March 5th, 2007

MCB 135k Discussion Lecture 14- 16, 18

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Neurons that can proliferate into adulthood include:

• Neuroblasts in the subventricular zone (SVZ) and subgranular layer which migrate towards the olfactory bulb and hippocampus respectively

• Dormant Neuroprogentior cells • Neuroglia

The rate of degeneration far exceeds the ability of these cells to compensate for neuronal loss

Research seeking to activate/increase proliferation of these cells to regenerate lost brain tissue (neural stem cells) in neurodegenerative diseases

Major Function of the Nervous SystemMajor Function of the Nervous System

The major function of the CNS is to The major function of the CNS is to communicate & to connect:communicate & to connect:

•with other CNS cellswith other CNS cells

•with peripheral tissues (outside CNS)with peripheral tissues (outside CNS)

•with the external environment (including physical and social with the external environment (including physical and social environments)environments)

This communication regulates:This communication regulates:•MobilityMobility•Sensory informationSensory information•Cognition Cognition •Affect and moodAffect and mood•Functions of whole-body systemsFunctions of whole-body systems

Neurons:

Axons- transmit signal, only one per cell

Dendrites- receive signal, numerous projections per cell

Glial Cells:

Astrocyte- structural/nutritional support for neurons

Oligodendrocyte- sheath axons, allow for faster action potential transmittance- protective roles

Microglia- neuronal immune cells

• In normal aging, moderate neuronal loss occurs in the:

Locus Ceruleus: nucleus in the brain stem (inferior to the cerebellum in the caudal midbrain/rostral pons) apparently responsible for the physiological reactions involved in stress and panic. This nucleus is the major location of neurons that release norepinephrine throughout the brain. Implicated in wide ranging disorders: depression, panic, anxiety disorders, Posttraumatic stress disorder

Substantia Nigra: A dark band of gray matter deep within the brain where cells manufacture the neurotransmitter dopamine for movement control. Degeneration of cells in this region may lead to a neurologic movement disorder such as Parkinson's disease

Nucleus basalis of meynert:Lateral part of the tuber cinereum that provides most of the acetylcholine to the cerebral cortex. Decrease in production seen in Alzheimer’s disease and Lewy Body dimentia.

Hippocampus: The part of the brain that assists in storing memory by sorting and sending new bits of information to be stored in appropriate sections of your brain and recalling them when necessary

Major functional deficits/ pathologies involve:

Motility (e.g. Parkinson’s Disease)

Senses and communication

Cognition (e.g. dementias)

Affect and mood (e.g. depression)

Blood circulation (stroke, multi-infarct dementia)

Pathological and Cellular Pathological and Cellular Changes with Normal AgingChanges with Normal Aging

Pathological and Cellular Pathological and Cellular Changes with Normal AgingChanges with Normal Aging

• Increased intracellular deposits of lipofuscinIncreased intracellular deposits of lipofuscin• Intracellular formation of PHFsIntracellular formation of PHFs• Accumulation of amyloid deposits in the neuritic Accumulation of amyloid deposits in the neuritic

plaques and surrounding the cerebral blood vesselsplaques and surrounding the cerebral blood vessels• Accumulation of Lewy bodiesAccumulation of Lewy bodies• Cell death (apoptosis, necrosis)Cell death (apoptosis, necrosis)

• Increased intracellular deposits of lipofuscinIncreased intracellular deposits of lipofuscin• Intracellular formation of PHFsIntracellular formation of PHFs• Accumulation of amyloid deposits in the neuritic Accumulation of amyloid deposits in the neuritic

plaques and surrounding the cerebral blood vesselsplaques and surrounding the cerebral blood vessels• Accumulation of Lewy bodiesAccumulation of Lewy bodies• Cell death (apoptosis, necrosis)Cell death (apoptosis, necrosis)

Key terms:

Lipofuscin: Lipofuscin are brown pigment granules representing lipid-containing residues of lysosomal digestion and considered one of the aging or "wear and tear" pigments; found in the liver, kidney, heart muscle, adrenals, nerve cells, and ganglion cells.

PHF: Paired helical filaments (PHF) are abnormal, approximately 20-25-nm wide periodically twisted filaments,

which accumulate in Alzheimer's disease (AD) brain and other neurodegenerative disorders, including corticobasal degeneration (CBD). PHF are primarily composed of highly phosphorylated tau protein,

proteins that interact with and stabilize microtubules, promote tubulin assembly (MAP).

Amyloid:insoluble fibrous protein aggregations sharing specific structural traits (cross-beta quaternary structure) commonly found in Alzheimer’s disease. Main constituent of amyloid plaques are Abeta (Amyloid beta)proteins, formed after cleavage of amyloid prescursor protein (APP). Autosomal-dominant mutations can cause early onset AD.

Lewy Body: abnormal aggregates of protein that develop inside nerve cells. A Lewy body is composed of the protein alpha-synuclein associated with other proteins such as ubiquitin, neurofilament protein, and alpha B crystallin. Linked to Parkinson’s disease.

Lipofuscin

PHF

Lewy Body

Short video on Parkinson’s Disease and GDNF therapy:http://www.youtube.com/watch?v=gnDHMveS9_M

Parkinson’s Disease:

Parkinson's disease (also known as Parkinson disease or PD) is a degenerative disorder of the central nervous system that often impairs the sufferer's motor skills and speech

Symptoms:

•Tremor

•Rigidity

•Bradykinesia/akinesia: respectively, slowness or absence of movement

•Postural Instability

•Gait abnormalities

•Fatigue

•Soft speech/Drooling

•Results from the loss of pigmented dopamine-secreting (dopaminergic) cells

•Neurons project to the striatum and their loss leads to alterations in the activity of the neural circuits within the basal ganglia that regulate movement, in essence an inhibition of the direct pathway and excitation of the indirect pathway.

•The direct pathway facilitates movement and the indirect pathway inhibits movement, thus the loss of these cells leads to a hypokinetic movement disorder.

•The lack of dopamine results in increased inhibition of the ventral lateral nucleus of the thalamus, which sends excitatory projections to the motor cortex, thus leading to hypokinesia.

•The mechanism by which the brain cells in Parkinson's are lost may consist of an abnormal accumulation of the protein alpha-synuclein bound to ubiquitin in the damaged cells. The alpha-synuclein-ubiquitin complex cannot be directed to the proteosome. This protein accumulation forms proteinaceous cytoplasmic inclusions called Lewy bodies.

Alzheimer's disease (AD), also known simply as Alzheimer's, is a neurodegenerative disease characterized by progressive cognitive deterioration together with declining activities of daily living and neuropsychiatric symptoms or behavioral changes. It is the most common type of dementia. The ultimate cause of the disease is unknown

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Three major competing hypotheses exist:

"cholinergic hypothesis" and suggests that AD begins as a deficiency in the production of the neurotransmitter acetylcholine

tau protein abnormalities initiate the disease cascade, supported by the long-standing observation that deposition of amyloid plaques do not correlate well with neuron loss

beta amyloid deposits are the causative factor in the disease - cytotoxicity of mature aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis and thus inducing apoptosis

OLD

YOUNG

0

200

400

600

800

Rea

ctio

n T

ime

(mse

c)2 Letters 6 Letters

FAST ---------------------> SLOW

Neural recruitment

Information processing speed

LESS ---------------------> MORE

Memory Load2 6 2 6

500

750

1000

1250

1500

Young Old

Reaction Time (msec)

YOUNG ELDERLYUNDER

RECRUITMENTOVER

RECRUITMENT

YOUNG

OLD

NON-SELECTIVE RECRUITMENT

FASTEST SLOWEST

YOUNG

OLD

ApoptosisProgrammed Cell Death - executed in such a way as to

safely dispose of cell corpses and fragments.

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•Evolutionarily conserved

•Occurs in all multicellular animals studies (plants too!)

•Stages and genes conserved from nematodes (worms)and flies to mice and humans

•Important in embryogenesis

•Selection/ Eliminates non-functional cells

•Immunity-eliminates dangerous cells

•Organ size - eliminates excess cells

•Tissue remodeling - mammary gland/ prostate

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Lack of proper apoptosis during development can lead to fused toes / fingers

APOPTOSIS: control

Receptor pathway (physiological):

Death receptors:(FAS, TNF-R, etc)

FAS ligand TNF

Deathdomains

Adaptor proteins

Pro-caspase 8 (inactive) Caspase 8 (active)

Pro-execution caspase (inactive)Execution caspase (active)

DeathMITOCHONDRIA

APOPTOSIS: control

Intrinsic pathway (damage):

Mitochondria

Cytochrome c release

Pro-caspase 9 cleavage

Pro-execution caspase (3) cleavage

Caspase (3) cleavage of cellular proteins,nuclease activation,

etc.

Death

BAXBAKBOKBCL-XsBADBIDB IKBIMNIP3BNIP3

BCL-2BCL-XLBCL-WMCL1BFL1DIVANR-13Several viral proteins

APOPTOSIS: control

Physiological Intrinsicreceptor pathway damage pathway

MITOCHONDRIAL SIGNALS

Caspase cleavage cascade

Orderly cleavage of proteins and DNA

CROSSLINKING OF CELL CORPSES; ENGULFMENT(no inflammation)

APOPTOSIS: Role in Disease

TOO MUCH: Tissue atrophy

TOO LITTLE: Hyperplasia

NeurodegenerationThin skin

etc

CancerAthersclerosis

etc

APOPTOSIS: Role in DiseaseAGING

Aging --> both too much and too little apoptosis(evidence for both)

Too much (accumulated oxidative damage?)---> tissue degeneration

Too little (defective sensors, signals?---> dysfunctional cells accumulatehyperplasia (precancerous lesions)

Discussion questions:

What are the function of glial cells in the nervous system?

What are the similarities and differences between Parkinson’s disease and Alzheimer’s diseases?

What does fMRI data reveal about memory tasks in old versus young individuals?

What roles does apoptosis have in disease? How can apoptosis be characterized as an example of antagonistic pleiotropy?