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Transgenic animal models of neurodegenerative diseases and their application to treatment development 
☆
Edward Rockenstein
a 
, Leslie Crews
 b
, Eliezer Masliah
a,b,
⁎
a 
 Department of Neurosciences, University of California, San Diego, La Jolla, California, USA
 b
 Department of Pathology, University of California, San Diego, La Jolla, California, USA
Received 22 May 2007; accepted 29 June 2007Available online 17 August 2007
Abstract
 Neurodegenerative disorders of the aging population affect over 5 million people in the US and Europe alone. The common feature is the progressiveaccumulationofmisfolded proteinswiththeformationoftoxicoligomers. Previousstudiesshowthatwhile inAlzheimer's disease(AD)misfolded amyloid-
β
 protein accumulates both in the intracellular and extracellular space, in Lewy body disease (LBD), Parkinson's disease (PD),Multiple System Atrophy (MSA), Fronto-Temporal dementia (FTD), prion diseases, amyotrophic lateral sclerosis (ALS) and trinucleotide repeat disorders(TNRD),theaggregatedproteinsaccumulate intheplasmamembraneandintracellularly.Proteinmisfoldingandaccumulationistheresult ofanalteredbalancebetweenproteinsynthesis,aggregationrateandclearance.Basedonthesestudies,considerableadvanceshavebeenmadeinthe past years in developing novel experimental models of neurodegenerative disorders. This has been in part driven by the identification of geneticmutations associated with familial forms of these conditions and gene polymorphisms associated with the more common sporadic variants of thesediseases. Transgenic and knock out rodents and
Drosophila
as well as viral vector driven models of Alzheimer's disease (AD), PD, Huntington'sdisease (HD) and others have been developed, however the focus for this review will be on rodent models of AD, FTD, PD/LBD, and MSA.Promising therapeutic results have been obtained utilizing amyloid precursor protein (APP) transgenic (tg) models of AD to develop therapiesincluding use of inhibitors of the APP-processing enzymes
β
- and
γ
-secretase as well as vaccine therapies.© 2007 Published by Elsevier B.V.
 Keywords:
Transgenic; Models; Neurodegenerative disease; Aging; Alzheimer's; Parkinson's; Lewy bodies; MSA
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10942. Modeling neurodegenerative disorders
in vivo
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10942.1. Overview of experimental animal models of neurodegenerative disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10942.2. Alzheimer's disease experimental models for therapeutic testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10942.3. APP tg animal models of AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10942.4. Tau pathology in tg models of AD and FTD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10952.5. Utilization of tg models expressing
α
-synuclein to investigate therapeutic approaches for PD and LBD . . . . . . . . . . 10972.6. Transgenic models expressing
α
-synuclein to investigate MSA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10983. Advantages and disadvantages of the use of tg animal models for therapy development for neurodegenerative disorders . . . . . 1099Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1099
 Available online at www.sciencedirect.com
Advanced Drug Delivery Reviews 59 (2007) 1093
–
1102www.elsevier.com/locate/addr 
☆
This review is part of the
Advanced Drug Delivery Reviews
theme issue on
“
Prediction of Therapeutic and Drug Delivery Outcomes Using Animal Models
”
.
⁎
Correspondingauthor.DepartmentofNeurosciences,UniversityofCaliforniaSanDiego,LaJolla,CA92093-0624,USA.Tel.:+18585348992;fax:+18585346232.
 E-mail address:
emasliah@ucsd.edu(E. Masliah).0169-409X/$ - see front matter © 2007 Published by Elsevier B.V.doi:10.1016/j.addr.2007.08.013
 
1. Introduction
Although dramatic progress has been made in understandingthe pathogenesis of neurodegenerative conditions of the aged population such as Alzheimer's disease (AD), Parkinson's dis-ease (PD), Lewy body disease (LBD), Multiple System Atrophy(MSA) and Fronto-Temporal dementia (FTD), to date most of these diseases are incurable. Because of the near epidemic proportionintheagingpopulation,thesedisordersposeaseriouschallenge to the health care system. Development of biologicalmouse models holds the promise of better understanding their  pathogenesis and discovering and testing new treatments.Loss of synapses is probably the common neuropathologicalfeature leading to dementia in these neurodegenerative disorders[1
–
3]. The unique patterns of cognitive impairment that character-ize AD, LBD and FTD in turn depends on the neural circuitryspecificallyaffected[4],theextentofthesynapto-dendriticdamage,and the speed with which the injury propagates[5,6]. Recent evidence supports the contention that neuronal cell death might occurlaterintheprogressionofneurodegenerationandthatdamageto the synapto-dendritic apparatus might be one of the earliest  pathological alterations[1,7
–
11]. This is accompanied by the ab-normalaccumulationofneuronalproteinsintheextracellularspace(
e.g.
; plaques, cerebral amyloid angiopathy [CAA]) or in intra-cellularcompartments(
e.g.
;tanglesandLewybodies[LBs]).Thus,when developing transgenic (tg) models of neurodegenerativedisorders it is important to target the selective circuitries affected inorder to mimic some of the learning and memory deficits charac-teristic of specific dementing conditions. Abnormal accumulationandmisfolding(toxicconversion)ofthesesynapticandcytoskeletal proteins are being extensively explored as key pathogenic eventsleading to neurodegeneration in AD, LBD and FTD[12
–
14].In AD, misfolded amyloid-
β
peptide 1
–
42 (A
β
1
–
42
), a proteolytic product of amyloid precursor protein (APP) metab-olism, accumulates in the neuronal endoplasmic reticulum (ER)and extracellularly[15
–
17]. In addition, the microtubule-associated protein Tau is hyperphosphorylated and accumulatesin the neurons, resulting in the formation of tangles. In LBD,abnormal accumulation of the synaptic protein
α
-synucleinoccurs in neuronal cell bodies, axons and synapses[18
–
20]andresults in the formation of LBs and Lewy neurites.The key pathogenic event triggering synaptic loss and se-lective neuronal cell death in these disorders is not yet com- pletely clear [1,21], however recent studies suggest that nervedamage might result from the conversion of normally nontoxicmonomers (and small oligomers) to toxic oligomers and proto-fibrils[22,23], whereas larger polymers and fibers that oftenconstitute the intracellular inclusions and extracellular lesionsmight not be as toxic[24,25].
2. Modeling neurodegenerative disorders
in vivo
2.1. Overview of experimental animal models of neurodegenerativedisease
Considerable advances have been made in the past years indeveloping novel experimental models of neurodegenerativedisorders[26].This dramatic progress has been in part driven bythe identification of genetic mutations associated with familialforms of these conditions and gene polymorphisms associatedwith the more common sporadic variants of these diseases.Single or combined tg and knockout (KO) models targetingmost of these genes in the rat, mouse[27],
Drosophila
[28]and
C. elegans
[29]have been developed[30,31]. However, it is important to emphasize that although each of these modelsrecapitulates one or various aspects of the particular disease,none of them completely reproduces all the clinico-pathologicalalterations of each disease.Several reviews have been recently published on the subject of tg modeling, and the reader is advised to consult them for additional information[32
–
40]. The focus of the present manuscript is on tg animal models of AD, FTD, PD and LBD based on the overexpression of a single wild-type (wt) or mutant molecule. These models are currently being used for testing newtreatments such as anti-aggregation agents, trophic factors,vaccines and small molecules that block the APP-processingenzymes
β
- and
γ
-secretase, and kinases.
2.2. Alzheimer's disease experimental models for therapeutictesting 
Alzheimer's disease is the most common neurodegenerativedisorder in the aging population and is characterized by the progressive and irreversible deafferentation of the limbic system,association neocortex and basal forebrain[41
–
46], accompanied by the formation of neuritic plaques, neurofibrillary tangles(NFTs)andneuropilthreads[47].Thisneurodegenerativeprocessis followed by reactive astrogliosis[48]and microglial cell proliferation[49,50]. Experimental models of AD could mimicindividual or multiple alterations found in AD; however, to thisdatenotasinglemodelmimicsallthealterationsobservedinAD.The best model to date is probably the aged monkey[51],however because of the time and cost involved in utilizing thismodel, most studies have been focused on developing murinemodels. Most of the recently developed tg animal models of ADare based on the targeted overexpression of single or multiplemutant molecules associated with familial AD (FAD). Currently,mutations in three genes have been described, namely APP, presenilin (PS)1 and PS2[52
–
56]. Other models have beenrecentlydevelopedinrats,drosophilaand
C.elegans
,eitherusingconstitutively active or regulatable promoters, or viral vectors.
2.3. APP tg animal models of AD
The main focus of the following sections in AD and FTDwill be on models involving amyloid deposition and Tau hy- perphosphorylation. In AD, mutations in PS1 and 2 and polymorphisms in apolipoprotein E (ApoE) have been alsolinked with AD and as such are important targets. Recentlydeveloped tg animal models have shown that it is possible toreproduce certain aspects of AD pathology over a shorter periodof time[57
–
59]. In this model, the platelet-derived growthfactor (
β
chain) (PDGF-
β
) promoter drives an alternativelyspliced human APP (hAPP) minigene (PDAPP) encoding the
1094
E. Rockenstein et al. / Advanced Drug Delivery Reviews 59 (2007) 1093
 – 
1102
 
APP V717F mutation associated with FAD, which generatesisoforms hAPP695, 751, 770[60,61]. This construct containsAPP introns 6
–
8, allowing alternative splicing of exons 7 and 8.This method confers a high ratio of mRNA encoding mutatedhAPP versus wt mouse APP and favors expression of hAPP751and hAPP770 over hAPP695[61]. Neuropathologically, thesetg animals display development of typical amyloid plaques,dystrophic neurites, loss of presynaptic terminals, astrocytosisand microgliosis[57,58,60].Other models have expressed mutant hAPP under theregulatory control of either the human or murine (m)Thy-1 promoter [62
–
65]or the protease-resistant prion protein (PrP) promoter [66,67]. Amyloid deposition begins at 12 months of age; however, co-expression of mutant PS1 accelerates amyloiddeposition, beginning at 4 months of age[66,68,69]. Another more recently developed model, where APP is also expressedunder the control of the PrP promoter, displays even earlier onset of amyloid deposition, starting at 3 months and pro-gressing to mature plaques and neuritic pathology from5 months of age, accompanied by high levels of A
β
1
–
42
[70].While the PrP promoter has provided several models that mimicaspects of FAD, other promoters targeting expression of APP toneurons provide alternative models demonstrating pathologythat recapitulate similar and additional aspects of FAD. In thisregard, we have generated lines of tg mice expressing hAPP751cDNA containing the London (V717I) and Swedish (K670M/  N671L) mutations under the regulatory control of the murine(m)Thy-1 gene (mThy1-hAPP751)[71]. Therefore, while ex- pression of mutant hAPP under the PDGF-
β
 promoter results inthe production of diffuse (and some mature) plaques[60,72], tgexpression of mutant hAPP under the mThy-1[62]and PrP[66,67]promoters favors the formation of mature plaques in thehippocampus and neocortex. This suggests that the differential patterns of A
β
deposition might be dependent on the specificneuronal populations selected by the promoter, levels of ex- pression and topographical distribution of the transgene andlevels of A
β
1
–
40
and A
β
1
–
42
. Consistent with this, in FAD andDown syndrome, production of high levels of A
β
1
–
42
results inearly plaque formation[73]. This suggests that early age of onset and plaque formation depends in high levels of A
β
1
–
42
 production[71].More recent models have been focusedtowards modeling therole of A
β
protofibril generation and other mutations in APP inthe pathogenesis of AD. Of them, the most interesting are thoseexpressing APP bearing the Arctic mutation. These mice rapidlydevelop extensive plaque formation[74]. For a review of theseand additional tg models of neurodegenerative disease, pleasevisit the Alzheimer's Forum website at:http://www.alzforum.org/res/com/tra.The relationship among the patterns of amyloid deposition,neurodegeneration and behavioral deficits in the tg models of AD is complex. One important finding common to several of these APP tg models is that there is no obvious neuronal drop-out in early stages[75,76]. In fact, the earliest neuronal pa-thology before amyloid deposition is the loss of synapses anddendrites in the limbic system and neocortex[72,77]. This isaccompanied by neurophysiological deficits and alterations inlong-termpotentiation(LTP)andfieldpotential[77,78].Sincethesynaptic damage in these mice correlates better with the levels of soluble A
β
1
–
42
than with plaques, it has been proposed that neurodegeneration might be associated more with the neurotoxiceffects of A
β
oligomers than with fibrillar amyloid[72]. Inagreementwiththispossibility,studiesinbrainsliceshaveshownthat A
β
oligomers rather than fibrillar amyloid are toxic tosynapses and depress LTP, leading to cognitive impairment [25].Other recently developed models have also focused ondefining the effects of APP and its products on functionalmarkers, including behavioral performance and LTP. Thesestudies have shown that overexpression of the C-terminal APPfragment C100 under the control of neurofilament (NF) promoter results in amyloid-like production and electrophysi-ological alterations[79]. Although these, as well as the other APP tg animal models, have been shown to be of significant interest, the basic principle for their success rests on the abilityto overexpress high levels of mutant APP, which in a way is arather non-physiological event and, with the exception of genemultiplication events[80], in sporadic AD there is no evidencefor upregulation of APP expression but rather a shift in the ratio between APP770 and 751 to APP695. In this regard, a previousstudy[81]has demonstrated frame shift mutations in APP andubiquitin genes in AD. It is conceivable that future tg modelsmight utilize this mechanism in an attempt to reflect the morecommon sporadic forms of the disease.
2.4. Tau pathology in tg models of AD and FTD
Although most of the APP tg models develop several fea-tures of AD including synaptic dysfunction, memory deficits,and amyloid deposition, modeling neurofibrillary pathology has been more difficult. The reason for this is unclear; however,some mutant APP tg models develop mild neurofibrillary pa-thology, but no paired-helical filaments (PHFs) or NFTs[82](for review see[40]). Abnormally phosphorylated Tau is amajor component of NFTs and recent studies have linked Taumutations to FTD with parkinsonism linked to chromosome 17(FTDP-17)[83,84], suggesting that dysfunction of Tau, as wellas formation of A
β
, can lead to neurodegeneration and de-mentia. Transgenic mice overexpressing either mutant forms of Tau (
e.g.
P301L) alone or in combination with APP have beendeveloped[85]. Neurofibrillary tangles composed of a highly- phosphorylated form of Tau are a characteristic neuropatholog-ical lesion of AD[86,87]. The tangle component of AD pathology is still missing from some of the current tg modelsand it appears that simply overexpressing Tau in neurons (asuccessful strategy in APP tg mice) might not be responsible for  NFT development [88].Although studies in tg mice expressing hTau isoforms and inanimals doubly-tg for Tau and mutant PS1 have shown asomatodendritic accumulation of phosphorylated Tau proteins(similar to the pre-tangle stage in AD) no NFTs were found[89],more recent studies in tg mice expressing hTau in central neuronsshowed progressive degeneration of nerves and muscles, thusthese animals cannot be tested in the Morris water maze anddie prematurely[90]. In tg mice overexpressing the P301L Tau
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