Alzheimer’s Disease: Amyloid Precursor Protein (APP) processing

Raf

sos

Grb2

PTB

Ras

MAPK

Ubiquilin

Mint - 2 Mint - 3Mint - 1

Fe65

AICD

C

PS1 / PS2

Pen-2Aph - 1α1

Aph - 1α2

Aph - 1βcleavage

activates

γ - secretase

γ - secretase

α - secretase

β - secretase

ADAM10

ADAM17

BACE1

BACE2

- 40

- 42

- 49

CLAC-P

Protease α2M

Aβ

AβAβ

AβAβ

Aβ

Protease IDE

Protease NEP

Protease PLG

N

APP

NCT

OLIGOMERIZATION DEGRADATIONCLEARANCE /

EXPORT

CYTOPLASM

Aβ

P3ApoE

ApoE

SH2

Shc

Aβ

Aβ

Aβ

Aβ Aβ Aβ

Aβ

Aβ

YENPTY

LRP

NOTCH

ErbB4

CD44

P75N

T

R

γ secretase

E-CADHERIN

InducesDbx1 cellsDbx2 cells

Txn of WntIgf2GLI-1PDGFRαPtc-1

Txn of MycAxinCycD1TGF-1PPARγCD44MMP-7etc.

Vertebrates Fly

DE

LTA1

DE

LTA2

DE

LTA3

DE

LTA4

JAG

GE

D1

JAG

GE

D2

CO

NTA

CT

IN

NB

3

DE

LTA

SE

RR

AT

ELA

G2

DSL1

C. elegans

NO

TCH

NO

TCH

TA

CE

NE

XT LR

P5/6

DA

LLY

DA

LLY - LIK

E

ME

GA

LIN

HIP

NIC

D

NIC

D

NICD

CycC, cdk8MAML

HATS

Hairless

Act-Ci Cos2

SuFu

SuFu SuFu

SuFu

SuFu

RepressorComplex

Fly

Vertebrates

Hes 1/3/5PreTαHey1/Hey2MAGCNPase

CBP, RBPjk (vertebrate)Su(H) (Fly)Lag 1 (C.elegans)

+Fbw7/Sel10

Proteosomaldegradation

CtBP

Slimb

KIF

Slimb

Rep-Ci

Fu

Act-Ci

Act-Ci

Act-Ci

Cos2

SuFu Fu

cAMPPS1/PS2 PEN-2 APH -1

Shh -Shh

Smo Ptc

Shh

SKN

GAS-1

Dhh Ihh

Cadherin

FZ

P

P PUb UbUbUb

Proteosomaldegradation

Palmitate

Cholesterol

NCT

WNT

β-catenin

β-catenin

β-catenin

β-catenin

β-catenin

α-catenin

GBP/Frat

p120

CK1

PP2A

GSK3B

PKA

PKA

CK1

Sgg

GSK3B

Axin

Pygo XSox17BCC9

CtBP

GrouchoSKIP

Syn3a CIR

SMRT

CtBP

LEF/TCF

LEF/TCF

APC

WntCerberus

WIF

Dkk

Frp

AKT Dsh

naked

GLI-2GLI-1 GLI-3

Groucho

CtBP

CSL

P P P P P

CSL

CSL

P

P+

Notch pathway shh pathway

wnt/β-catenin pathway

NUCLEUS

Neurogenesis signaling pathways: Notch | Shh | β-catenin

gene

transcription

Homer AdenylatecyclaseGi/q

Glutamate

mGLu

R

TrkA

/B/C

AM

PA/K

aina

te

P 2X1,

2, 3

p75NTR

Eph

rin

Eph

A/B

*

Anandamide

2-AG

CB1/2

i

GPCRs TYROSINE KINASES ION CHANNELS

PLCβ/γ PKC

PKK2

nNOS

Src

PDEI PKA

CREB

NFkB

GF

Rα

2G

FR

α1

GF

Rα

4G

FR

α3

Ne

urt

uri

nG

DN

F

Pe

rse

pin

Art

em

in BDNF

NGF

NT-3

NT-4/5

Neurotrophins

CalcineurinRhoA

ROCK

actin

RasGAP

FAK

ERK

Src

FRS2

PiP3/4

PTEN PKC

AKT/PKB

Ras

Raf

MEK

ERK

MEK 1/2

ERK 1/2

RSKELKGSK3

c-fos

BadASK1

MKK3/6

p38MAPK

MSK1

MAPK

DAG

* forward/reverse signalling

inhibitory pathway

NMDAR

Glutamate

ATP

Ca2+Na+ Ca2+

CaM

nNOS SynGAP

CaMK

IP3

released

Ca2+

released

RE

T

Ly

n

Fyn

NcK

Ep

he

xin

Grb4

Grb2

Src

SOS

PLC

γ

PI3

KPI3K Shc

PD

2R

GS

3

PSD95Gi

CR

EB

CR

EB

c-ju

n

c-fo

s

Ser133

CREB

CR

EB

CR

EB

CR

EB

CR

EB

Cell survival

Growth,

development &

differentiation

Cytoskeleton

dynamics, neurite

extension

Short term

plasticity

Long term

synaptic

plasticity (LTP)

Apoptosis

ER

PI3K

RacGTPase

JNK

NFκB

Grb2

SOS

RAS

PLC

γ

PI3

K Shc

CYTOPLASM

NUCLEUSCRE CRE CRE

gene transcription

AP1

GABA A

GlyR

nAChR

α /

β /γ

GABA ACh

Glycine

Cl-

Cl-

Cl-

HAP1

GRIF

1

GA

BA

RA

P

Gephyrin

Gephyrin

Rapsin

Syn

trophin

Inhibition

of signaling

Excitation

of signaling

Neurotransmission: Receptor and channel signaling

Parkinson’s Disease: Pathways

aggregation

UPSmisfolded

protein

E1

(Dorfin)(SIAH) O-linked

glycosylation

Neurodegeneration

Protofibrils

fibrils

mitochondrialDNA polymorphisms

ATPAmp+PPi

α-synuclein

substrates

Ub Ub Ub Ub Ub Ub Ub UbUb

Ub

Ub

Ub

Ubdegraded

protein

Ca2+

p25

Cdk5

CAK p35

c-Abl

Cdk5

UbUb

Ub

Ub

Ub

Ub

Ub

Ub

Ub

DJ-1PINK-1

Death stimuli

CalpainsCdk5-p25

αSP16

Lewy bodyDorfin P

Oxidative

stress

Nucleartargets

e.g MEF2 p53

Cytoplasmictargetse.g tau

NMDAR

Cellsurvival

Dopamine

oxidation

mitochondrial

dysfunction

Genetic Mutation

Toxicity

DA DA DA

PINK-1 S

DJ-1

Sp22α

tubulins

p38

Synphilin-1

cdcrel-1Cyclin E

CHIP

Synaptotagmin XI

PACRG

PGP9.5

UBL Ring 1 Ring 2IBR(Parkin)

Ubch8 E2 Ubch7

UCHL1

CYTOPLASM

Adapted from: He & KoprivicaAnn. Rev. Neuroscience 2004 (27: 341-68)

*NgR1 is activated when in a complex withLINGO-1 and p75 or LINGO-1 and TROY/TAJ

Growth conecollapse

Inhibition ofneurite outgrowth

Inhibition ofneurite outgrowth

Reorganizationof cytoskeleton

structures

Actinomyosincontractility

Actin assembly

Myelin inhibition

p75

p75 CTF

Amino Nogo

RIP

GDP

cAMP

PKA

Rac1

Arginase I

PI4P5K

PIP2

Polyamines

Cdc42

N-WASP

PAK1

MLC Kinase

Cdc42

GTP

Ca2+

Glial Cell

NeuronalGrowthCone

Ca2+

influx

Nucleus

?

LING

O-1

PKC

Rho G

EF

Rho G

DI

NgR

2

EphrinB

3E

phA4A

nnexin II

NgR

1*

GT

1b

GD

1a

TAJ/T

RO

Y

MLC

ROCK

RhoA

RhoA

MLCphosphatase

α secretase

γ secretase

Sema4D / CD100 NogoA / Nogo 66 OMgp MAG CspG

Unknow

n Receptor

PlexinB

1

CYTOPLASM

Axonal regeneration: Myelin inhibitors

Fas Ligand TNF Lymphotoxin TWEAK TRAIL CD95L

DC

R3

Fas

TN

FR

1

TR

AM

P

DA

XX

NIK

tBiD

tBiD

TR

AILR

DC

R 1/2

OP

G

FADD

FAD

D

FADDFADD

FADDFADD FA

DD

TRADD

FAF

v FLIPc FLIP

CD95

BAXBAKBCL2BAD

NOXA

Bcl-xL

PUMA

VDAC

SMAC

HTRA2

Cyto c

Cyto c

ROCK-1 FodrinGas 2

TRADD

RAiDD

CellShrinking

APAF1

APAF1

p53

Procaspase 8cleavage

ActivatedCaspase 8

ActivatedCaspase 8

ActivatedCaspase 8

Caspase 9

Caspase 3

Caspase 6

Caspase 3

Caspase 10

Caspase 2

Sphingomyelinase

Caspase 7

Caspase 9

Apoptosis

Lamin AD4GDJLamin B1/2, Rb,DNA-PK

Kinase

Lamin A

CeramideJNK

NFκB

cIAP

Caspase 6,7

BiD Cleavage

Cleavage

CYTOPLASM

Neurodegeneration: Role of mitochondrial and death receptor pathways

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