Animal Model of EA

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Alzheimers & Parkinsons

Disease Laboratory, Brain

& Mind Research Institute,

University of Sydney,100

Mallett Street, Camperdown,

NSW 2050, Australia.

Correspondence to J.G.

email:

[email protected]

doi:10.1038/nrn2420

Nucleus basalis of Meynert

A group of cholinergic nerve

cells in the basal forebrain, with

numerous projections to the

cortex.

Disinhibition

A reduced capacity to control

and coordinate the immediate

impulsive response to a distinct

situation.

Animal models of Alzheimers diseaseand frontotemporal dementia

Jrgen Gtz and Lars M. Ittner

Abstract | Insoluble protein aggregates have been linked to Alzheimers disease (AD) and

frontotemporal dementia (FTD). Recent work in transgenic mice has shed light on the role

of these aggregates by identifying soluble oligomeric species that may interfere with

essential cellular mechanisms at an early disease stage. This review summarizes what we

have learned about the roles of these proteins from transgenic mice and invertebrate speciessuch as flies and worms. Proteomic and transcriptomic analyses of tissue from these animal

models have identified new molecules with crucial roles in disease. Moreover, transgenic

animals have been instrumental in defining drug targets and designing novel therapeutic

strategies. With advanced imaging techniques that can be used in both humans and mice

an early, preclinical diagnosis of AD and FTD could be within reach.

Dntia is dfind as a lss f intllctal abilitis thatis sr ngh t intrfr ith scial r ccpatinalfnctining.Alzhirs disas (AD) is th st c-n cas f dntia, cprising 5070% f all cass.Frnttpral dntia (FTD) is lss cn, btaks p 50% f dntia cass prsnting bfr ag60 (REF. 1). At prsnt nithr can b crd.

Drgs that ar crrntl prscribd fr AD can hasr sid-ffcts in patints ith FTD2. Frthrr,FTD itslf inclds sral clinical ntitis that rqirbttr bichical charactrizatin. Thrfr, itis iprati t dlp tls that nabl an arl,diffrntial diagnsis.

Anial dls ha bn sfl in disscting thpathgnic chaniss f AD and FTD. Hr intrdc th nrpathlg, gntics and clinicalfatrs f AD and FTD, and dscrib hat halarnd abt ths disass fr transgnic rt-

brat and inrtbrat dls. This Ri fcss nrcnt dlpnts and ais t intgrat fnctinalgnics, nl iaging tchniqs and n cncptsin thrap.

A brief overview of AD and FTD

Clinical features.AD is charactrizd b arl rdficits, flld b th gradal rsin f thr cg-niti fnctins. Th st sr nrpathlgicalchangs ccr in th hippcaps, flld b thassciatin crtics and sbcrtical strctrs, incld-ing th agdala and nucleus basalis of Meynert3. Incntrast t AD, hich is charactrizd prdinantl

b r lss, FTD is assciatd ainl ithbhairal ipairnt sch as disinhibition, lss finitiati r apath. Lss f intrst in th nirn-nt, sr lss in dgnt and insight, ngligncf prsnal hgin, rbal and phsical aggrssi-nss, alchl abs, rstlssnss, hprralit andstrtpical bhair ar additinal fatrs fFTD4. Th arag ag f diagnsis f FTD is abt 60,hich is arnd 10 ars bfr th arag spradicAD (SAD) patint is diagnsd5,6. Patints ith FTDftn displa astrical atrph f th frntal andtpral crtx. Thr is idnc that tr nrndisas and FTD cxist, and that th tr sptsight prcd, cincid r fll th dlpnt fcgniti and bhairal changs1. Frthrr, lat-nst parkinsnis is bsrd in a significant sbstf patints ith FTD.

Neuropathology.Th AD brain is charactrizd b as-si nrnal cll and snaps lss at spcific sits7, asll as -alid plaqs and nrfibrillar lsins.Th ar prtin cpnnt f plaqs is th plpp-tid A that is drid fr alid prcrsr prtin(APP; BOX 1). Th nrfibrillar lsins cntain hpr-phsphrlatd aggrgats f th icrtbl-assciatdprtin ta and ar fnd in cll bdis and apicaldndrits as nrfibrillar tangls (NFTs), in distal dn-drits as nrpil thrads, and in th abnral nritsthat ar assciatd ith s -alid plaqs. NFTsar als abndant in FTD, in hich thr is an absncf rt plaqs8.

R E V I E W S

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b

a

c

APP PSEN1 TAU

APP (APP23) Tau (pR5)

APPswe

Tg2576 (hPrP)APP23 (mThy1.2)APPV717F

PDAPP (PDGF)

PSEN1M146I/M146I

APPsweTauP301L

3xtg-AD (mThy1.2)

TauP301L

JNPL3 (mPrP)pR5 (mThy1.2)TauP301S

P301S tau (mThy1.2)PS19 (mPrP)

A plaque NFTs

Mouse (APP23) Mouse (pR5)Human (AD) Human (AD)

Time(months)

Cortex

Amygdala

Hippocampus

transgnic ic (FIG. 1 and Spplntar InfratinS1 (tabl)). Ths incld N279K, K280, P301L, P301S,v337 and R406w.

Th xistnc f a sbgrp f patints ith FTD ithn ta aggrgatin as nigatic fr s ti. Thisdntia, charactrizd b ta-ngati and biqitin-psiti lsins, is n trd FTLD-u r FTDu-17,althgh th iplicatin f this nnclatr that thlsins in ta-psiti FTD ar biqitin-ngati isislading. mst cass f FTDu-17 ar spradic, tgrndbraking rk shd that FTDu-17 can bcasd b lss-f-fnctin tatins in progranulin(PGRN)18,19. Sn aftr, th TAR DNA-binding prtinTDP-43 as idntifid in biqitin-psiti inclsins

in bth FTLD-u and spradic atrphic latralscl-rsis (ALS), sggsting that th pathlg f ths tdisrdrs rlaps20. mtatins in th gn ncdingTDP-43, TARDBP, in bth failial and spradic cassf ALS ha sinc bn idntifid2123. Siilar t ta, thTDP-43 fnd in th lsins is hprphsphrlatd,biqitinatd and carbx-trinall trncatd20.

FTD ith inclsin bd path and Pagt disasf bn is a rar, atsal-dinant disrdr casdb tatins in alsin-cntaining prtin (VCP), anssntial cpnnt f th ERassociated degradation(eRAD) prcss24. TDP-43, bt nt vCP, acclats inth biqitin-psiti inclsins f this disrdr. TDP-43ths ss t b a cn pathlgical sbstrat in

aris tps f FTLD-u that ar casd b diffrntgntic altratins25. Nithr vCP nr TDP-43 ha bnxprssd in transgnic ic s far, and althgh PGRNknckt ic ha bn gnratd, aspcts rlatd tFTD ha nt bn addrssd26. T dat, 11 tatinsha bn idntifid in VCP, 9 in TARDBP, 62 in PGRNand 42 inMAPT17.

Transgenic mouse models of dementia

Th finding that, in th failial frs f AD and FTD,th gns that ncd th prtins that ar dpsitdin plaqs and NFTs (APPand MAPT, rspctil)ar tatd sggstd a casal rl fr ths prtinsin disas and ld t th gnratin f transgnic ani-al dls27 (Spplntar Infratin S1 (tabl)).Hr fcs n th st rcnt adancs and thn insights int th disas that ths dls hapridd. Fi rcnt k pblicatins ar highlightdin BOX 2.

Tau models. Th first ta transgnic s dl(Spplntar Infratin S1 (tabl)) xprssd thlngst han ild-tp (wT) ta isfr in n-rns28. Pretangle fratin and hprphsphrlatinf ta as bsrd. Hr, it as anthr 5 arsbfr th xprssin f han FTD tant P301L tarprdcd aggrgatin and NFT-fratin in ic29,30

(FIG. 1). Ths ic ha bc a idl sd tl tstd disas-rlatd pathgnic chaniss27,31 andrcnt dls ha bilt n thir sccss.

In an lgant std, it as shn that spprssinf P301L ta xprssin in rTg4510 ta transgnicic, hich nrall xprss th tant prtin at a

Figure 1 | rdg aq ad nFT tag m. a | Plaques are

produced by expressing mutant amyloid precursor protein (APP), as found in patients

with familial Alzheimers disease (FAD), both with and without mutantPSEN1, and

neurofibrillary tangles (NFTs) are produced by expressing mutant tau, as found inpatients with frontotemporal dementia with Parkinsonism linked to chromosome 17

(FTDP17). A few exemplary mutations are listed (grey boxes) together with their strain

names and the promoters (in brackets) that were used for expression (strains reviewed

in REF. 31). More strains are listed in the Supplementary information S1. b | Progression

of the pathology in APP23 and pR5 mice. NFT formation in pR5 mice is initiated in the

amygdala and eventually found in the hippocampus, whereas the cortex is virtually

spared. Plaque formation in the APP23 mice is prominent in the cortex and in the

hippocampus. This reflects, to some extent, the situation in the brain of patients with

AD, in which plaques and NFTs are anatomically separated. | Representative Aplaques from an APP23 and a human AD brain visualized with the dye thioflavin S are

shown on the left. For comparison, NFTs from a pR5 and a human AD brain, visualized

with the Gallyas silver impregnation technique, are shown on the right. These images

highlight the similarities of the brain lesions in transgenic mice and in patients with AD.

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ER-associated degradation

(ERAD). Pathway which targets

misfolded proteins from the

endoplasmic reticulum for

degradation by the

proteasome.

Pre-tangle

A somatic accumulation of

hyperphosphorylated tau

without fibrillar deposition.

Pretangles represent early

stages of NFT formation.

high ll, rrss bhairal ipairnts in thsic, althgh NFT fratin cntins32. This sg-gstd that slbl ta rathr than NFTs, is nrtxic(BOXES 1,2). It shld hr b ntd that n ndrths spprssd cnditins P301L ta xprssin asnl rdcd t lls cparabl t thr strains ftransgnic ic that xprss P301L ta ndr cn-

trl f a nn-indcibl prtr and dlp NFTs(Spplntar Infratin S1 (tabl)).

Bth ligdndrcts and astrcts cntain fila-nts ta inclsins in patints ith FTD. This asdlld in vivo b xprssing P301L and wT hanta ndr th cntrl f th 2 ,3-cclic ncltid3- phsphdistras and glial fibrillar acidic pr-tin (GFAP) prtrs, rspctil33,34. Bth strainsprsntd nrnal dsfnctin and axnal dgnratin,shing that glial ta pathlg als affcts nrns.

Nrnal lss is lr in th P301L ta dls than inP301S ta ic, cnsistnt ith th arl nst f FTDin patints carring th P301S tatin35(FIG. 1). In n

P301S strain, in hich th s prin prtin (PrP)prtr as sd, ta xprssin casd prnncdnrnal lss in sral brain aras and ntriclarnlargnt, as in patints ith FTD36. Ipaird sn-aptic fnctin and snaps lss prcdd nrdgn-ratin b sral nths. Frthrr, th incrasdctkin xprssin and arl icrglial actiatin snin this dl sggsts that nrinflaatin ight bassciatd ith ta pathlg36,37,38. In P301S ta ic,ta pathlg as attnatd and srial iprdpn inspprssin ith FK50636.

Takn tgthr, ths ta transgnic dls f FTDprd that FTDP-17 tatins acclrat ta aggrga-tin, and cas nr-cll dsfnctin and lss in vivo(Spplntar Infratin S1 (tabl)). Frthrr,ta transgnic ic dl an iprtant aspct f FTDssch as prgrssi spranclar pals (PSP) and crtic-basal dgnratin (CBD): th xhibit glial pathlgthat affcts nrnal fnctin, and hnc bhairalrad-ts39. Finall, ths transgnic dls ar als al-abl tls fr AD rsarch, as aspcts f thir pathlg

sch as snaps lss r inflaatin ar als fatrsf AD.

Modelling the Atau axis. mic xprssing tantAPP, hich rprdc -alid plaq fratin andr ipairnt, ha bc th st idlsd tl t std AD-rlatd pathgnic cha-niss in vivo (FIGS 1,2; Spplntar InfratinS1 (tabl)). A can prt a ta pathlg, althghrcnt data sh that ta rdctin blcks A-diatdtxicit40(BOX 2). Crssing th APP transgnic strainTg2576 ith th P301L ta transgnic strain jNPL3,r intracrbral inctin f th lng fr f A,A

42

, int a scnd P301L ta transgnic strain, pR5,incrasd ta phsphrlatin and a pr-xisting NFTpathlg30,41. Siilarl, NFT fratin as aggra-

atd b infsing jNPL3 ic intracrbrall ithbrain xtracts fr agd APP tant ic (APP23ic), r b crssing APP23 and jNPL3 ic42. Thisffct cld b diatd b th ta kinas glcgnsnthas kinas 3 (GSK3)43, hich als appars trglat APP prcssing44. Siilarl, stdis in iclacking th cis/trans-israsPIN1, hich dlatsta phsphrlatin45, ha rald that this nzprts th claag f APP b-scrtas46. Bcbining th xprssin f APPs and P301L tan a PSEN1m146v/ backgrnd th 3xtg-AD s

dl as gnratd; this dl clsl rcapitlatshan AD pathlg47(FIG. 1). Frthrr, a knck-in apprach as sd t crat th APP(SL)PS1KIic, hich cbins tatins in PSEN1 ithrxprsssin f a tant fr f han APP,rslting in a 50% lss f CA1 nrns at 10 nthsf ag48. Ths cbinatrial apprachs ha prnt b r sccssfl in dlling AD. Althgh

MAPT tatins ar nt fnd in FAD, xprssinf FTDP-17 tant ta tgthr ith tant APPrsltd in a cplt AD-lik pathlg in ic,hich cld nt b achid b r rxprssinf ithr wT r tantAPPaln.

Box 2 | Selected recent advances provided by animal models

Ta dt b A-mdatd txtyTau pathology in Alzheimers disease (AD) was thought to be downstream of A.However, slightly higher tau levels increase the AD risk162. When human amyloid

precursor protein (hAPP)-expressing mice were crossed onto tauknockout

backgrounds this prevented behavioural deficits, without altering the high A levels40.Tau reduction also protected mice against pentylene-tetrazole(PTZ)-mediated

excitotoxicity40

. Reducing tau levels could therefore be a powerful treatment option40

.Earlier findings in cultured hippocampal neurons derived from tau/and transgenic

mice support this notion139. A mechanistic explanation is eagerly awaited.

cmm mam f A ad Prions are infectious and intracerebral injection causes them to spread in the brain.

Intracerebral injections of AD-patient and APP23 transgenic brain extracts induced Adeposits in APP23 transgenic mice163. Subsequent injections of APP23 and APP/PSEN1

extracts into APP23 and APP/PSEN1 mice resulted in four different types of pathology.

This shows that, similar to prion disease159, exogenously induced amyloidosis depends

on both the host and the source of the agent, suggesting the existence of polymorphic

A strains reminiscent of prion strains163.

idb tag ytm t nFT t t

The rTg4510 tau transgenic model examined whether NFT formation is related to

functional impairment32. These mice express doxycycline-repressible human P301L

mutant tau and develop NFTs, neuron loss and behavioural impairment. Following a

reduction of transgenic tau, memory function was recovered and the number of neurons

stabilized, but NFTs continued to accumulate. This shows that elevated levels of tau

impair memory function but that NFTs are not sufficient to cause cognitive decline or

neuronal death.

T a f tx

Natural Aoligomers that disrupt cognitive function in rats165 were identified, followedby the A*56 species in Tg2576 mice164. The appearance of A*56 correlated withmemory loss at 6 months. A*56 infusion into young rat brains transiently disruptedshort-term but not spatial memory. A*56 impaired memory independently of Aplaquesor neuronal loss, and might contribute to cognitive deficits associated with AD164. A*56has since been correlated with memory impairment in additional APP mouse models 166.

BAce ba t

The role of the -secretase BACE as a therapeutic target in AD is contradictory. BACE isrequired to cleave A from its precursor but this study shows that it also has a role in

myelinating axons167. BACE is required for processing of neuregulin (NRG1), an axonallyexpressed factor required for glial cell development and myelination167and implicated in

schizophrenia168. It remains to be seen whether BACE has other substrates that are

associated with disease169.

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b

c

d

a MutantControl

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Session (day)

Meannumber

oferrors

co

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Numberof

correctchoices

1 2 3 4 5 6 7 8

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comt

Trial

Escapelatency(s)

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frequency(%)

X X

mt

Familiar objectNovel object

Secretase models. B gnticall intrfring ith - and-scrtas actiit, th rl f ths nzs in APPprcssing, A dpsitin and r ipairnthas bn stablishd, ith iplicatins fr tratntstratgis (Spplntar Infratin S1 (tabl)).Altring -scrtas actiit b xprssin f m146LPSeN1 in an APP transgnic backgrnd incrasdA

42fratin and dpsitin. Bhairal dficits

and nrnal lss r als bsrd, n bfr Aas dpsitd49,50. Srprisingl, this ffct as nr prnncd pn ral f ndgns sPSeN1 in PSeN1m146v/

knck-in ic, sggsting that

wT PSeN1 is prtcti51.Rdcing th actiit f th -scrtas BACe b

crssing APP transgnic ic nt a BACE/ back-grnd rdcd A fratin and dpsitin52,53,

Figure 2 | Baa tt d t a mmy ft AD m md. Behavioural tests are essential to

functionally validate Alzheimers disease (AD) models and assess treatments. Some routine methods to assess

hippocampusdependent memory functions are shown. a | The Morris water maze measures spatial reference memory.

Mice are trained in a circular pool filled with an opaque liquid. Distant visual cues are provided for navigation around thepool. A platform is hidden just below the water surface. Mice swim until they find the platform. There are different ways to

perform the test and also many parameters to assess memory, including path length and time to find the platform (escape

latency). The test can be divided into two phases, an acquisition phase followed by a reversal phase during which the

platform is moved to the opposite corner. b | The Ymaze measures spatial working memory. One arm is blocked off while

the mouse explores the other two arms for about 15 minutes. After several hours, the blocked arm is uncovered and the

mouse is allowed to explore the maze. Memory is judged to be better when the mouse does not enter the arm it has entered

before but explores the novel arm (X). | The radial arm maze measures shortterm working memory. During training, a

food pellet is placed at the end of each arm. In the test phase, which is without pellets, the mouse must go down each arm

only once to successfully complete the maze, using shortterm memory and spatial cues to remember which arms have

already been visited. d | In the novel object recognition test the mouse is placed in an enclosure where it is exposed to

two objects for a defined time. The mouse is removed and later retested in the same environment, in which one of the two

previously used objects has been replaced with a novel object. The time spent on exploring the new object is recorded and

reflects ability to remember what is new and what is old. co, control; mt, mutant.

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Drosophila melanogaster

Often simply termed

Drosophila, belongs to the

family of fruitflies and is widely

used as a genetic model

organism.

Hirano body

Intraneuronal, often rodlike

aggregate of actin and

associated proteins found in

certain neurodegenerative

disorders, such as Alzheimers

disease and Creutzfeldt

Jakob disease.

cnrsl transgnic BACe rxprssin incrasdA gnratin and plaq fratin in APP/BACeic54. BACE-dficinc als rrsd th bhairalchangs bsrd in sral APP transgnic strains52,55.exprssin f th -scrtas ADAm10 in APP trans-gnic ic als rdcd A fratin, aliratdbhairal dficits and nhancd LTP ipairnt,priding in vivo idnc fr ADAm10 as a fnctinal-scrtas56.

ApoE models. Th alllAPOE4 is a ar risk factrfr AD. Crssing APP transgnic PDAPP (platlt-drid grth factr prtr-xprssing APP) icnt anApoE/ backgrnd strngl rdcd A llsand dpsitin in th brain57, hras lntiiral dlirfApoE4 incrasd A fratin58. Th stat f Apelipidatin and slbilit als ipacts n alid-gnsis5961, as shn in thr indpndnt stdis thatcrssd diffrnt transgnic APP ic ith ic lackingATP-binding casstt transprtr A1 (ABCA1), a prtinthat rs chlstrl and phsphlipids fr clls

(Spplntar Infratin S1 (tabl)).ABCA1/ icha lr crbral Ape lls; hr, th rnantApe is ainl carbnat-inslbl, hich incrass itsalidgnic ptntial5961. TransgnicABCA1 r-xprssin in PDAPP ic significantl rdcd Alls and plaq brdn62.

Axonal transport models. Axnal transprt alng icr-tbls is diatd b kinsin and dnin prtins 63.Disrptd axnal transprt has bn iplicatd in thpathlg f AD and axnal transprt dfcts ha bnbsrd in ta and APP transgnic ic33,64,65. mrr,rdctin f kinsin light chain in Klc+/ ic incrasdaxnal dfcts and alidgnic APP prcssing hncrssd ith APP transgnic ic65. Bth ta and APPight b dirctl inld in axnal transprt: ta rg-lats tr-prtin binding t icrtbls and APPlinks tr prtins t cargs6668. Hr, t hatxtnt incrasd ta binding t icrtbls cntribtst th transprt dfcts in AD66, is nclar: in AD, ta ishprphsphrlatd, hich rdcs its assciatin ithicrtbls69. Anthr pssibilit is that ta intractsdirctl ith prtins f th tr cplx, thrbaltring axnal transprt70.

Beyond the rodent models

Studies in fruit flies. Inrtbrat dls, and in partic-lar th fl, ha rgd as a prfl tl fr stdingnrdgnratin71. A dzn diffrnt transgnic linscan b gnratd siltansl, liciting s nis-nss in rsarchrs rking ith ic. Hr highlights f th rcnt insights int disas pathlg thatha rgd fr this rk.

exprssin f ithr wT r R406w han ta in flisprdcs adlt nst, prgrssi nrdgnratin andpratr dath, and nhancs th acclatinand txicit f FTDP-17 ta xprssd pannrnall rin chlinrgic nrns72. Th nrdgnratin ccrsitht NFT fratin, hich is cnsistnt ith stdis

in ic32(BOX 2). A nrfibrillar pathlg ith tafilants as bsrd hn wT ta-xprssing flisc-xprssd th Drosophila melanogasterGSK3 kinashlg Shagg, indicating that incrasd taphsphrlatin prtd ta filant fratin73.This std highlights a rl fr GSK3 in diating thffcts f A n ta in AD40.

oxidati strss has bn iplicatd in AD and FTD.Gntic dnrglatin f antixidant dfnc pathasin R406w ta flis nhancd ta txicit and nrnaldath74. Adinistratin f th anti-xidant-tcphrl(itain e) spprssd ta-indcd nrtxicit. InR406w ta flis in hich xidati strss as indcd bgntic aniplatin f anti-xidant nzs, th c-jnN-trinal kinas (jNK) patha and th cll ccl ractiatd74. This links xidati strss t cll-ccl actia-tin and spprts th hpthsis that AD ight inla failr f itsis75. Data fr wT and R406w taflis sggst that cll-ccl actiatin is dnstra fta phsphrlatin and that actiatin f ToR (targtf rapacin kinas) b ta rxprssin indcd

nrdgnratin in a cll-ccl-dpndnt annr76.As A cass xidati strss ths findings als haiplicatins fr AD.

Fr a thraptic pint f i it is nclar hthrspcific ta kinass and phsphatass, r rallta phsphrlatin shld b targtd (FIG. 3). Spcificphsphrlatin sits in ta ha bn linkd t tatxicit and NFT fratin30,77, bt n rk inD. melanogasterindicats that ltipl phsphrlatinsits ight rk in cncrt t prt nrtxicit78.

Actin-cntaining Hirano bodies ar fnd in annrdgnrati disass and th ar prdi-nantl lcalizd t th CA1 rgin f th hippcaps.R406w ta-indcd nrdgnratin as shnt b assciatd ith th acclatin f filantsactin-cntaining rds79, an f hich cntaindcfilin and phsphrlatd ta. Rds r als fndin th brain f rTg4510 ic, in hich ta xprssinis indcibl79 (Spplntar Infratin S1 (tabl)),and th changs in actin strctr r shn t ccrdnstra f ta phsphrlatin79. Th ffcts f tar ptntiatd b A, and this snrgistic ffct alsrqird ta phsphrlatin79.

In D. melanogaster, th prtin cpnnts f-scrtas arhighl cnsrd80, hras -scrtasactiit is r l r absnt81. An APP-lik prtin(APPL) is prsntin flis, althgh, as in ic, th A

dain is nt cnsrd. Transgnic xprssin f wTr tatd han APP incrasd cll dath in th laralbrain81. This txicit dpndd n bth A and th car-bx-trinal tail f APP. Discssins abt th rlatitxicit f fibrillar, prtfibrillar and ligric A sp-cis ar nging. Th rcnt dlpnt f antibdisthat ar spcific fr distinct tps f aggrgats, ightprid a tl t addrss this qstin8284.

ubiqilin ariants ha bn assciatd ith anincrasd risk fr SAD85, bt indpndnt stdisar aaitd t cnfir thir rl. In D. melanogaster,rxprssin f biqilin rscd a dgnrati phntp casd b rxprssin f prsnilin and

R E V I E W S

http://ca.expasy.org/uniprot/O35598http://ca.expasy.org/uniprot/P41233http://ca.expasy.org/uniprot/P92208http://ca.expasy.org/uniprot/P14599http://ca.expasy.org/uniprot/P14599http://ca.expasy.org/uniprot/P92208http://ca.expasy.org/uniprot/P41233http://ca.expasy.org/uniprot/O35598


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|

Human APP1

Human

Zebrafish

Mouse

Chimpanzee

EVKMDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKK

EVKMDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKK

ELRMEAEERHS---EVYHQKLVFFAEDVSSNKGAIIGLMVGGVVIATIIVITLVMLRKK

EVKMDAEFGHDSGFEVRHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKK

a

b Human tau1 441

P P P P PPPP

Human

Zebrafish

C. elegans

Mouse

Epitope

APKTPPS SPGSPGTP GS R SRTPSLP T V VRTPPKSPSS KIGSTEN/KIGSLDN VYKSPVVSGDTSPRH MVDSPQL

MVDSPQLVYKSPVVSGDTSPRHKIGSTEN/KIGSLDN

KIGSTEN/KVGSLEN

KIGSLDN/KVGSTAN

KVGSVTN/KVGSKTN

VVRTPPKSPSA

VVRTPPKSPGS

RSRTPSLPTSPGSPGTPGS

SPASRSSTPG

SPKTPPG

PVKTPTS

+

+

+

276 317 770

-secretase -secretase -secretase

A

A40/42

AT270 CP13/AT8 CP3/AT100 TG3/AT180 12E8 PHF1 pS422181 422404396262 356231 235212 214202 205

170 411393385251 345220 224201 2031 91 19 4

163 224131 135114 118

110

2x297 ( 325) 356 ( 384)

184 ( 243 ) 275 ( 305)Drosophila 2x

Rational mutagenesis

Targeted mutation of a gene of

interest based on previous

analysis (for example,

sequence alignment or

functional domains/motifs),

often using sitedirected

mutagenesis.

Caenorhabditis elegansA roundworm (nematode) that

has become a major model

organism for molecular and

developmental biology.

Modifier screen

Screen in which random

mutations are introduced into

an organism with a preexisting

phenotype, using a mutagen

such as NethylNnitrosourea

(ENU). Mutants that modify

(enhance or suppress) the

preexisting phenotype are

then isolated.

RNA interference

(RNAi). A method by which

doublestranded RNA is used

to cause rapid degradation of

endogenous RNA thereby

precluding translation. This

provides a simple way of

studying the effects of the

absence of a gene product.

Forward genetic screen

A genetic analysis that

proceeds from phenotype to

genotype by positional cloning

or candidategene analysis

c-xprssin f biqilin ith han APP rdcdAPP lls86.

Th rlati cntribtin f th t frs f A(A

40and A

42) t disas is a attr f dbat. In

D. melanogaster, A42

xprssin casd th fratinf diffs alid dpsits, ag-dpndnt larning dfi-cits and nrdgnratin. A

40casd siilar larning

dficits itht aggrgatin and nrdgnratin87.Rational mutagenesis applid t th A

42pptid cnfird

that th rat f aggrgat fratin in vitro is linkd tbrain txicit88. Frthrr, flis xprssing wT A

42

r e22G A42

had a dian srial f 24 and 8 das,rspctil, hras A

40-xprssing flis had a dian

srial f 30 das, indicating that A40

is nn-txicand pssibl prtcti87.

In hans, PSENtatins cas FAD ith an agf nst ranging fr 24 t 65 ars. whn PSENta-tins r intrdcd int D. melanogaster PSEN, th

actiitis f th tant prsnilins r linkd tth ag f nst f AD, sggsting that disas srit inhans is casd priaril b th tatins and nt bnlinkd gntic r pigntic difirs89.

D. melanogaster is an xcllnt sst fr drgscrning. Th flis shrt lifspan, cbind ith thirsall siz and l cst, alls a singl labratr tkp sral hndrd thsand siltansl90. Frxapl, t dlp -scrtas inhibitrs as AD drgs,sid-ffcts rlatd t ipaird Ntch signalling nd tb prcldd. Th binding sit f th -scrtas inhibi-tr DAPT is cnsrd in D. melanogasterand DAPTadinistratin cass a phntp siilar t that licitd

b tatins in th Ntch signalling patha, sggst-ing that D. melanogasteris a sitabl sst fr in vivopr-scrning f candidat -scrtas inhibitrs91.

Studies in nematodes.Caenorhabditis elegans als has ashrt lif span and modifier screens and RNA interference(RNAi) ar asir in rs than flis, as th can bgrn n agar plats cntaining gnticall difidbactria. Hr tlin s f th as in hichths xprints ha nhancd r ndrstanding fAD and FTD.

exprssin f wT and tant ta in C. elegans ladst bhairal and snaptic abnralitis, ith tantta casing an arlir and r sr phntp92,93.Th rl f th ta biqitin-ligas CHIP in th fra-tin f inslbl ta filants (hich as first shn inic), as cnfird b rslts f an RNAi-diatddnrglatin f CHIP in natds94. In additin,

th C. elegans hlg f th ctskltal rglatrprtin enabld, uNC-34, as idntifid b a forwardgeneticscreen fr tatins that alirat th ta-indcd crdinatin phntp95. C. elegans asals instrntal in idntifing aph-1 and pn-2 ascpnnts f th -scrtas cplx96.

egg-laing in C. elegans is cntrlld b a sipltr prgra and ths, prids a straightfrardrad-t f tr bhair97. A dfcti gg-laingphntp can b casd b tatins in th PSENhlg, sel12. A suppressor screen rald that atranscriptin factr, a histn dactlas and a histndthlas cld spprss th gg-laing dfct and

Figure 3 | sq agmt f A ad ta fm tbat ad tbat . a | Sequence alignment of

A and flanking sequences from the human, chimpanzee, mouse and zebrafish. Owing to the sequence, all but mouseamyloid precursor protein (APP) can be proteolytically cleaved to form A

40/42. b | The longest human tau isoform, htau40,

contains two aminoterminal inserts (blue) and four microtubulebinding domains (green). Routinely used

phosphorylationdependent antitau antibodies are listed (grey boxes) along with the respective phosphorylationsite

and flanking sequences. As can be seen from the alignment of the tau sequences in five species, mouse and human tau are

highly homologous, which explains why most of the phosphorylationdependent antibodies that are listed react with both

human and murine tau.

R E V I E W S

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=172303&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=172303&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum


8/13

Suppressor screen

A system used to identify

genes that, when

overexpressed, lead to the

suppression of a mutant

phenotype.

Transcriptomics

Largescale studies of the

expression of genes at

the mRNA level, typically

carried out using microarray

technology.

Proteomics

Largescale studies of the

proteome, which comprises all

proteins produced by an

organism or system. This might

also include the analysis of

protein function, structures

and secondary modifications,

using techniques such as

massspectrometry.

Mass-spectrometric analysis

A technique used to identify

and measure biological and

chemical compounds. It

involves ionization, followed

by the use of a magnetic or

electrical field. Applications

include the identification ofproteins and sequencing

of oligosaccharides.

State 3 respiration

Active respiration after adding

a limited amount of ADP. The

rate after all the ADP has been

phosphorylated to ATP is

termed state 4 respiration.

Uncoupled respiration

Respiration upon adding a

reagent such as oligomycin

(complex V inhibitor) that

uncouples from ATPase.

hnc rsc th tant prsnilin-rlatd phntp98.A rlatil high thrghpt thd f assssing gg-laing has bn dlpd b asring th chitinasthat is rlasd b hatching ggs99.

Animal models and functional genomics

Transcriptomics and proteomics ar incrasingl bingapplid t bth patints and anial dls f AD andFTD, hr th ha alld th idntificatin f nldiffrntiall rglatd gns and prtins100(FIG. 4).Ths thds can b sd t r-dfin and sbdiidAD and FTD n th basis f bichical critria. Thanalzd atrial inclds han brain, crbrspinalflid (CSF) and plasa, as ll as tiss cltr clls andbrain and spinal crd tiss fr anial dls 101,102.whras transcriptics ffrs th pssibilit f xa-ining singl clls r n sbclllar cpartnts,prtics has nt t attaind this ll f snsitiit101.Hr, dscrib h th analsis f anial dls bths tchniqs has cntribtd t th ndrstandingf AD and FTD.

Wild-type mice provide the setting. T prid a fra-rk fr th analsis f transgnic brains it is snsiblt analz wT ic and idntif sbrgin- r clltp-spcific transcripts. In anial dls, tiss canb dissctd itht th pstrt dla rqirdfr han tiss. whn sbrgin-spcific RNA tran-scripts r cpard ithin th s hippcaps,th axial diffrnc bsrd as 7.6-fld (thatas Est1 nrichd in dntat grs) and n gn asxclsil xprssd in an n rgin103. A rlatdstd cpard gn xprssin in th crtx, crbl-l and idbrain, and shd that lss than 1% fth gns xaind r nrichd in an ara104. Thhippcaps, agdala and ntrhinal crtx shdsiilar xprssin prfils104. Anthr std idnti-fid diffrntiall nrichd gns in th agdala thatxhibitd bndaris f xprssin crrspnding tct-architctnicall dfind sbncli105. Althghrginal gn/prtin xprssin diffrncs ar nt thsl basis f slcti lnrabilit, stdis lik ths,tgthr ith dtrining diffrntial actiit pat-trns, shld hlp s t ndrstand h crtain brainrgins ar r prn t dgnratin in disasssch as AD and FTD.

Focusing on mitochondria. Sral xplanatins f th

nrdgnratin fnd in AD ha bn prpsd,s f hich ha als bn als iplicatd in FTD.Gntic, clinical and bichical idnc spprtsth alid cascad hpthsis in FAD106, hras thxidatin daag hpthsis is attracti in SAD. Thishpthsis rlaps ith th axn transprt failrhpthsis: itchndria ar bth a targt and srcf racti xgn spcis (RoS) and thir transprt isipaird in disas107.

A massspectrometric analysis f pR5 ic (FIG. 1)rald drglatin f itchndrial rspiratrchain cplx cpnnts (inclding cplx v) andantixidant nzs, and itchndrial dsfnctin108.

Frthrr, dcrasd cplx v lls ha bnfnd in th brains f patints carring th P301L tatatin108. Stdis n Sod2/ ic that lack th dtxi-fing nz sprxid distas 2 shd that it-chndrial strss can cas ta hprphsphrlatin109.This iplis that a icis ccl f altratins in ta andxidati strss can cas nrdgnratin.

Crssing transgnic ic rxprssing th it-chndrial nz A-binding alchl dhdrgnas(ABAD) ith APP tant j20 ic has bn shn tcas th gnratin f RoS and spatial larning andr dficits110. As AD is assciatd ith snapsfailr7, snaptsal fractins fr Tg2576 icha bn analzd b ass spctrtr111(FIGS 1,4).Significant diffrncs r fnd in mitochondrialhsp70. whn snaptic and nnsnaptic itchndriar prifid fr Tg2576 brains and cpard,nrs diffrncs in th prtin sbnit cpsi-tin f rspiratr chain cplxs I and III r fnd.Fnctinal xainatin rald ipairnt in state 3respiration and uncoupled respiration in brain itchndria

fr ng Tg2576 ic111, siilar t ths bsrd inpR5 ic108. As this ipairnt ccrrd bfr NFTfratin and A plaq dpsitin, itchndria arthght t b arl targts f A and ta aggrgats.

Focusing on stress response and inflammation. Anprglatin f xidati strss-rlatd, apptsis-rlatdand pr-inflaatr signalling gns has bn fndin th CA1 rgin f th brains f patints ith AD112.Siilarl, in thr APP transgnic dls, gns ncdingprtins inld in th in rspns, carbhdrattablis and prtlsis r drglatd. ScrningjNPL3 ic (FIG. 1) idntifid drglatd inflaatindiatrs and apptsis inhibitrs113. In th pR5 strain114,

glyoxalase I(GLo1) as fnd t b th nl prglatdgn115. Glxalas I is ssntial fr th dtxificatinf dicarbnl cpnds, prnting th fratin fadancd glcatin nd (AGe) prdcts that prt thfratin f RoS. Cparati prtics applid tA

42-tratd P301L ta xprssing nrblasta clls

and th agdala f pR5 ic strtaxicall inctd ithA

42idntifid prtins inld in th strss-rspns

that ar assciatd ith prtin flding, incldingvCP116. In bth ic and D. melanogaster, a prcin-snsiti ainpptidas (PSA) as idntifid as a sp-prssr f ta-indcd nrdgnratin. Hr,nlik ta, PSA did nt altr APP lls in vitro117.

PSA is th ar pptidas rspnsibl fr digstingplgltain sqncs rlasd b prtassdring prtin dgradatin.

Learning and memory-related genes. whn APP/PSeN1transgnic ic r analzd fr diffrntial RNAxprssin sral gns that ar ssntial fr lng-trptntiatin (LTP) and r fratin r fndt b dnrglatd in A plaq-cntaining aras. Asthr r n apparnt changs in snaptic strctr,r lss in ths ic ight dl th arl rdsfnctin that is sn in patints ith AD bfrsnapss and nrns dgnrat118. epidilgical

R E V I E W S

http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2739&ordinalpos=4&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2739&ordinalpos=4&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSum


9/13

|

AD mouse model

in vitro

Cell culture

Human tissue

Brain (dissection)

LC-Nanospray

Sample preparationand fractionation

Gene-chip(mRNA; miRNA)

2D-PAGE Antibody arrayMultiplex western

Mass spectrometry

Validation

Mouse models

N

N

N N

S

NN

N

N H

O

Cl

idnc sggsts that actiit and xrcis ar crrlatdith a latr nst f AD and placing APP/PSeN1 tanttransgnic ic in an nirnntall nrichd nirn-nt significantl rdcd th A plaq brdn. man

f th gns that r spcificall prglatd in APP/PSeN1 tant ic liing in th nrichd nirnntar inld in larning and r, nrgnsisand cll srial pathas, ipling that actiit has apsiti ffct n plasticit-rlatd gns119.

Althgh s fnctinal gnics stdis f trans-gnic dls f dntia ral f drglatd gn/prtin-catgris, thrs indicat that an fnctinalcatgris ar drglatd, ftn rlatd t prcsssknn t b iprtant in AD pathphsilg120.This is, in part, d t diffrncs in tiss cplxit,statistical stringnc and anntatin sftars101. Thchallng fr th ftr is t idntif arl changs bthith rspct t ag f nst and th tiss r clllarcpartnt in hich pathlg is initiatd, hich illffr th pssibilit f a targtd intrfrnc ith thdisas prcss.

Imaging animal models

Th clinical diagnsis f AD and FTD rains agand inclds rcrding th patint histr, xclsin

f dprssin and thr cass f dntia, labratrtsts (t rl t diabts fr xapl), nrlgicaland ntal xainatins and incrasingl, iagingtchniqs. Th tchniqs that ar sd fr prclinicaldiagnsis incld positron emission tomography (PeT),computed tomography (CT), magnetic resonance imaging(mRI) and multiphoton imaging. Althgh ltiphtniaging is cpatibl ith han and s tiss nrns and A plaqs ha a siilar dinsin inbth spcis th frr tchniqs rqir a highrrsltin in anials d t thir ch sallr brainstrctrs. In principl, iaging in anials prids atl t nn-inasil nitr pathlgical changs andt crrlat ths ith bhairal changs.

visalizing A dpsitin in vivo ight cntribt ta dfiniti diagnsis f AD and t nitring th sc-css f tratnts. An arl prb as a d calld BSB((trans,trans)-1-br-2,5-bis-(3-hdrxcarbnl-4-hdrx)strlbnzn), hich as sd t labl Aplaqs in Tg2576 ic121. In rcnt ars th nlPeT tracr 11C-lablld Pittsbrgh Cpnd-B (PIB),hich binds t A plaqs, has arsd significantattntin122. PIB as shn t ntr th brain qickland labl plaqs ithin ints123. It as sd as aPeT tracr in APP transgnic ic bt initiall faild trflct th ant f A124. entall, in APP23 ic,an ag-dpndnt incras in radiligand binding as

fnd t b cnsistnt ith prgrssi A accla-tin125. Iprtantl, A rdctins pn accinatinith an anti-A-antibd r rflctd b rdcdbinding f11C-PIB.

Hr, thr ar sral liitatins f PeT,inclding a high ariabilit in nral cntrls, lspatial rsltin, th nd fr prbs that st bsnthsizd, prifid and qickl sd, and th highcst. In additin, PeT stdis rqir p t 45 intsf scanning, hich pss particlar prbls fr thldrl and patints ith dntia. B cntrast, mRI isp t 50-fld chapr, th rsltin is high, th prbsr cntrast nhancrs can b strd fr xtndd

Figure 4 | Aat f fta gm t AD m md. Functional

genomics is increasingly being applied to animal models of Alzheimers disease (AD) 100.

In most instances some kind of prefractionation is required to reduce the complexity

of the sample or to remove overtly abundant mRNAs or proteins. Prefractionation can

be at the level of subcellular compartments, based on biochemical or biophysical

characteristics, or by dissecting subregions of the brain. Genechips determine

differences in mRNA and, more recently, in micro RNA (miRNA) levels100. Mass

spectrometry might involve prior separation on twodimensional polyacrylamide gels

(2DPAGE) and cutting out of protein spots or, alternatively, protein mixtures might be

fed, through liquid chromatography (LC)nanospray, directly into the massspectrometer. Antibody arrays and multiplex Western blotting are biased massscale

approaches to quantitatively determine differences in protein levels and post

translational modifications, such as phosphorylation. Functional genomics data are

highly dependent on a proper normalization and validation, both functionally and in

human and animal tissue; this can be done using techniques such as Western blotting

and immunohistochemistry101.

R E V I E W S



10/13

Positron emission

tomography

(PET). In vivo imaging

technique used for diagnostic

examination that involves the

acquisition of physiological

images based on the detection

of positrons, which are emitted

from a radioactive substance

previously administered to thepatient.

Computed tomography

Imaging technique that exploits

the differences in absorption of

Xrays by different tissues to

give highcontrast images of

anatomical structures.

Computed tomography has

relatively poor softtissue

contrast, so iodinated contrast

agents, which perfuse different

tissue types at different rates,

are commonly used to

delineate tumours.

Magnetic resonanceimaging

A noninvasive method used to

obtain images of living tissue. It

uses radiofrequency pulses

and magnetic field gradients;

the principle of nuclear

magnetic resonance is used to

reconstruct images of tissue

characteristics (for example,

proton density or water

diffusion parameters).

Multiphoton imaging

A noninvasive form of

microscopy in which a

fluorochrome that wouldnormally be excited by a single

photon is stimulated quasi

simultaneously by several

photons of lower energy. Under

these conditions, fluorescence

increases as a function of the

square of the light intensity,

and decreases approximately

as the square of the distance

from the focus. Because of this

behaviour, only fluorochrome

molecules near the plane of

focus are excited, greatly

reducing light scattering and

photodamage.

prids and thr is n radiacti xpsr126. whnTg2576 ic r adinistrd th 19F-cntainingalidphilic Cng rd-tp cpnd FSB((e,e)-1-flr-2,5-bis-(3-hdrxcarbnl-4-hdrx)strlbnzn)intransl, A plaqscld b isalizd b mRI. Frthrr, agnticrsnanc spctrscp can b sd t asr altra-tins in tablits that ar prgnstic arkrs frnrdgnratin127.

what is n ndd ar PeT tracrs fr pathlgi-cal strctrs thr than plaqs (sch as th NFTs), ata rsltin that is cpatibl ith th siz f sbrain strctrs. It is xpctd that iaging, tgthrith th dlpnt f biarkrs in CSF and bld,ill lad t an arl diffrntial diagnsis f AD.

Therapeutic strategies

Thr is n cr fr AD r FTD and th aailabl trat-nt is nl sptatic. Hr, clinical trials thatar basd n th ndrling bilg f disas ar nth a (s Frthr infratin). Ths incld ac-

cinatin, anti-inflaatr drgs and dlatrsf fratin, aggrgatin and claranc f A andta. man f th n thraptic stratgis ha thirfndatin in transgnic anial rk128; highlighta f f ths hr.

Vaccination targeting A. vaccinatin trials targtingA in ic and hans ha bn rid in REF. 129.In brif, bth acti and passi accinatin strat-gis ha bn sccssfl in A plaq-fring ic.vaccinatin f ng PDAPP ic ith th A

42pp-

tid, fr xapl, prnts th dlpnt f nriticA plaqs, and in ldr ic it significantl rdcsth130. An A-dirctd passi accinatin apprachas als ffcti131. vaccinatin rdcd ag-dpndntlarning dficits, hich crrlatd ith rdctins inbth slbl A and ta132.

encragd b th fficac in ic, a clinical trialas lanchd ith AN-1792-cntaining pr-aggrgatdsnthtic A

42and th adant QS-21 (REF. 133).

Th Phas IIa trial as haltd pratrl as 6% fth patints h had rcid th accin dlpdningncphalitis; hr, as s patints dl-pd A-antibd titrs that crrlatd ith a sldcgniti dclin134, th dlpnt f antibd frag-nts and hanizd A-spcific antibdis is ngingand s ar crrntl in clinical trials (s Frthr

infratin).

Reduction of tau. At first sight, a ta-dirctd ac-cinatin apprach ds nt appar fasibl, bcasta is priaril an intraclllar prtin. Thrfr itas srprising, and ncraging, t find that accina-tin f jNPL3 ic ith a ta pptid cntaining thPHF1 phsph-pitp rdcd aggrgatd ta llsand sld prgrssin f an NFT-rlatdtr ph-ntp135. In this std, anti-ta antibdisntrd thbrain and bnd t pathlgical ta136. An indpndntta accinatin std is aaitd and clinical trials hant t startd.

T cpnsat fr th lss f tas icrtbl-stabilizing fnctin (as hn it is phsphrlatd ithas lss icrtbl-binding capacit), intrapri-tnal inctins f th icrtbl-binding andstabilizing drg paclitaxl, r adinistrd t icrxprssing wT ta137. This rstrd fast axnaltransprt in spinal crd axns and aliratd tripairnt 137. whn NFT-fring P301S ta ic(PS19 ic, Spplntar Infratin S1 (tabl)), inhich icrglial actiatin prcds NFT fratin,r tratd ith th inspprssant FK506, anincras in srial, an attnatin f nrinfla-atin, and an aliratin f th ta pathlgas bsrd36. Siilarl, FK506 iprd rfnctins in Tg2576 ic138. Anthr rcnt findingis that th incrasd lthalit f A-prdcing trans-gnic ic cld b prntd b brding th APPtransgn nt a ta-dficint backgrnd (BOX 2). Thisstrngthns th ida that a rdctin f ta cld b anffcti tratnt stratg fr AD40,139.

Role of diet. Th rl f dit in prnting AD hasgaind incrasd rcgnitin. Calric rstrictin (CR)rdcd A plaq nbrs in t APP transgnicstrains and rdcd astrct actiatin140. Bth intr-ittnt fasting and CR aliratd th bhairalphntp f 3xtg-AD ic141. A lls and ta phs-phrlatin r nt altrd in th intrittnt fast-ing grp, sggsting that this stratg ight pridprtctin dnstra f ta and A.

on prtin iplicatd in CR-diatd lngitis th dactlas sirtin 1 (SIRT1). whn ic r-xprssing p25, an actiatr f th ta kinas cdk5, rinctd ith th anti-xidant rsratrl, hippcapalnrdgnratin as rdcd, larning dficin-cis r prntd and a dcras in th actlatinf th knn SIRT1 sbstrats PGC-1 and p53 asbsrd142.

othr ditar stratgis incld th s f anti-xidants sch as Ginkgo biloba r th grn ta c-pnnt pigallcatchin-3-gallat, hich rdc Agnratin in Tg2576 ic, pssibl b actiating th-scrtas patha143. A dit nrichd in ga-3plnsatratd fatt acids (PFAs) rdcd A plaqsin Tg2576 ic pssibl b inflncing th latralbran bilit f APP and its scrtass, as llas scrtas actiit144. Zinc tablis has als bniplicatd in -alid plaq fratin145. Nnatal

ga-3 PFA dficinc casd rxprssin f thzinc transprtr ZnT3 in rats and altratins in brainand plasa zinc lls145.

whthr r gring ndrstanding f th ipr-tanc f dit in AD ill lad t lifstl changs isqstinabl; hr th finding that drat cn-sptin f rd in attnats A nrpathlg andr ipairnt in Tg2576 ic ight b asirt translat int dail practic146. whthr th rd inshld b cnsd ith A-xprssing transgnicptats, th fding f hich has bn shn t licitan in rspns and partiall rdc A plaqs inTg2576 ic, rains t b sn147.

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Other strategies targeting Aand tau. Frthr thrapticstratgis that ha bn tstd in ic incld rdcingA prdctin b inhibiting - and -scrtas acti-it, r b prting its claranc thrgh nprilsin rinslin-dgrading nz148. othr thrapis plth s f scarinic agnists and chlating agnts149,150.Antixidants and inhibitrs f th prtass caspas-3 andcalpain ha bn cnsidrd, as APP and ta ar bthsbstrats f ths nzs151. Siilarl, nn-stridalanti-inflaatr drgs (NSAIDs) ar cnsidrd frtratnt and prntin f AD and ha bn tstd inanial dls152. As ta is hprphsphrlatd in bthAD and FTD, kinass ar prising targts, althghtargting ths nzs is nt triial, bcas th haltipl sbstrats in an rgans44. Lithi is sd ttrat biplar disrdr and thr is cnflicting idncrgarding hthr it is ffcti in AD. Chrnic adin-istratin in agd 3xTg-AD ic rdcd ta phsphr-latin b rdcing GSK3 actiit, bt did nt altr Alls r r fnctins153. In a rlatd std lithirdcd APP phsphrlatin and hnc, A lls154.

whn all tratnt stratgis in ic ar cnsidrd cncld that anial xprintatin is absltlssntial. Hr, th lssn larnd fr th A-dirctd accinatins is t b particlarl carfl in dirctltranslating anial findings t th han patint.

Outlook

Anial dls cntin t ha a cntral rl in ADrsarch. Rcntl, a ar fcs has bn n cbi-natrial apprachs that rl n a liitd nbr fbasic dls ith a prnncd pathlg. Th dlsight nt accratl rprdc th anatical distri-btin f th lsins in han brain, bt bichicallth ar r siilar t th han cnditin. As faras r and tr fnctins, nranat andth ndcrin sst ar cncrnd, th s dlsar sprir t th inrtbrat ns. Hr, rcntrk in inrtbrat spcis highlights thir adantagsfr disscting signalling pathas, prfring di-fir scrnings r analzing failis f tatins inparalll.

what ill th ftr bring? w xpct that thr illb a idr applicatin f iaging tchniqs t anialdls. Sral tas ha applid fnctinal gnicst thir dls and ith th adnt f antibd arrasand th rging rl f iRNAs bcing clar, it islikl that th cing ars ill s a assi incras

in th s f ths tchniqs. Th nar ftr ill shhthr th crrnt clinical trials ill b fritfl andlad t a ral cr f AD and FTD. Finall, nxpctdrslts in anial dls cld rtrn s f thcrrnt hpthss.

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AcknowledgementsWe apologize to those whose work has not been cited due to

space limitations. J.G. is a Medical Foundation Fellow. This

work has been supported by the University of Sydney, theNational Health & Medical Research Council (NHMRC), the

Australian Research Counci l (ARC), the New South Wales

Government through the Ministry for Science and Medical

Research (BioFirst Program), the Nerve Research Foundation,

the Medical Foundation (University of Sydney) and the Judith

Jane Mason & Harold Stannett Williams Memorial

Foundation to J.G. and the ARC, NHMRC and Deutsche

Forschungsgesellschaft (DFG) to L.M.I.

DATABASESEntrez Gene:http://www.ncbi.nlm.nih.gov/entrez/query.

fcgi?db=gene

APOE| GLO1|MAPT|PGRN|PSEN1|PSEN2|TARDBP|VCP|

OMIM:http://www.ncbi.nlm.nih.gov/entrez/query.

fcgi?db=OMIM

Alzheimers disease | amyotrophic lateralsclerosis |

frontotemporal dementia |

UniProtKB:http://ca.expasy.org/sprot

ABCA1|ADAM10|APP |APPL | BACE|CHIP|GSK3 |JNK |PIN1|SIRT1|tau | TDP43 |

FURTHER INFORMATIONJrgen Gtzs homepage:http://www.bmri.org.au/

alzheimer.html

Alzforum index of drugs in clinical trials:http://www.

alzforum.org/drg/drc/default.asp

SUPPLEMENTARY INFORMATIONSee online article:S1(table)

All links Are AcTive in The online pDF

R E V I E W S
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genehttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=genehttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=348&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2739&ordinalpos=4&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2739&ordinalpos=4&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4137&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4137&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4137&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2896&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2896&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5663&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5664&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5664&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5664&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23435&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23435&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7415&ordinalpos=1&itool=EntrezSystem2.PEntrez.Gene.Gene_ResultsPanel.Gene_RVDocSumhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIMhttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIMhttp://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=104300http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=105400http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=105400http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=105400http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600274http://ca.expasy.org/sprothttp://ca.expasy.org/sprothttp://ca.expasy.org/uniprot/P41233http://ca.expasy.org/uniprot/P41233http://ca.expasy.org/uniprot/O35598http://ca.expasy.org/uniprot/O35598http://ca.expasy.org/uniprot/O35598http://ca.expasy.org/uniprot/P05067http://ca.expasy.org/uniprot/P05067http://ca.expasy.org/uniprot/P145

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