease. CNS Neurol Disord Drug Targets. 2011 Jun;10(4):459-85

Authors: Abdel-Salam OM Abstract Alzheimer's disease (AD) is a progressive neurodegenerative disorder whichimpairs the memory and intellectual abilities of the affected individuals. Loss of episodic as well as semantic memory is

an early and principal feature. The basal forebrain cholinergic system is the population of neurons most affected by the

neurodegenerative process. Extracellular as well as intracellular deposition of beta-amyloid or Abeta (Abeta) protein,

intracellular formation of neurofibrillary tangles and neuronal loss are the neuropathological hallmarks of AD. In the last

few years, hopes were raised that cell replacement therapy would provide cure by compensating the lost neuronal

systems. Stem cells obtained from embryonic as well as adult tissue and grafted into the intact brain of mice or rats

were mostly followed by their incorporation into the host parenchyma and differentiation into functional neural lineages.


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In the lesioned brain, stem cells exhibited targeted migration towards the damaged regions of the brain, where they

engrafted, proliferated and matured into functional neurones. Neural precursor cells can be intravenously administered

and yet migrate into brain damaged areas and induce functional recovery. Observations in animal models of AD have

provided evidence that transplanted stem cells or neural precursor cells (NPCs) survive, migrate, and differentiate into

cholinergic neurons, astrocytes, and oligodendrocytes with amelioration of the learning/memory deficits. Besides

replacement of lost or damaged cells, stem cells stimulate endogenous neural precursors, enhance structural

neuroplasticity, and down regulate proinflammatory cytokines and neuronal apoptotic death. Stem cells could also be

genetically modified to express growth factors into the brain. In the last years, evidence indicated that the adult brain of

mammals preserves the capacity to generate new neurons from neural stem/progenitor cells. Inefficient adult

neurogenesis may contribute to the pathogenesis of AD and other neurodegenerative disorders. An attempt at

mobilizing this endogenous pool of resident stem-like cells provides another attractive approach for the treatment of

AD. Studies in patients with AD indicated decreased hippocampal volume derived by neurodegeneration. Intriguingly,

many drugs including antidepressants, lithium, acetyl cholinesterase inhibitors, and ginkgo biloba, were able to

enhance the impaired neurogenesis in this disease process. This paved the way towards exploring the possible

pharmacological manipulation of neurogenesis which would offer an alternative approach for the treatment of AD.


Encapsulated native and glucagon-like peptide-1 transfected human mesenchymal stem cells in a transgenic

mouse model of Alzheimer's disease.

Related Articles Encapsulated native and glucagon-like peptide-1 transfected human mesenchymal stem cells in a

transgenic mouse model of Alzheimer's disease. Neurosci Lett. 2011 Jun 15;497(1):6-10 Authors: Klinge PM,Harmening K, Miller MC, Heile A, Wallrapp C, Geigle P, Brinker T Abstract Encapsulated human mesenchymal stem

cells(MSC) are studied in a double transgenic mouse model of Alzheimer's disease (AD) after intraventricular

implantation at 3 months of age. Abeta 40/42 deposition, and glial (GFAP) and microglial (CD11b) immunoreactivity

were investigated 2 months after transplantation of either native MSC or MSC transfected with glucagon-like peptide-1

(GLP-1). CD11b immunostaining in the frontal lobes was significantly decreased in the GLP-1 MSC group compared to

the untreated controls. Also, the plaque associated GFAP immunoreactivity was only observed in one of four animals in

the GLP-1 MSC group. Abeta 40 whole brain ELISA was decreased in the MSC group: 86.065.2 pg/ml (untreated

control) vs. 78.6711.2 pg/ml (GLP-1 MSC group) vs.70.911.1 pg/ml (MSC group, p

Stem cell factor plasma levels are decreased in Alzheimer's disease patients with fast cognitive decline after

one-year follow-up period: the Pythia-study.

Related Articles Stem cell factor plasma levels are decreased in Alzheimer's disease patients with fast cognitive decline

after one-year follow-up period: the Pythia-study. J Alzheimers Dis. 2011;26(1):39-45 Authors: Laske C, Sopova K,

Hoffmann N, Stransky E, Hagen K, Fallgatter AJ, Stellos K, Leyhe T Abstract Alzheimer's disease (AD) is the most

common cause of cognitive decline in the elderly and is characterized by massive neuronal loss in the brain. Stem cell

factor (SCF) is a hematopoietic growth factor that promotes neuroprotective effects and supports neurogenesis in the

brain. Decreased SCF plasma levels have been described in AD patients. Whether SCF plasma levels are also

associated with the rate of cognitive decline in AD patients has not been reported so far. In the present study, we

demonstrate that SCF plasma levels are significantly decreased in AD patients with fast cognitive decline (decrease of

Mini-Mental State Examination [MMSE] score > 4 after one year; n = 12) compared to AD patients with slow cognitive

decline (decrease of MMSE score 4 after one year; n = 28) (fast versus slow cognitive decline: mean SD: 1051.1 178.7 versus 1237.9 274.2 pg/ml; p = 0.037). Moreover, SCF plasma levels correlated with the rate of cognitive

decline after one year follow-up period (r = 0.315; p = 0.048). In a multiple linear regression analysis, independent

predictors of the rate of cognitive decline in our study cohort were age, MMSE scores at baseline, SCF plasma levels,

as well as brain-derived neurotrophic factor and activated glycoprotein (GP) IIb/IIIa. These results suggest that lowerSCF plasma levels are associated with a higher rate of cognitive decline in AD patients. Thus, treatment strategies

increasing SCF plasma levels could be useful for delaying the progression of AD. Further prospective studies are

needed to elucidate the value of plasma SCF in a multimarker approach determining AD prognosis. PMID: 21593573


Combined effects of hematopoietic progenitor cell mobilization from bone marrow by granulocyte colony

stimulating factor and AMD3100 and chemotaxis into the brain using stromal cell-derived factor-1 in an


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Alzheimer's disease mouse model.

Related Articles Combined effects of hematopoietic progenitor cell mobilization from bone marrow by granulocyte

colony stimulating factor and AMD3100 and chemotaxis into the brain using stromal cell-derived factor-1 in anAlzheimer's disease mouse model. Stem Cells. 2011 Jul;29(7):1075-89 Authors: Shin JW, Lee JK, Lee JE, Min WK,

Schuchman EH, Jin HK, Bae JS Abstract Transplantation of bone marrow-derived stem cells (BMSCs) has been

suggested as a potential therapeutic approach to prevent neurodegenerative diseases, but it remains problematic due

to issues of engraftment, potential toxicities, and other factors. An alternative strategy is pharmacological-induced

recruitment of endogenous BMSCs into an injured site by systemic administration of growth factors or chemokines.

Therefore, the aim of this study was to examine the effects of therapy involving granulocyte colony stimulating factor

(G-CSF)/AMD3100 (CXCR4 antagonist) and stromal cell-derived factor-1 (SDF-1) on endogenous BM-derivedhematopoietic progenitor cell (BM-HPC) recruitment into the brain of an Alzheimer's disease (AD) mouse model. To

mobilize BM-HPCs, G-CSF was injected intraperitoneally and boosted by AMD3100. Simultaneously, these mice

received an intracerebral injection with SDF-1 to induce migration of mobilized BM-HPCs into brain. We found that thememory deficit in the AD mice was significantly improved by these treatments, but amyloid deposition wasunchanged. Interestingly, microglial activation was increased with alternative activation of microglia to a neuroprotective

phenotype. Furthermore, by generating an amyloid precursor protein/presenilin 1-green fluorescent protein (GFP)

chimeric mouse, we ascertained that the GFP positive microglia identified in the brain were BM-derived. Additionally,

increased hippocampal neurogenesis and improved memory was observed in mice receiving combined

G-CSF/AMD3100 and SDF-1, but not in controls or animals receiving each treatment alone. These results suggestthat SDF-1 is an effective adjuvant in inducing migration into brain of the endogenous BM-HPCs, mobilized byG-CSF/AMD3100, and that the two can act synergistically to produce a therapeutic effect. This approach warrants

further investigation as a potential therapeutic option for the treatment of AD patients in the future. PMID: 21608078


Amitriptyline-mediated cognitive enhancement in aged 3Tg Alzheimer's disease mice is associated with

neurogenesis and neurotrophic activity.

Related Articles Amitriptyline-mediated cognitive enhancement in aged 3Tg Alzheimer's disease mice is associatedwith neurogenesis and neurotrophic activity. PLoS One. 2011;6(6):e21660 Authors: Chadwick W, Mitchell N, Caroll J,

Zhou Y, Park SS, Wang L, Becker KG, Zhang Y, Lehrmann E, Wood WH, Martin B, Maudsley S Abstract Approximately

35 million people worldwide suffer from Alzheimer's disease (AD). Existing therapeutics, while moderately effective, are

currently unable to stem the widespread rise in AD prevalence. AD is associated with an increase in amyloid beta (A)oligomers and hyperphosphorylated tau, along with cognitive impairment and neurodegeneration. Several

antidepressants have shown promise in improving cognition and alleviating oxidative stress in AD but have failed as

long-term therapeutics. In this study, amitriptyline, an FDA-approved tricyclic antidepressant, was administered orally toaged and cognitively impaired transgenic AD mice (3TgAD). After amitriptyline treatment, cognitive behavior testingdemonstrated that there was a significant improvement in both long- and short-term memory retention. Amitriptyline

treatment also caused a significant potentiation of non-toxic A monomer with a concomitant decrease in cytotoxicdimer A load, compared to vehicle-treated 3TgAD controls. In addition, amitriptyline administration caused asignificant increase in dentate gyrus neurogenesis as well as increases in expression of neurosynaptic marker proteins.

Amitriptyline treatment resulted in increases in hippocampal brain-derived neurotrophic factor protein as well as

increased tyrosine phosphorylation of its cognate receptor (TrkB). These results indicate that amitriptyline has

significant beneficial actions in aged and damaged AD brains and that it shows promise as a tolerable novel

therapeutic for the treatment of AD. PMID: 21738757 [PubMed - indexed for MEDLINE]

Production of monocytic cells from bone marrow stem cells: therapeutic usage in Alzheimer's disease.

Related Articles Production of monocytic cells from bone marrow stem cells: therapeutic usage in Alzheimer's disease.J Cell Mol Med. 2012 May;16(5):1060-73 Authors: Magga J, Savchenko E, Malm T, Rolova T, Pollari E, Valonen P,

Lehtonen , Jantunen E, Aarnio J, Lehenkari P, Koistinaho M, Muona A, Koistinaho J Abstract Accumulation of amyloid (A) is a major hallmark in Alzheimer's disease (AD). Bone marrow derived monocytic cells (BMM) have been shownto reduce A burden in mouse models of AD, alleviating the AD pathology. BMM have been shown to be more efficientphagocytes in AD than the endogenous brain microglia. Because BMM have a natural tendency to infiltrate into the

injured area, they could be regarded as optimal candidates for cell-based therapy in AD. In this study, we describe a

method to obtain monocytic cells from BM-derived haematopoietic stem cells (HSC). Mouse or human HSC were

isolated and differentiated in the presence of macrophage colony stimulating factor (MCSF). The cells were


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characterized by assessing the expression profile of monocyte markers and cytokine response to inflammatory

stimulus. The phagocytic capacity was determined with A uptake assay in vitro and A degradation assay of nativelyformed A deposits ex vivo and in a transgenic APdE9 mouse model of AD in vivo. HSC were lentivirally transducedwith enhanced green fluorescent protein (eGFP) to determine the effect of gene modification

stem cell treatment alzheimer's disease - asci - asian stem cell institute

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