autism, schizophrenia and alzheimer’s disease · autism, schizophrenia and alzheimer’s disease....

Illana Gozes PhD Professor of Clinical Biochemistry Lily and Avraham Gildor Chair for the Investigation of Growth Factors Adams Super Center for Brain Studies amp Edersheim Levie-Gitter fMRI Institute (wwwbraintauacil) Head the Dr Diana and Zelman Elton (Elbaum) Laboratory for Molecular Neuroendocrinology Department of Human Molecular Genetics and Biochemistry Tel Aviv University Sackler Faculty of Medicine Sagol School of Neuroscience Israel

Laboratory Members PhD students Anna Malishkevich Yanina Ivashco-Pachima Avia Merenlender-Wagner Adva Hadar Iris Grigg and Shlomi Sragovich Master Students Evgenia Maryanovsky Regina Ostritsky Sinaya Vaisburd Gal Hacohen-Kleiman Noy Amram Livnat Bacal and Yarden Ziv Dr Eliezer Giladi PhD Laboratory Manager

TAU collaborators Dr David Gurwitz Dr Segev Barak Dr Rina Rosin-Arbesfeld Dr Joel Hirsch Dr Leonid Mittelman Dr Metsada Pasmanik-Chor and Adva Yeheskel

Molecules that make our minds fighting autism schizophrenia and Alzheimerrsquos disease

Imagine your brain as a large rail transportation system and your 100 billion nerve cells = trains while your brain ldquosupport cellsrdquo are the train tracks

Now imagine disruption in connectivity hellip (~100 trillion points of connection)hellip

Can we fix it

And he does not talk

Michael J Fox

Ronald Reagan

John Nash from the film ldquoA Beautiful Mindrdquo

Lou Gehrig Maurice Ravel Margaret Thatcher

Muhammad Ali

Cognitive Development and Aging Dementia

Autism Intellectual disability and facial dysmorphisms caused by mutations in

ADNP Nature Genetics 46 380ndash384 (2014)

Nature Genetics

Volume

46

Pages

380ndash384

Year published

(2014)

DOI

httpwwwncbinlmnihgovgtrtests515961methodology


Michael J Fox

Ronald Reagan



Muhammad Ali




Nature Genetics

Volume

46

Pages

380ndash384

Year published

(2014)

DOI


Autism Spectrum Disorder

Autism spectrum disorder (ASD) refers to a range of disorders lsquotriad of impairmentsrsquo

(1) social and emotional understanding

(2) all aspects of communication

(3) flexibility in thinking and behavior

(Wing 1996)

Dr Hans Asperger Dr Leo Kanner

Connecting Autism Cancer and Alzheimerrsquos disease

TauAutophagy Apoptosis Regulating gt400 Genes

ADNP

Disease Injury

Brain support cell-derived protectants

Our Discovery Protective Platforms

ADNP platform

Davunetide NAP D-NAP

DementiaCognitive impairment

Alzheimerrsquos and Parkinsonrsquos disease schizophrenia

ADNF platform

D-SAL AL-309 (9 aa)

SAL AL-209 (9 aa)

Neuropathies

Activity-Dependent Neurotrophic Factor

Activity-Dependent Neuroprotective Protein

NAPVSIPQ SALLRSIPA

Brenneman DE Gozes I (1996) A femtomolar-acting neuroprotective peptide J Clin Invest 972299-2307

Bassan M Zamostiano R Davidson A Pinhasov A Giladi E Perl O Bassan H Blat C Gibney G Glazner G Brenneman DE Gozes I (1999) Complete sequence of a novel protein containing a femtomolar-activity-dependent neuroprotective peptide J Neurochem 721283-1293

Neuropeptides

Activity-Dependent Neuroprotective Protein (ADNP)

Our papers J Biol Chem 2012 287(48)40173-85 J Mol Neurosci 2008 35127-41 J Neurochem 2008105537-45 J Biol Chem 200728234448-56 Dev Biol 2007303814-24 J Pharmacol Exp Ther 2007323438-434 Pharmacol Ther 2007 114146-54 CNS Drug Rev 200511353-68 Brain Res Dev Brain Res 200314483-90 Neuron Glia Biol 2004 Aug1(3)193-199

gt 1 No ADNP ndash No brain

gt 2 ADNP is part of a large protein complex - SWISNF regulating gt400 genes and determining nerve cell shape and brain structure

gt 3 As part of the SWISNF ADNP associated with

proteins regulating tau splicing

1

2

2

Schirer Y Malishkevich A Ophir Y Lewis J Giladi E Gozes I Novel Marker for the Onset of Frontotemporal Dementia Early Increase in Activity-Dependent Neuroprotective Protein (ADNP) in the Face of Tau Mutation PLoS One 2014 9(1) e87383

3

Pinhasov A Mandel S Torchinsky A Giladi E Pittel Z Goldsweig AM Servoss SJ Brenneman DE Gozes I (2003) Activity-dependent neuroprotective protein a novel gene essential for brain formation Brain Res Dev Brain Res 144 83-90

Organogenesis

Neuroogenesis

Regulation of

Transcription

Lytic

vacuole

Lipid

Transport

Coagulation

E9-95 ADNP knock out embryo

ADNP regulates ApoE ndash the major risk gene for Alzheimerrsquos disease

Gene Array ADNP Regulates gt400 Genes

Mandel S Rechavi G Gozes I (2007) Activity-dependent neuroprotective protein (ADNP) differentially interacts with chromatin to regulate genes essential for embryogenesis Dev Biol 303 814-824

Bioinformatics The ADNP Network

Gozes Yeheskel Pasmanik-Chor Activity-Dependent Neuroprotective Protein (ADNP) A Case Study for Highly Conserved Chordata-Specific Genes Shaping the Brain and Mutated in Cancer J Alzheimers Dis 2015 Jan 145(1)57-73 doi 103233JAD-142490

httpwwwadnpgenecom Feb (0) doi 101038ng2899 Nat Genet 46380-384

Gozes Yeheskel and Pasmanik-Chor J Alzheimers Dis 2015 Jan 145(1)57-73 doi 103233JAD-142490

Specific to Chordata

0010203040506

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleADNP

Males Females

Rela

tive m

RN

A c

onte

nt

00

1

2

3

4

5

Postmortem ADNP

0

05

1

15

2

25

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleelF4E

0

005

01

015

02

025

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleADNP2

0

5

10

15

20

25

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleAPOE

0

05

1

15

2

25

ADNP++ ADNP+-

2^-

dC

t

Male 9 month oldelF4E

Sexual Dichotomy Gene Expression

Human six-month-old mice

Malishkevich A Amram N Hacohen-Kleiman G Magen I Giladi I Gozes I Activity-Dependent Neuroprotective Protein (ADNP) Exhibits Striking Sexual Dichotomy Impacting on Autistic and Alzheimers Pathologies Transl Psychiatry 2015 Feb 35e501 doi 101038tp2014138

Behavior

Serum Proteomics Only ADNP Decreases in Alzheimer

Fernandez-Montesinos R Torres M Baglietto-Vargas D Gutierrez A Gozes I Vitorica J amp Pozo D (2010) Activity-dependent neuroprotective protein (ADNP) expression in the amyloid precursor proteinpresenilin 1 mouse model of Alzheimers disease J Mol Neurosci 41 114-120 J Proteomics 2012 Jun 2775(12)3617-29 doi 101016jjprot201204017 Activity-dependent neuroprotector homeobox protein A candidate protein identified in serum as diagnostic biomarker for Alzheimers disease Yang MH et al Alzheimerrsquos disease (AD) serum proteins were analyzed using two-dimensional gel electrophoresis combined with nano-high performance liquid chromatography electrospray ionization tandem mass spectrometry (nano-HPLC-ESI-MSMS) followed by peptide fragmentation patterning Results suggested that ADNP may play an important role in slowing the progression of clinical symptoms of AD

Tangle-like pathology (not seen in healthy brain) ADNP decorates microtubules (healthy)

J Pharmacol Exp Ther 2007323438-434 Neuron Glia Biol 2004 Aug1(3)193-199

ADNP Haploinsufficiency Modelling Tauopathy

ADNP partial deficiency a window to the mouse brain

Healthy Sick ADNP-deficiency results in brain ndash cell death (green ndash fluoro-Jade)

Davunetide (NAP) Discovery

NAP = NAPVSIPQ

Our papers J Neurochem 1999 72(3)1283-93 J Mol Neurosci 2000 1461-8 J Biol Chem 2001 276708-14 Curr Alzheimer Res 2009 6455-60 J Mol Neurosci 2008 35127-41 J Neurochem 2008105537-45 J Biol Chem 200728234448-56 Dev Biol 2007303814-24 Brain Res Dev Brain Res 200314483-90 Curr Pharm Des 201117(10)1040-4 Curr Pharm Des 2011 17 (25) 2603-12 Curr Pharm Des 2011 17 (31) 3413-7 PLoS One 20127(12)e51458 Eur J Pharmacol 20096189-14 Int J Alzheimers Dis 20122012

gt Calculated molecular mass for ADNP-1235628 Da

gt A large protein (limited bioavailability)

gt Davunetide NAPVSIPQ is the smallest active fragment of ADNP which provides brain bioavailability and nerve cell protection

O2-Glucose-Deprivation +NAP

Protecting Microtubules

ADNP Contains a small neuroprotective epitope Protecting against apoptosis

NAP Complements ADNP (+-) Cognitive Deficiency

Morris water maze test of brain function

J Pharmacol Exp Ther 2007323438-449

0

10

20

30

40

50

60

70

80

90

100

day1 day2 day3 day4 day5

late

ncy (

sec)

ADNP++

ADNP+-

ADNP+- NAP

gt ADNP-deficient mice (+-) display impaired learning and memory in the Morris water maze (latency to reach the hidden platform is not reduced after training)

gt Impairment is significantly reversed by treatment with NAP

gt Parallel protection against tau pathology is seen also in models of Alzheimerrsquos disease and related neurodegenerations (tau mutant mice)

Tau pathology NAP protects

Neurobiol Dis 2009 May34(2)381-8

Tau mutant mice

mutant mice A small protecting snippet against protein deficits

Microtubules are Essential Within the Nerve Cell

Neurodegeneration gt Destabilization and breakdown of microtubules

gt Tau hyperphosphorylation

gt Progressive loss of function

gt Leads to cell death

Microtubules

Essential for neuronal structure and function

Neuroprotection gt Davunetide (NAP) crosses the human blood brain

barrier

gt Reduces Tau hyperphosphorylation

gt Stabilizes and repairs microtubules

gt Enhances dendritic spine formation

gt Restores neuronal structure and function

Gozes I Littauer UZ Tubulin microheterogeneity increases with rat brain maturation Nature 1978 276 411-13 Gozes I Sweadner KJ Multiple tubulin forms are expressed by a single neurone Nature 1981 294 477-80 Gozes I Barstable CJ Monoclonal antibodies that recognize discrete forms of tubulin Proc Natl Acad Sci USA 792579-83 Gozes et al Curr Alzheimer Res 2009 6455-60 OzhellipGozes Mol Psychiatry 2014 Oct19(10)1115-24

MAP2

Spines connections

Microtubules End Binding Proteins Providing Microtubule Dynamics

NAPח

NAP increases microtubule end binding protein association with tubulin

NAP increases ADNP Association with microtubule end binding proteins

ldquoMolecules that make our mindsrdquo

EB3

Micro

tub

ule

EB3

EB3+1

p140Cap (SIP)

SrcFyn

NM

DA

R

P

EB31

P

TAU

CLASP2 (SxIP)

APC

APC2 (SSIP)

APC2 EB3

Drebrin

ADNP (SIP)

NAP

The NAP-Motif of Activity-Dependent Neuroprotective Protein (ADNP) Regulates Dendritic Spines through Microtubule End Binding (EB) Proteins

Oz S Kapitansky O Ivashco-Pachima Y Malishkevich A Giladi E Skalka N Rosin-Arbesfeld R Mittelman L Sege O Hirsch JA and Gozes I The NAP-Motif of Activity-Dependent Neuroprotective Protein (ADNP) Regulates Dendritic Spines through Microtubule End Binding Proteins Mol Psychiatry 2014 Oct19(10)1115-24

+NAP

NAPADNP increases synaptic

connections through EB (green)

Synapse Formation

Micro

tub

ule

EB3 EB3

EB3+1

NAP

EB31 EB3

ADNP (NAP)

Synaptic plasticity

NAP ADNP (NAP)

LC3

Autophagosome

LC3 LC3

LC3

LC3 LC3

NAP ADNP (NAP)

bbbbbbbbbbb

Bridging Autopahgy and Microtubules

Immunoprecipitation (IP) of ADNP reveals direct

interaction with microtubule associated protein 1

light chain 3 (LC3B) a major regulator of

autophagy by Western analysis The ADNP

LC3B interaction correlates with the level of

ADNP expression a strong interaction in normal

mice (ADNP++ right band) and a weaker

interaction in ADNP+- mice (left band) The

interaction of ADNP with LC3B was

augmented in the presence of NAP

MerenlenderndashWagner A Malishkevich A Shemer Z Udawela M Gibbons A Scarr E Dean B Levine J Agam G and Gozes I (2013) Autophagy plays a key role in the pathophysiology of schizophrenia Mol Psychiatry 2015 Feb20(1)126-32 doi 101038mp2013174 Epub 2013 Dec 24

Esteves AR Gozes I Cardoso SM (2014) The rescue of microtubule-dependent traffic recovers mitochondrial function in Parkinsons disease Biochim Biophys Acta 1842 7-21

NAP Enhances Microtubule Invasion to the Tip of the Nerve Fortifying Cell Communication

Calculation = Area occupied by dynamic (+Tyr)-tubulin (red left grey right) in the distal-peripheral growth cone (ROI)

PLoS One 20127(12)e51458

Invasion of dynamic microtubules

Increases microtubule dynamics at the tip of the growth cone

Enlisting Tau (Ties) Back to the Microtubules (Train Tracks)

gt NAP increases the tubulin and tau content of microtubules under conditions of zinc intoxication (note zinc accumulation is a prominent feature of Alzheimerrsquos disease pathology)

S Oz Y Ivashco-Pachima and I Gozes PLoS One 20127(12)e51458

NAP enlists tau to microtubules

S Quraishe C M Cowan and A Mudher University of Southampton Southampton Molecular Psychiatry 2013 EPUB

By enlisting taubuilding microtubules NAP provides protection against impairments in material (axonal) transport in nerve cells ndash key to brain communication

24 hours 15 min 3min 3min 3min 3min 3min 3min 3min 3min 3min 3min 3min

Colchicine

microtubule

disruption

Anesthesia and

MnCl2 or water

administration

NAP (colchicine

group) and

control placebo

Animal transfer

to magnet

3 Control

acquisitions 11 Acquisitions for estimation of axonal

transport (Manganese contrast)

07

08

09

1

11

12

13

14

15

12 15 18 21 24 27 30 33 36 39 42 45 48

Norm

aliz

ed

sig

na

l in

ten

sity

Time (min)

NAP Prevents Axonal Transport Deficits Mouse

Y Jouroukhin R Ostritsky Y Assaf G Pelled E Giladi and I Gozes Neurobiology of Disease 2013 5679-94

Protection against axonal impairment is coupled to protection against tau pathology in an ALS model

State of the art measurements of axonal transport inhaled MnCl2 provides an MRI contrasting agent (white below) Measurements of progression in the olfactory bulb show disruption by microtubule breakdown (colchicine) and protection by NAP

-08

-06

-04

-02

0

02

04

06

08

Normal DD Normal NAP Heterozygous

DD

Heterozygous

NAP

D 2

Cognitive Improvement in a Schizophrenia Model

DD=placebo Heterozygous= Schizophrenia model

Working Hypothesis

gt The stable tubule-only polypeptide (STOP) knockout mice have been shown to provide a valid model for schizophrenia

gt The capacity of the mice to discriminate between novel object and familiar object was calculated as discrimination capacity D2

gt The ldquoschizophrenicrdquo mice (microtubule-deficient) show markedly decreased memory

gt NAP ameliorates this deficiency

Microtubule dysfunction in schizophrenia Merenlender-Wagner et al Peptides 2010311368 Gozes Peptides 201132428 Olson Prize Molecular Psychiatry 2013 Dec 24 doi 101038mp2013174 Autophagy 2014 Dec 210(12)2324-32 doi 104161155486272014984274

Insert

STOP++ STOP+-

BE

CN

1

NAP treatment reverses BECN1 reduction in STOP+- mouse hippocampus

The STOP+- Mouse Model Mimics Schizophrenia NAP Compensation

Beclin1

MerenlenderndashWagner A Shemer Z Touloumi O Lagoudaki R Giladi E Andrieux A Grigoriadis NC and Gozes I (2014) New horizons in schizophrenia treatment Autophagy 2014 Dec 210(12)2324-32 doi 104161155486272014984274

Beclin1

Cleaning and

recycling system

LC3

LC3

LC3


Significant Improvement in Schizophrenia Patients

-30

-20

-10

0

10

20

30

40

50

placebo 5 mg QD 15 mg BID placebo 5 mg QD 15 mg BID

Daily Activities Change-from-Baseline

T-Sc

ore

(C

FB)

Week 6 Week 12

Conclusion

Statistically significant treatment effect of davunetide (NAP) 5 mg once daily -QD (p=0023) and combined treatment groups (high dose twice daily ndash BID + low dose once daily) versus placebo (p=0015) (mixed model ANCOVA)

No statistical significance between davunetide groups

Associated with in vivo neuroprotection

Javitt et al (2012) Effect of the neuroprotective peptide davunetide (AL-108) on cognition and functional capacity in schizophrenia Schizophr Res 136 25-31

Jarskog et al(2013) Effects of Davunetide on N-acetylaspartate and Choline in Dorsolateral Prefrontal Cortex in Patients with Schizophrenia Neuropsychopharmacology 38 1245-52 Original support NIA NIMH ISOA Allon Therapeutics

Translation into clinical trials

ALZHEIMERrsquoS DISEASE

Alois Alzheimer

Auguste D

-20

0

20

40

60

80

100

0 4 8 12 16

Week

DM

TS

12 s

ec d

ela

y (

C

FB

)

placebo 5 mg QD 15 mg BID

p=0067

p=0039

p=0064p=0038

Drug administration Follow-up

Davunetide (15 mg x2day) Improves Memory in aMCI Patients

Statistically significant dose dependent and durable impact seen on memory

change from background (CFB) delayed matching to sample (DMTS)

Michael J Fox

Ronald Reagan



Muhammad Ali

We Fight Against Their Disease

Autism Schizophrenia and Alzheimerrsquos Disease

Jarskog et al

Neuropsychopharmacology

2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]

Effects of Davunetide on N-

acetylaspartate and Choline in

Dorsolateral Prefrontal Cortex

in Patients with Schizophrenia

Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12

Effect of the neuroprotective

peptide davunetide (AL-108)

on cognition and functional

capacity in schizophrenia

Clinical Translation

Medical Validation by

Others

A Glimpse at Our Recent Work

The rescue of microtubule-dependent traffic recovers mitochondrial function in Parkinsons disease AR Esteves I Gozes SM Cardoso

Biochim Biophys Acta 2014 Jan1842(1)7-21


Molecular Psychiatry Translational Psychiatry Autophagy and Pharmacology Research amp Perspectives 2014 2015

Thanks

Tel Aviv University (TAU)

Imagine your brain as a large rail transportation system and your 100 billion nerve cells = trains while your brain ldquosupport cellsrdquo are the train tracks

Now imagine disruption in connectivity hellip (~100 trillion points of connection)hellip

Can we fix it


Michael J Fox

Ronald Reagan



Muhammad Ali




Nature Genetics

Volume

46

Pages

380ndash384

Year published

(2014)

DOI



Michael J Fox

Ronald Reagan



Muhammad Ali




Nature Genetics

Volume

46

Pages

380ndash384

Year published

(2014)

DOI







(Wing 1996)




ADNP

Disease Injury



ADNP platform




ADNF platform

D-SAL AL-309 (9 aa)

SAL AL-209 (9 aa)

Neuropathies



NAPVSIPQ SALLRSIPA



Neuropeptides







1

2

2


3


Organogenesis

Neuroogenesis

Regulation of

Transcription

Lytic

vacuole

Lipid

Transport

Coagulation










0010203040506

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleADNP

Males Females

Rela

tive m

RN

A c

onte

nt

00

1

2

3

4

5

Postmortem ADNP

0

05

1

15

2

25

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleelF4E

0

005

01

015

02

025

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleADNP2

0

5

10

15

20

25

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleAPOE

0

05

1

15

2

25

ADNP++ ADNP+-

2^-

dC

t





Behavior









NAP = NAPVSIPQ











0

10

20

30

40

50

60

70

80

90

100


late

ncy (

sec)

ADNP++

ADNP+-

ADNP+- NAP






Tau mutant mice







Microtubules



barrier






MAP2

Spines connections


NAPח




EB3

Micro

tub

ule

EB3

EB3+1

p140Cap (SIP)

SrcFyn

NM

DA

R

P

EB31

P

TAU

CLASP2 (SxIP)

APC

APC2 (SSIP)

APC2 EB3

Drebrin

ADNP (SIP)

NAP



+NAP



Synapse Formation

Micro

tub

ule

EB3 EB3

EB3+1

NAP

EB31 EB3

ADNP (NAP)

Synaptic plasticity

NAP ADNP (NAP)

LC3

Autophagosome

LC3 LC3

LC3

LC3 LC3

NAP ADNP (NAP)

bbbbbbbbbbb
















PLoS One 20127(12)e51458










Colchicine

microtubule

disruption

Anesthesia and

MnCl2 or water

administration

NAP (colchicine

group) and

control placebo

Animal transfer

to magnet

3 Control



07

08

09

1

11

12

13

14

15

12 15 18 21 24 27 30 33 36 39 42 45 48

Norm

aliz

ed

sig

na

l in

ten

sity

Time (min)





-08

-06

-04

-02

0

02

04

06

08


DD

Heterozygous

NAP

D 2



Working Hypothesis






Insert

STOP++ STOP+-

BE

CN

1



Beclin1


Beclin1

Cleaning and

recycling system

LC3

LC3

LC3



-30

-20

-10

0

10

20

30

40

50



T-Sc

ore

(C

FB)

Week 6 Week 12

Conclusion








Alois Alzheimer

Auguste D

-20

0

20

40

60

80

100

0 4 8 12 16

Week

DM

TS

12 s

ec d

ela

y (

C

FB

)


p=0067

p=0039

p=0064p=0038





Michael J Fox

Ronald Reagan



Muhammad Ali



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks



Michael J Fox

Ronald Reagan



Muhammad Ali




Nature Genetics

Volume

46

Pages

380ndash384

Year published

(2014)

DOI



Michael J Fox

Ronald Reagan



Muhammad Ali




Nature Genetics

Volume

46

Pages

380ndash384

Year published

(2014)

DOI







(Wing 1996)




ADNP

Disease Injury



ADNP platform




ADNF platform

D-SAL AL-309 (9 aa)

SAL AL-209 (9 aa)

Neuropathies



NAPVSIPQ SALLRSIPA



Neuropeptides







1

2

2


3


Organogenesis

Neuroogenesis

Regulation of

Transcription

Lytic

vacuole

Lipid

Transport

Coagulation










0010203040506

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleADNP

Males Females

Rela

tive m

RN

A c

onte

nt

00

1

2

3

4

5

Postmortem ADNP

0

05

1

15

2

25

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleelF4E

0

005

01

015

02

025

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleADNP2

0

5

10

15

20

25

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleAPOE

0

05

1

15

2

25

ADNP++ ADNP+-

2^-

dC

t





Behavior









NAP = NAPVSIPQ











0

10

20

30

40

50

60

70

80

90

100


late

ncy (

sec)

ADNP++

ADNP+-

ADNP+- NAP






Tau mutant mice







Microtubules



barrier






MAP2

Spines connections


NAPח




EB3

Micro

tub

ule

EB3

EB3+1

p140Cap (SIP)

SrcFyn

NM

DA

R

P

EB31

P

TAU

CLASP2 (SxIP)

APC

APC2 (SSIP)

APC2 EB3

Drebrin

ADNP (SIP)

NAP



+NAP



Synapse Formation

Micro

tub

ule

EB3 EB3

EB3+1

NAP

EB31 EB3

ADNP (NAP)

Synaptic plasticity

NAP ADNP (NAP)

LC3

Autophagosome

LC3 LC3

LC3

LC3 LC3

NAP ADNP (NAP)

bbbbbbbbbbb
















PLoS One 20127(12)e51458










Colchicine

microtubule

disruption

Anesthesia and

MnCl2 or water

administration

NAP (colchicine

group) and

control placebo

Animal transfer

to magnet

3 Control



07

08

09

1

11

12

13

14

15

12 15 18 21 24 27 30 33 36 39 42 45 48

Norm

aliz

ed

sig

na

l in

ten

sity

Time (min)





-08

-06

-04

-02

0

02

04

06

08


DD

Heterozygous

NAP

D 2



Working Hypothesis






Insert

STOP++ STOP+-

BE

CN

1



Beclin1


Beclin1

Cleaning and

recycling system

LC3

LC3

LC3



-30

-20

-10

0

10

20

30

40

50



T-Sc

ore

(C

FB)

Week 6 Week 12

Conclusion








Alois Alzheimer

Auguste D

-20

0

20

40

60

80

100

0 4 8 12 16

Week

DM

TS

12 s

ec d

ela

y (

C

FB

)


p=0067

p=0039

p=0064p=0038





Michael J Fox

Ronald Reagan



Muhammad Ali



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks



Michael J Fox

Ronald Reagan



Muhammad Ali




Nature Genetics

Volume

46

Pages

380ndash384

Year published

(2014)

DOI







(Wing 1996)




ADNP

Disease Injury



ADNP platform




ADNF platform

D-SAL AL-309 (9 aa)

SAL AL-209 (9 aa)

Neuropathies



NAPVSIPQ SALLRSIPA



Neuropeptides







1

2

2


3


Organogenesis

Neuroogenesis

Regulation of

Transcription

Lytic

vacuole

Lipid

Transport

Coagulation










0010203040506

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleADNP

Males Females

Rela

tive m

RN

A c

onte

nt

00

1

2

3

4

5

Postmortem ADNP

0

05

1

15

2

25

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleelF4E

0

005

01

015

02

025

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleADNP2

0

5

10

15

20

25

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleAPOE

0

05

1

15

2

25

ADNP++ ADNP+-

2^-

dC

t





Behavior









NAP = NAPVSIPQ











0

10

20

30

40

50

60

70

80

90

100


late

ncy (

sec)

ADNP++

ADNP+-

ADNP+- NAP






Tau mutant mice







Microtubules



barrier






MAP2

Spines connections


NAPח




EB3

Micro

tub

ule

EB3

EB3+1

p140Cap (SIP)

SrcFyn

NM

DA

R

P

EB31

P

TAU

CLASP2 (SxIP)

APC

APC2 (SSIP)

APC2 EB3

Drebrin

ADNP (SIP)

NAP



+NAP



Synapse Formation

Micro

tub

ule

EB3 EB3

EB3+1

NAP

EB31 EB3

ADNP (NAP)

Synaptic plasticity

NAP ADNP (NAP)

LC3

Autophagosome

LC3 LC3

LC3

LC3 LC3

NAP ADNP (NAP)

bbbbbbbbbbb
















PLoS One 20127(12)e51458










Colchicine

microtubule

disruption

Anesthesia and

MnCl2 or water

administration

NAP (colchicine

group) and

control placebo

Animal transfer

to magnet

3 Control



07

08

09

1

11

12

13

14

15

12 15 18 21 24 27 30 33 36 39 42 45 48

Norm

aliz

ed

sig

na

l in

ten

sity

Time (min)





-08

-06

-04

-02

0

02

04

06

08


DD

Heterozygous

NAP

D 2



Working Hypothesis






Insert

STOP++ STOP+-

BE

CN

1



Beclin1


Beclin1

Cleaning and

recycling system

LC3

LC3

LC3



-30

-20

-10

0

10

20

30

40

50



T-Sc

ore

(C

FB)

Week 6 Week 12

Conclusion








Alois Alzheimer

Auguste D

-20

0

20

40

60

80

100

0 4 8 12 16

Week

DM

TS

12 s

ec d

ela

y (

C

FB

)


p=0067

p=0039

p=0064p=0038





Michael J Fox

Ronald Reagan



Muhammad Ali



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks







(Wing 1996)




ADNP

Disease Injury



ADNP platform




ADNF platform

D-SAL AL-309 (9 aa)

SAL AL-209 (9 aa)

Neuropathies



NAPVSIPQ SALLRSIPA



Neuropeptides







1

2

2


3


Organogenesis

Neuroogenesis

Regulation of

Transcription

Lytic

vacuole

Lipid

Transport

Coagulation










0010203040506

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleADNP

Males Females

Rela

tive m

RN

A c

onte

nt

00

1

2

3

4

5

Postmortem ADNP

0

05

1

15

2

25

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleelF4E

0

005

01

015

02

025

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleADNP2

0

5

10

15

20

25

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleAPOE

0

05

1

15

2

25

ADNP++ ADNP+-

2^-

dC

t





Behavior









NAP = NAPVSIPQ











0

10

20

30

40

50

60

70

80

90

100


late

ncy (

sec)

ADNP++

ADNP+-

ADNP+- NAP






Tau mutant mice







Microtubules



barrier






MAP2

Spines connections


NAPח




EB3

Micro

tub

ule

EB3

EB3+1

p140Cap (SIP)

SrcFyn

NM

DA

R

P

EB31

P

TAU

CLASP2 (SxIP)

APC

APC2 (SSIP)

APC2 EB3

Drebrin

ADNP (SIP)

NAP



+NAP



Synapse Formation

Micro

tub

ule

EB3 EB3

EB3+1

NAP

EB31 EB3

ADNP (NAP)

Synaptic plasticity

NAP ADNP (NAP)

LC3

Autophagosome

LC3 LC3

LC3

LC3 LC3

NAP ADNP (NAP)

bbbbbbbbbbb
















PLoS One 20127(12)e51458










Colchicine

microtubule

disruption

Anesthesia and

MnCl2 or water

administration

NAP (colchicine

group) and

control placebo

Animal transfer

to magnet

3 Control



07

08

09

1

11

12

13

14

15

12 15 18 21 24 27 30 33 36 39 42 45 48

Norm

aliz

ed

sig

na

l in

ten

sity

Time (min)





-08

-06

-04

-02

0

02

04

06

08


DD

Heterozygous

NAP

D 2



Working Hypothesis






Insert

STOP++ STOP+-

BE

CN

1



Beclin1


Beclin1

Cleaning and

recycling system

LC3

LC3

LC3



-30

-20

-10

0

10

20

30

40

50



T-Sc

ore

(C

FB)

Week 6 Week 12

Conclusion








Alois Alzheimer

Auguste D

-20

0

20

40

60

80

100

0 4 8 12 16

Week

DM

TS

12 s

ec d

ela

y (

C

FB

)


p=0067

p=0039

p=0064p=0038





Michael J Fox

Ronald Reagan



Muhammad Ali



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks




ADNP

Disease Injury



ADNP platform




ADNF platform

D-SAL AL-309 (9 aa)

SAL AL-209 (9 aa)

Neuropathies



NAPVSIPQ SALLRSIPA



Neuropeptides







1

2

2


3


Organogenesis

Neuroogenesis

Regulation of

Transcription

Lytic

vacuole

Lipid

Transport

Coagulation










0010203040506

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleADNP

Males Females

Rela

tive m

RN

A c

onte

nt

00

1

2

3

4

5

Postmortem ADNP

0

05

1

15

2

25

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleelF4E

0

005

01

015

02

025

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleADNP2

0

5

10

15

20

25

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleAPOE

0

05

1

15

2

25

ADNP++ ADNP+-

2^-

dC

t





Behavior









NAP = NAPVSIPQ











0

10

20

30

40

50

60

70

80

90

100


late

ncy (

sec)

ADNP++

ADNP+-

ADNP+- NAP






Tau mutant mice







Microtubules



barrier






MAP2

Spines connections


NAPח




EB3

Micro

tub

ule

EB3

EB3+1

p140Cap (SIP)

SrcFyn

NM

DA

R

P

EB31

P

TAU

CLASP2 (SxIP)

APC

APC2 (SSIP)

APC2 EB3

Drebrin

ADNP (SIP)

NAP



+NAP



Synapse Formation

Micro

tub

ule

EB3 EB3

EB3+1

NAP

EB31 EB3

ADNP (NAP)

Synaptic plasticity

NAP ADNP (NAP)

LC3

Autophagosome

LC3 LC3

LC3

LC3 LC3

NAP ADNP (NAP)

bbbbbbbbbbb
















PLoS One 20127(12)e51458










Colchicine

microtubule

disruption

Anesthesia and

MnCl2 or water

administration

NAP (colchicine

group) and

control placebo

Animal transfer

to magnet

3 Control



07

08

09

1

11

12

13

14

15

12 15 18 21 24 27 30 33 36 39 42 45 48

Norm

aliz

ed

sig

na

l in

ten

sity

Time (min)





-08

-06

-04

-02

0

02

04

06

08


DD

Heterozygous

NAP

D 2



Working Hypothesis






Insert

STOP++ STOP+-

BE

CN

1



Beclin1


Beclin1

Cleaning and

recycling system

LC3

LC3

LC3



-30

-20

-10

0

10

20

30

40

50



T-Sc

ore

(C

FB)

Week 6 Week 12

Conclusion








Alois Alzheimer

Auguste D

-20

0

20

40

60

80

100

0 4 8 12 16

Week

DM

TS

12 s

ec d

ela

y (

C

FB

)


p=0067

p=0039

p=0064p=0038





Michael J Fox

Ronald Reagan



Muhammad Ali



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks


Disease Injury



ADNP platform




ADNF platform

D-SAL AL-309 (9 aa)

SAL AL-209 (9 aa)

Neuropathies



NAPVSIPQ SALLRSIPA



Neuropeptides







1

2

2


3


Organogenesis

Neuroogenesis

Regulation of

Transcription

Lytic

vacuole

Lipid

Transport

Coagulation










0010203040506

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleADNP

Males Females

Rela

tive m

RN

A c

onte

nt

00

1

2

3

4

5

Postmortem ADNP

0

05

1

15

2

25

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleelF4E

0

005

01

015

02

025

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleADNP2

0

5

10

15

20

25

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleAPOE

0

05

1

15

2

25

ADNP++ ADNP+-

2^-

dC

t





Behavior









NAP = NAPVSIPQ











0

10

20

30

40

50

60

70

80

90

100


late

ncy (

sec)

ADNP++

ADNP+-

ADNP+- NAP






Tau mutant mice







Microtubules



barrier






MAP2

Spines connections


NAPח




EB3

Micro

tub

ule

EB3

EB3+1

p140Cap (SIP)

SrcFyn

NM

DA

R

P

EB31

P

TAU

CLASP2 (SxIP)

APC

APC2 (SSIP)

APC2 EB3

Drebrin

ADNP (SIP)

NAP



+NAP



Synapse Formation

Micro

tub

ule

EB3 EB3

EB3+1

NAP

EB31 EB3

ADNP (NAP)

Synaptic plasticity

NAP ADNP (NAP)

LC3

Autophagosome

LC3 LC3

LC3

LC3 LC3

NAP ADNP (NAP)

bbbbbbbbbbb
















PLoS One 20127(12)e51458










Colchicine

microtubule

disruption

Anesthesia and

MnCl2 or water

administration

NAP (colchicine

group) and

control placebo

Animal transfer

to magnet

3 Control



07

08

09

1

11

12

13

14

15

12 15 18 21 24 27 30 33 36 39 42 45 48

Norm

aliz

ed

sig

na

l in

ten

sity

Time (min)





-08

-06

-04

-02

0

02

04

06

08


DD

Heterozygous

NAP

D 2



Working Hypothesis






Insert

STOP++ STOP+-

BE

CN

1



Beclin1


Beclin1

Cleaning and

recycling system

LC3

LC3

LC3



-30

-20

-10

0

10

20

30

40

50



T-Sc

ore

(C

FB)

Week 6 Week 12

Conclusion








Alois Alzheimer

Auguste D

-20

0

20

40

60

80

100

0 4 8 12 16

Week

DM

TS

12 s

ec d

ela

y (

C

FB

)


p=0067

p=0039

p=0064p=0038





Michael J Fox

Ronald Reagan



Muhammad Ali



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks








1

2

2


3


Organogenesis

Neuroogenesis

Regulation of

Transcription

Lytic

vacuole

Lipid

Transport

Coagulation










0010203040506

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleADNP

Males Females

Rela

tive m

RN

A c

onte

nt

00

1

2

3

4

5

Postmortem ADNP

0

05

1

15

2

25

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleelF4E

0

005

01

015

02

025

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleADNP2

0

5

10

15

20

25

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleAPOE

0

05

1

15

2

25

ADNP++ ADNP+-

2^-

dC

t





Behavior









NAP = NAPVSIPQ











0

10

20

30

40

50

60

70

80

90

100


late

ncy (

sec)

ADNP++

ADNP+-

ADNP+- NAP






Tau mutant mice







Microtubules



barrier






MAP2

Spines connections


NAPח




EB3

Micro

tub

ule

EB3

EB3+1

p140Cap (SIP)

SrcFyn

NM

DA

R

P

EB31

P

TAU

CLASP2 (SxIP)

APC

APC2 (SSIP)

APC2 EB3

Drebrin

ADNP (SIP)

NAP



+NAP



Synapse Formation

Micro

tub

ule

EB3 EB3

EB3+1

NAP

EB31 EB3

ADNP (NAP)

Synaptic plasticity

NAP ADNP (NAP)

LC3

Autophagosome

LC3 LC3

LC3

LC3 LC3

NAP ADNP (NAP)

bbbbbbbbbbb
















PLoS One 20127(12)e51458










Colchicine

microtubule

disruption

Anesthesia and

MnCl2 or water

administration

NAP (colchicine

group) and

control placebo

Animal transfer

to magnet

3 Control



07

08

09

1

11

12

13

14

15

12 15 18 21 24 27 30 33 36 39 42 45 48

Norm

aliz

ed

sig

na

l in

ten

sity

Time (min)





-08

-06

-04

-02

0

02

04

06

08


DD

Heterozygous

NAP

D 2



Working Hypothesis






Insert

STOP++ STOP+-

BE

CN

1



Beclin1


Beclin1

Cleaning and

recycling system

LC3

LC3

LC3



-30

-20

-10

0

10

20

30

40

50



T-Sc

ore

(C

FB)

Week 6 Week 12

Conclusion








Alois Alzheimer

Auguste D

-20

0

20

40

60

80

100

0 4 8 12 16

Week

DM

TS

12 s

ec d

ela

y (

C

FB

)


p=0067

p=0039

p=0064p=0038





Michael J Fox

Ronald Reagan



Muhammad Ali



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks


Organogenesis

Neuroogenesis

Regulation of

Transcription

Lytic

vacuole

Lipid

Transport

Coagulation










0010203040506

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleADNP

Males Females

Rela

tive m

RN

A c

onte

nt

00

1

2

3

4

5

Postmortem ADNP

0

05

1

15

2

25

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleelF4E

0

005

01

015

02

025

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleADNP2

0

5

10

15

20

25

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleAPOE

0

05

1

15

2

25

ADNP++ ADNP+-

2^-

dC

t





Behavior









NAP = NAPVSIPQ











0

10

20

30

40

50

60

70

80

90

100


late

ncy (

sec)

ADNP++

ADNP+-

ADNP+- NAP






Tau mutant mice







Microtubules



barrier






MAP2

Spines connections


NAPח




EB3

Micro

tub

ule

EB3

EB3+1

p140Cap (SIP)

SrcFyn

NM

DA

R

P

EB31

P

TAU

CLASP2 (SxIP)

APC

APC2 (SSIP)

APC2 EB3

Drebrin

ADNP (SIP)

NAP



+NAP



Synapse Formation

Micro

tub

ule

EB3 EB3

EB3+1

NAP

EB31 EB3

ADNP (NAP)

Synaptic plasticity

NAP ADNP (NAP)

LC3

Autophagosome

LC3 LC3

LC3

LC3 LC3

NAP ADNP (NAP)

bbbbbbbbbbb
















PLoS One 20127(12)e51458










Colchicine

microtubule

disruption

Anesthesia and

MnCl2 or water

administration

NAP (colchicine

group) and

control placebo

Animal transfer

to magnet

3 Control



07

08

09

1

11

12

13

14

15

12 15 18 21 24 27 30 33 36 39 42 45 48

Norm

aliz

ed

sig

na

l in

ten

sity

Time (min)





-08

-06

-04

-02

0

02

04

06

08


DD

Heterozygous

NAP

D 2



Working Hypothesis






Insert

STOP++ STOP+-

BE

CN

1



Beclin1


Beclin1

Cleaning and

recycling system

LC3

LC3

LC3



-30

-20

-10

0

10

20

30

40

50



T-Sc

ore

(C

FB)

Week 6 Week 12

Conclusion








Alois Alzheimer

Auguste D

-20

0

20

40

60

80

100

0 4 8 12 16

Week

DM

TS

12 s

ec d

ela

y (

C

FB

)


p=0067

p=0039

p=0064p=0038





Michael J Fox

Ronald Reagan



Muhammad Ali



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks







0010203040506

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleADNP

Males Females

Rela

tive m

RN

A c

onte

nt

00

1

2

3

4

5

Postmortem ADNP

0

05

1

15

2

25

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleelF4E

0

005

01

015

02

025

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleADNP2

0

5

10

15

20

25

ADNP++ ADNP+-

2^-

dC

t

Male

FemaleAPOE

0

05

1

15

2

25

ADNP++ ADNP+-

2^-

dC

t





Behavior









NAP = NAPVSIPQ











0

10

20

30

40

50

60

70

80

90

100


late

ncy (

sec)

ADNP++

ADNP+-

ADNP+- NAP






Tau mutant mice







Microtubules



barrier






MAP2

Spines connections


NAPח




EB3

Micro

tub

ule

EB3

EB3+1

p140Cap (SIP)

SrcFyn

NM

DA

R

P

EB31

P

TAU

CLASP2 (SxIP)

APC

APC2 (SSIP)

APC2 EB3

Drebrin

ADNP (SIP)

NAP



+NAP



Synapse Formation

Micro

tub

ule

EB3 EB3

EB3+1

NAP

EB31 EB3

ADNP (NAP)

Synaptic plasticity

NAP ADNP (NAP)

LC3

Autophagosome

LC3 LC3

LC3

LC3 LC3

NAP ADNP (NAP)

bbbbbbbbbbb
















PLoS One 20127(12)e51458










Colchicine

microtubule

disruption

Anesthesia and

MnCl2 or water

administration

NAP (colchicine

group) and

control placebo

Animal transfer

to magnet

3 Control



07

08

09

1

11

12

13

14

15

12 15 18 21 24 27 30 33 36 39 42 45 48

Norm

aliz

ed

sig

na

l in

ten

sity

Time (min)





-08

-06

-04

-02

0

02

04

06

08


DD

Heterozygous

NAP

D 2



Working Hypothesis






Insert

STOP++ STOP+-

BE

CN

1



Beclin1


Beclin1

Cleaning and

recycling system

LC3

LC3

LC3



-30

-20

-10

0

10

20

30

40

50



T-Sc

ore

(C

FB)

Week 6 Week 12

Conclusion








Alois Alzheimer

Auguste D

-20

0

20

40

60

80

100

0 4 8 12 16

Week

DM

TS

12 s

ec d

ela

y (

C

FB

)


p=0067

p=0039

p=0064p=0038





Michael J Fox

Ronald Reagan



Muhammad Ali



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks










NAP = NAPVSIPQ











0

10

20

30

40

50

60

70

80

90

100


late

ncy (

sec)

ADNP++

ADNP+-

ADNP+- NAP






Tau mutant mice







Microtubules



barrier






MAP2

Spines connections


NAPח




EB3

Micro

tub

ule

EB3

EB3+1

p140Cap (SIP)

SrcFyn

NM

DA

R

P

EB31

P

TAU

CLASP2 (SxIP)

APC

APC2 (SSIP)

APC2 EB3

Drebrin

ADNP (SIP)

NAP



+NAP



Synapse Formation

Micro

tub

ule

EB3 EB3

EB3+1

NAP

EB31 EB3

ADNP (NAP)

Synaptic plasticity

NAP ADNP (NAP)

LC3

Autophagosome

LC3 LC3

LC3

LC3 LC3

NAP ADNP (NAP)

bbbbbbbbbbb
















PLoS One 20127(12)e51458










Colchicine

microtubule

disruption

Anesthesia and

MnCl2 or water

administration

NAP (colchicine

group) and

control placebo

Animal transfer

to magnet

3 Control



07

08

09

1

11

12

13

14

15

12 15 18 21 24 27 30 33 36 39 42 45 48

Norm

aliz

ed

sig

na

l in

ten

sity

Time (min)





-08

-06

-04

-02

0

02

04

06

08


DD

Heterozygous

NAP

D 2



Working Hypothesis






Insert

STOP++ STOP+-

BE

CN

1



Beclin1


Beclin1

Cleaning and

recycling system

LC3

LC3

LC3



-30

-20

-10

0

10

20

30

40

50



T-Sc

ore

(C

FB)

Week 6 Week 12

Conclusion








Alois Alzheimer

Auguste D

-20

0

20

40

60

80

100

0 4 8 12 16

Week

DM

TS

12 s

ec d

ela

y (

C

FB

)


p=0067

p=0039

p=0064p=0038





Michael J Fox

Ronald Reagan



Muhammad Ali



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks





0

10

20

30

40

50

60

70

80

90

100


late

ncy (

sec)

ADNP++

ADNP+-

ADNP+- NAP






Tau mutant mice







Microtubules



barrier






MAP2

Spines connections


NAPח




EB3

Micro

tub

ule

EB3

EB3+1

p140Cap (SIP)

SrcFyn

NM

DA

R

P

EB31

P

TAU

CLASP2 (SxIP)

APC

APC2 (SSIP)

APC2 EB3

Drebrin

ADNP (SIP)

NAP



+NAP



Synapse Formation

Micro

tub

ule

EB3 EB3

EB3+1

NAP

EB31 EB3

ADNP (NAP)

Synaptic plasticity

NAP ADNP (NAP)

LC3

Autophagosome

LC3 LC3

LC3

LC3 LC3

NAP ADNP (NAP)

bbbbbbbbbbb
















PLoS One 20127(12)e51458










Colchicine

microtubule

disruption

Anesthesia and

MnCl2 or water

administration

NAP (colchicine

group) and

control placebo

Animal transfer

to magnet

3 Control



07

08

09

1

11

12

13

14

15

12 15 18 21 24 27 30 33 36 39 42 45 48

Norm

aliz

ed

sig

na

l in

ten

sity

Time (min)





-08

-06

-04

-02

0

02

04

06

08


DD

Heterozygous

NAP

D 2



Working Hypothesis






Insert

STOP++ STOP+-

BE

CN

1



Beclin1


Beclin1

Cleaning and

recycling system

LC3

LC3

LC3



-30

-20

-10

0

10

20

30

40

50



T-Sc

ore

(C

FB)

Week 6 Week 12

Conclusion








Alois Alzheimer

Auguste D

-20

0

20

40

60

80

100

0 4 8 12 16

Week

DM

TS

12 s

ec d

ela

y (

C

FB

)


p=0067

p=0039

p=0064p=0038





Michael J Fox

Ronald Reagan



Muhammad Ali



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks







Microtubules



barrier






MAP2

Spines connections


NAPח




EB3

Micro

tub

ule

EB3

EB3+1

p140Cap (SIP)

SrcFyn

NM

DA

R

P

EB31

P

TAU

CLASP2 (SxIP)

APC

APC2 (SSIP)

APC2 EB3

Drebrin

ADNP (SIP)

NAP



+NAP



Synapse Formation

Micro

tub

ule

EB3 EB3

EB3+1

NAP

EB31 EB3

ADNP (NAP)

Synaptic plasticity

NAP ADNP (NAP)

LC3

Autophagosome

LC3 LC3

LC3

LC3 LC3

NAP ADNP (NAP)

bbbbbbbbbbb
















PLoS One 20127(12)e51458










Colchicine

microtubule

disruption

Anesthesia and

MnCl2 or water

administration

NAP (colchicine

group) and

control placebo

Animal transfer

to magnet

3 Control



07

08

09

1

11

12

13

14

15

12 15 18 21 24 27 30 33 36 39 42 45 48

Norm

aliz

ed

sig

na

l in

ten

sity

Time (min)





-08

-06

-04

-02

0

02

04

06

08


DD

Heterozygous

NAP

D 2



Working Hypothesis






Insert

STOP++ STOP+-

BE

CN

1



Beclin1


Beclin1

Cleaning and

recycling system

LC3

LC3

LC3



-30

-20

-10

0

10

20

30

40

50



T-Sc

ore

(C

FB)

Week 6 Week 12

Conclusion








Alois Alzheimer

Auguste D

-20

0

20

40

60

80

100

0 4 8 12 16

Week

DM

TS

12 s

ec d

ela

y (

C

FB

)


p=0067

p=0039

p=0064p=0038





Michael J Fox

Ronald Reagan



Muhammad Ali



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks



NAPח




EB3

Micro

tub

ule

EB3

EB3+1

p140Cap (SIP)

SrcFyn

NM

DA

R

P

EB31

P

TAU

CLASP2 (SxIP)

APC

APC2 (SSIP)

APC2 EB3

Drebrin

ADNP (SIP)

NAP



+NAP



Synapse Formation

Micro

tub

ule

EB3 EB3

EB3+1

NAP

EB31 EB3

ADNP (NAP)

Synaptic plasticity

NAP ADNP (NAP)

LC3

Autophagosome

LC3 LC3

LC3

LC3 LC3

NAP ADNP (NAP)

bbbbbbbbbbb
















PLoS One 20127(12)e51458










Colchicine

microtubule

disruption

Anesthesia and

MnCl2 or water

administration

NAP (colchicine

group) and

control placebo

Animal transfer

to magnet

3 Control



07

08

09

1

11

12

13

14

15

12 15 18 21 24 27 30 33 36 39 42 45 48

Norm

aliz

ed

sig

na

l in

ten

sity

Time (min)





-08

-06

-04

-02

0

02

04

06

08


DD

Heterozygous

NAP

D 2



Working Hypothesis






Insert

STOP++ STOP+-

BE

CN

1



Beclin1


Beclin1

Cleaning and

recycling system

LC3

LC3

LC3



-30

-20

-10

0

10

20

30

40

50



T-Sc

ore

(C

FB)

Week 6 Week 12

Conclusion








Alois Alzheimer

Auguste D

-20

0

20

40

60

80

100

0 4 8 12 16

Week

DM

TS

12 s

ec d

ela

y (

C

FB

)


p=0067

p=0039

p=0064p=0038





Michael J Fox

Ronald Reagan



Muhammad Ali



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks



EB3

Micro

tub

ule

EB3

EB3+1

p140Cap (SIP)

SrcFyn

NM

DA

R

P

EB31

P

TAU

CLASP2 (SxIP)

APC

APC2 (SSIP)

APC2 EB3

Drebrin

ADNP (SIP)

NAP



+NAP



Synapse Formation

Micro

tub

ule

EB3 EB3

EB3+1

NAP

EB31 EB3

ADNP (NAP)

Synaptic plasticity

NAP ADNP (NAP)

LC3

Autophagosome

LC3 LC3

LC3

LC3 LC3

NAP ADNP (NAP)

bbbbbbbbbbb
















PLoS One 20127(12)e51458










Colchicine

microtubule

disruption

Anesthesia and

MnCl2 or water

administration

NAP (colchicine

group) and

control placebo

Animal transfer

to magnet

3 Control



07

08

09

1

11

12

13

14

15

12 15 18 21 24 27 30 33 36 39 42 45 48

Norm

aliz

ed

sig

na

l in

ten

sity

Time (min)





-08

-06

-04

-02

0

02

04

06

08


DD

Heterozygous

NAP

D 2



Working Hypothesis






Insert

STOP++ STOP+-

BE

CN

1



Beclin1


Beclin1

Cleaning and

recycling system

LC3

LC3

LC3



-30

-20

-10

0

10

20

30

40

50



T-Sc

ore

(C

FB)

Week 6 Week 12

Conclusion








Alois Alzheimer

Auguste D

-20

0

20

40

60

80

100

0 4 8 12 16

Week

DM

TS

12 s

ec d

ela

y (

C

FB

)


p=0067

p=0039

p=0064p=0038





Michael J Fox

Ronald Reagan



Muhammad Ali



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks


Micro

tub

ule

EB3 EB3

EB3+1

NAP

EB31 EB3

ADNP (NAP)

Synaptic plasticity

NAP ADNP (NAP)

LC3

Autophagosome

LC3 LC3

LC3

LC3 LC3

NAP ADNP (NAP)

bbbbbbbbbbb
















PLoS One 20127(12)e51458










Colchicine

microtubule

disruption

Anesthesia and

MnCl2 or water

administration

NAP (colchicine

group) and

control placebo

Animal transfer

to magnet

3 Control



07

08

09

1

11

12

13

14

15

12 15 18 21 24 27 30 33 36 39 42 45 48

Norm

aliz

ed

sig

na

l in

ten

sity

Time (min)





-08

-06

-04

-02

0

02

04

06

08


DD

Heterozygous

NAP

D 2



Working Hypothesis






Insert

STOP++ STOP+-

BE

CN

1



Beclin1


Beclin1

Cleaning and

recycling system

LC3

LC3

LC3



-30

-20

-10

0

10

20

30

40

50



T-Sc

ore

(C

FB)

Week 6 Week 12

Conclusion








Alois Alzheimer

Auguste D

-20

0

20

40

60

80

100

0 4 8 12 16

Week

DM

TS

12 s

ec d

ela

y (

C

FB

)


p=0067

p=0039

p=0064p=0038





Michael J Fox

Ronald Reagan



Muhammad Ali



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks




PLoS One 20127(12)e51458










Colchicine

microtubule

disruption

Anesthesia and

MnCl2 or water

administration

NAP (colchicine

group) and

control placebo

Animal transfer

to magnet

3 Control



07

08

09

1

11

12

13

14

15

12 15 18 21 24 27 30 33 36 39 42 45 48

Norm

aliz

ed

sig

na

l in

ten

sity

Time (min)





-08

-06

-04

-02

0

02

04

06

08


DD

Heterozygous

NAP

D 2



Working Hypothesis






Insert

STOP++ STOP+-

BE

CN

1



Beclin1


Beclin1

Cleaning and

recycling system

LC3

LC3

LC3



-30

-20

-10

0

10

20

30

40

50



T-Sc

ore

(C

FB)

Week 6 Week 12

Conclusion








Alois Alzheimer

Auguste D

-20

0

20

40

60

80

100

0 4 8 12 16

Week

DM

TS

12 s

ec d

ela

y (

C

FB

)


p=0067

p=0039

p=0064p=0038





Michael J Fox

Ronald Reagan



Muhammad Ali



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks









Colchicine

microtubule

disruption

Anesthesia and

MnCl2 or water

administration

NAP (colchicine

group) and

control placebo

Animal transfer

to magnet

3 Control



07

08

09

1

11

12

13

14

15

12 15 18 21 24 27 30 33 36 39 42 45 48

Norm

aliz

ed

sig

na

l in

ten

sity

Time (min)





-08

-06

-04

-02

0

02

04

06

08


DD

Heterozygous

NAP

D 2



Working Hypothesis






Insert

STOP++ STOP+-

BE

CN

1



Beclin1


Beclin1

Cleaning and

recycling system

LC3

LC3

LC3



-30

-20

-10

0

10

20

30

40

50



T-Sc

ore

(C

FB)

Week 6 Week 12

Conclusion








Alois Alzheimer

Auguste D

-20

0

20

40

60

80

100

0 4 8 12 16

Week

DM

TS

12 s

ec d

ela

y (

C

FB

)


p=0067

p=0039

p=0064p=0038





Michael J Fox

Ronald Reagan



Muhammad Ali



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks


-08

-06

-04

-02

0

02

04

06

08


DD

Heterozygous

NAP

D 2



Working Hypothesis






Insert

STOP++ STOP+-

BE

CN

1



Beclin1


Beclin1

Cleaning and

recycling system

LC3

LC3

LC3



-30

-20

-10

0

10

20

30

40

50



T-Sc

ore

(C

FB)

Week 6 Week 12

Conclusion








Alois Alzheimer

Auguste D

-20

0

20

40

60

80

100

0 4 8 12 16

Week

DM

TS

12 s

ec d

ela

y (

C

FB

)


p=0067

p=0039

p=0064p=0038





Michael J Fox

Ronald Reagan



Muhammad Ali



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks


Insert

STOP++ STOP+-

BE

CN

1



Beclin1


Beclin1

Cleaning and

recycling system

LC3

LC3

LC3



-30

-20

-10

0

10

20

30

40

50



T-Sc

ore

(C

FB)

Week 6 Week 12

Conclusion








Alois Alzheimer

Auguste D

-20

0

20

40

60

80

100

0 4 8 12 16

Week

DM

TS

12 s

ec d

ela

y (

C

FB

)


p=0067

p=0039

p=0064p=0038





Michael J Fox

Ronald Reagan



Muhammad Ali



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks



-30

-20

-10

0

10

20

30

40

50



T-Sc

ore

(C

FB)

Week 6 Week 12

Conclusion








Alois Alzheimer

Auguste D

-20

0

20

40

60

80

100

0 4 8 12 16

Week

DM

TS

12 s

ec d

ela

y (

C

FB

)


p=0067

p=0039

p=0064p=0038





Michael J Fox

Ronald Reagan



Muhammad Ali



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks



Alois Alzheimer

Auguste D

-20

0

20

40

60

80

100

0 4 8 12 16

Week

DM

TS

12 s

ec d

ela

y (

C

FB

)


p=0067

p=0039

p=0064p=0038





Michael J Fox

Ronald Reagan



Muhammad Ali



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks


-20

0

20

40

60

80

100

0 4 8 12 16

Week

DM

TS

12 s

ec d

ela

y (

C

FB

)


p=0067

p=0039

p=0064p=0038





Michael J Fox

Ronald Reagan



Muhammad Ali



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks


Michael J Fox

Ronald Reagan



Muhammad Ali



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks



Jarskog et al


2013 Jan 16 doi

101038npp201323 [Epub

ahead of print]





Javitt et al

Schizophr Res 2012

Apr136(1-3)25-31 doi

101016jschres201111001

Epub 2011 Dec 12







Others






Thanks


Thanks


autism, schizophrenia and alzheimer’s disease · autism, schizophrenia and alzheimer’s disease....

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