NEURAL PLASTICITY VOLUME 12, NO. 4, 2005

Genetic Mouse Models of AIzheimer's Disease

Yann S. Mineur, Declan McLoughlin, Wim E. Crusio and Frans Sluyter4

Yale School ofMedicine, Department ofPsychiatry, New Haven, CT 06508, USA; 201d Age Psychiatry, Institute ofPsychiatry, De Crespigny Park, London, SE5 8AF, UK; 3Laboratoire de Neurosciences Cognitives, UMR 5106, Talence, France;4SGDP Centre, 41nstitute ofPsychiatry, De Crespigny Park, London, SE5 8AF, UK

SUMMARY million individuals are currently afflicted in the United States (U.S.), an incidence expected to rise In the current minireview, we focus on to up to 16 million by the year 2050 (Hebert et al., genetic mouse models of Alzheimer's disease 2003). (AD). Because various excellent, up-to-date Extracellular neuritic plaques and intraneuronal reviews, special issues, and reliable websites are neurofibrillary tangles (NFTs) are the two classical already dedicated to the genetics of Alzheimer's hallmark microscopic pathologies of AD disease in general and of animal models in (Lovestone & McLoughlin, 2002; Selkoe, 2004). particular, this review is not meant to be Neuritic plaques comprise a dense core of comprehensive. Rather, we aim to steer the [3-amyloid peptide (AI3) that is surrounded by Alzheimer's novice through the recent mouse dystrophic neurites. These plaques precipitate and literature on AD. Special attention will be paid deposit around , mainly those in the limbic to genetic models that have been tested system and cortex (Glenner & Wong, 1984a, 1984b; behaviorally. Glenner et al., 1984). This 'choking' mechanism will ultimately lead to neuronal death, which is believed to be responsible for phenotypical INTRODUCTION in affected patients (Wilquet & De Strooper, 2004). Alzheimer's disease (AD) is the most common The microtubule-associated protein, tau, is the cause of dementia in the elderly, the fourth most principal component of NFTs (Stoothoff & common cause of death in westem industrialized Johnson, 2005). Tau function is regulated by phos- nations, and one of the major contributors to the phorylation and in AD, tau is abnormally hyper- global burden of disease (WHO, 2000). No phosphorylated, leading to disruption of micro- disease-modifying treatment is currently available. tubule dynamics, impaired axonal transport, and The onset of dementia in AD is insidious, and its tau polymerization, which results in the formation course is relentlessly progressive and characterized of intraneuronal NFTs and ultimately neuronal by global cognitive decline, involving , death. For a pathological diagnosis of AD, both orientation, judgment, and reasoning. Nearly 4.5 neuritic plaques and NFTs are required. It is now generally believed that abnormal production and aggregation of AI3 (especially the more fibrillogenic A42 isoform) are primary Reprint requests to: Y.S. Mineur, Yale School of Medicine, Department of Psychiatry, 34 Park Street, 3rd Floor Research, pathogenic events in AD and that NFTs are farther New Haven, CT 06508, USA; e-mail [email protected] downstream in the pathogenesis, commonly referred

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Fig. 1: Schematic overview of the amyloid cascade hypothesis See text for more information.

to as the "amyloid hypothesis" (Fig. 1). This behavior in a manner that is both rapid, potent and hypothesis is to some extent controversial as transient (Cleary et al., 2005). For a detailed plaques and tangles have been found in the discussion on the amyloid hypothesis, the reader is of non-demented individuals as well (albeit in lower referred to Hardy & Selkoe (2002) and Marchesi abundance). Moreover, the exact sequence and (005). implication of the different biological processes involved in AD are not yet entirely clear. Although neurodegeneration, amyloid plaques, and NFTs are GENETICS widely accepted as part of the disease, to determine to what extent those factors contribute As in most complex disorders, play an to dementia and to what extent they are inter- important role in the pathogenesis of AD. One of connected to each other remains difficult. the most effective methods to ascertain the input Nevertheless, recent studies have revealed that of genetic factors is the classical twin method. By soluble oligomers of AI3 can disrupt synaptic comparing genetically related individuals, e.g. function (Walsh & Selkoe, 2004), mediate neuronal monozygotic and dizygotic twins, this method is dysfunction in AD (Walsh & Selkoe, 2004), and able to estimate the relative contribution of both are both necessary and sufficient to disrupt learning genetic and environmental factors, as well as their GENETIC MOUSE MODELS OF ALZHEIMER'S DISEASE 301

interaction for more detailed information, see, identifying the effect of a on a more among others Boomsma et al., 2002). Studies over elementary (neuro)biological trait is easier than the last decades have rendered estimates of the identifying its effect on a complex trait with heritability of AD, i.e. the proportion of phenol- dichotomous diagnostic categories. typic variation that can be attributed to genetic A[3 is a 40-42 amino acid peptide derived from effectsmbetween 48 and 75% (Bergem et al., 1997; proteolytic processing of a much larger precursor Raiha et al., 1996), depending on, among others, molecule, the amyloid precursor protein (APP). the age of the population under investigation The catalyzing this reaction are termed (early-onset vs. late-onset) and the type of study "secretases": 13-secretase (BACE1) first cleaves at (incidence vs. prevalence). the N-terminus of AI3 and then 13-secretase cleaves The search for the actual genes has proven to at the C-terminus (Fig. 2). The bulk of APP, be difficult. To date, possession of the 134 allele of however, is cleaved by t-secretase within the AI3 ApoE is the most robust genetic susceptibility domain to produce the C-terminal fragment, C83, factor for late-onset AD but is neither necessary which can be further cleaved intramembranously nor sufficient to cause disease (Tanzi & Bertram, by /-secretase to produce peptide P3 and the APP 2005). Other genes involved are the genes intracellular domain (AICD), which can trans- encoding amyloid precursor protein (APP), pre- locate to the nucleus to participate in gene trans- senilin-1 (PSEN1), and presenilin-2 (PSEN2). cription events (Cao & Sudhof, 2001; see Fig. 2). Specific mutations in these genes cause early-onset Mismetabolism of APP, especially an increase familial AD (EOFAD). First discovered in 1991 of the more fibrillogenic cerebral A[3. ending at (Goate et al., 1991), the number of these fully position 42 (AI342) compared with the one ending penetrant mutations has expanded exponentially. at position 40 (AI340), can lead to an abnormal Although such mutations are rare (< 5% of all production and aggregation of All and as a result AD cases), the affected geneswand the biochemical to AD. In consequence, the genes encoding the -, pathways they represent--are excellent starting 13-, and ),-secretases can be considered candidate points for the genetic and functional analysis of genes for AD. Other candidate genes are those that AD. Mutations in the gene encoding tau, however, code for proteins affecting AI3 clearance and de- cause a range of different disorders, which are gradation, as well as AI3 toxicity and inflamma- collectively referred to as "tauopathies" (Ingram & tion. For a review on the genetics of the amyloid Spillantini, 2002). None of these disorders has any cascade, the reader is referred to Tanzi & Bertram appreciable AD pathology, confirming the contri- (2005). bution of tau to be further downstream in the pathogenesis of AD. Another advantage, from a genetic point of ANIMAL MODELS view, in the study of AD is the central role of in the amyloid hypothesis. Hence, by definition Many AD studies have been aimed at the (but in contrast to most psychiatric disorders), a analysis and manipulation of AI3 peptides. In this clearly defined neuronal intermediate phenotype, respect, animal models have been very valuable as also called an endophenotype, can be further nearly all studies in humans are necessarily based explored. This approach is extremely useful in the on postmortem tissues where there is considerable genetic analysis of a complex disorder because variation in quality because of the technical (agonal state of the , post-mortem interval, for more information http://www.molgen.ua.ac.be/ADMutations tissue fixation and storage, tissue pH) and 302 Y.S. MINEUR ET AL. biological (age at death, gender, medication and be controlled and hence manipulated. Sample sizes substance abuse) state of the autopsy brain (for can be increased when necessary. Perhaps most detailed information, see Katsel et al., 2005). important, animals can be experimented upon and, There are other reasons, though, why animal accordingly, can provide answers to questions that models are indispensable. Their environment can cannot be answered in humans.

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Fig. 2: APP processing pathways. A: APP is an integral transmembrane protein (N-terminal is extracellular; C-terminal is cytoplasmatic). The C-terminal of AI3 (red 'block') is embedded within the (area between dashed lines). B: Non-amyloidogenic pathway. APP is cleaved by the membrane-associated metalloprotease a- secretase within the AI3 domain, thereby preventing the formation of AI3. This results in the release of the large soluble extracellular N-terminal portion ofAPP (APPsa) and C83 (C-terminal fragment of 83 residues). C83 might be further processed by ),-secretase to release the p3 peptide, which is considered non-amyloidogenic, and the APP intracellular domain (AICD). C: Amyloidogenic pathway. APP is cleaved by two distinct proteases: 13- and ),-secretase. First, 13-Secretase, (BACE1 13-site APP-cleaving enzyme) cleaves APP at the N- terminal region of the AI3 sequence, resulting in the soluble APPsl3 and the amyloidogenic C99 (C-terminal fragment of 99 residues). Second, y-secretase cleaves C99, resulting in AICD and AI3. GENETIC MOUSE MODELS OF ALZHEIMER'S DISEASE 303

Although this review will concentrate on exists when the risk for a disease is known to mouse models of AD, invertebrate models such as involve similar genetic components both in Drosophila sp. and C. elegans should not be dis- humans and in the animal model, whereas carded too easily. Despite their clear disadvantages predictive validity usually refers to how useful --they are not mammals and therefore lack the animal models are for predicting the efficacy brain structures typical of those--they do have and safety of drugs. added value in the study of AD, especially, at a practical level. They are smaller, cheaper to house and breed, and have shorter generation times than MOUSE MODELS FOR ALZHEIMER'S DISEASE any mammal, which allows the breeding of many generations in a short time span. Last, but certainly At the start of this outline, it is important to not least, is the advantage of a less stringent realize that both in (semi-) natural and in legislation. Thus, transgenic fly and worm AD laboratory conditions mice do not develop plaques models exist both with regard to AI3 and tau and tangles, hence the development of mouse expression (for recent reviews, see Brandt et al., models for AD implies manipulations by the 2005; Lee et al., 2005; Link, 2005). experimenter. Such manipulations can be either Mice are the most popular animal models for genetic or invasive, the latter generally being the AD nowadays, the main reason being that their exogenous administration of different AI3 peptides genome can be manipulated relatively easily. This into the normal rodent brain. Both techniques have advantage has resulted in a variety of genetic their advantages and handicaps but are essentially mouse models, although rat models do exist as complementary. In this review, we will focus on well (see for instance, Hu et al., 2004). Before we genetically modified mouse models of AD. For a dive into the pool of knockouts, knockins, .and recent review on mouse models of AD involving transgenics, we would like to remind the reader of exogenous AI3 administration and their comparison what a good animal model for AD theoretically to transgenic models, the reader is referred to stiould be like. Stephan & Phillips (2005). 1. First, this model should be reliable, which refers to the stability and reproducibility of the Genetically modified strains phenotype, across time and preferably also across laboratories, although the latter is far The amyloid hypothesis has also played a from easy (Crabbe et al., 1999). major role in the development of transgenic mouse 2. Second, this model should have validity with models. By definition, genes that code for APP AD. Validity implies four different features. and the enzymes involved in the processing of Face validity refers to the similarity between APP to AI3 are good candidates for manipulation; the animal model and the disease of interest, therefore, not surprisingly, to date, a multitude of i.e. AD. Hence, the model should mimic the genetically modified strains exist that attempt to behavioral characteristics of AD---e.g. cognitive unravel specific parts of the amyloid pathway. The decline--as well as possible. genetically modified strains entail the following: 3. Construct validity is another factor and exists (a) Classical and conditional knockouts (KO). In when the model either relies or elucidates the classical KOs, the function of the gene under same basic underlying mechanism as AD, such investigation is abolished from a very early as the accumulation of AI3 peptides and/or stage of development. In conditional KOs, hyperphosphylation of tau. Genetic validity there is either a temporal restriction (gene 304 Y.S. MINEUR ET AL.

function is abolished at certain premeditated high AI3 levels, which, in turn, lead to robust time windows) or a regional restriction (no cognitive disturbances. Thus, both lines can show gene function in certain brain regions). A learning deficits over time and in different combination of both is also possible; laboratories. This point is rather important as the (b) Transgenics, in which a foreign gene, e.g. replicability of the (endo)phenotype over time and human APP, is inserted into the genome; across laboratories are essential conditions for a (c) K nockins, in which very specific mutations are reliable animal model. An additional strength of introduced in the gene leading to a loss of these particular lines is that they show deficits in activity of the proteins encoded by the targeted several different cognitive tets, which indicates gene (although the gene expression per se is that the behavioral consequences of high AI3 not voided as it is in KOs). levels, i.e. poorer performance in cognitive tests compared with control animals, are general rather Moreover, combinations of (a), (b), and (c) are than test specific. For instance, Tg2576 mice, possible. Strains having one gene knocked out and developed by Hsiao et al. (1996), have compara- another inserted into the genome and overex- tively more difficulties in a specific version of the pressed (KO/Tg) are quite common nowadays. water navigation task than their control littermates. Even triple transgenics are being used in mouse Both their acquisition of hidden platform locations models of AD. and their retention of spatial reference information are affected. This effect is progressive and starts as early as 6 months of age (Westerman et al., 2002). APP transgenics In a different laboratory, the same transgenics also show performance deficits in an adapted version of The first successful genetically modified the Barnes maze (Pompl et al., 1999), whereas in mouse models in AD research were transgenic and yet another lab they perform poorer in a T-maze increased the load of A[3 by increasing the load of alternation task and are impaired at acquiring fear its precursor APP. In general, a human APP to the conditioning context (Corcoran et al., 2002). (hAPP) genemusually a mutant form linked to Not unexpectedly, the search for biochemical inherited early onset forms of AD--is inserted into targets has widened beyond overexpression of the genome. If successful, this procedure leads to mutant forms of the human APP gene. From a the overexpression of the transgene in question genetic point of view, all the genes encoding the and, consequently, to increased levels of APP. To secretases that cleave the APP molecule can be our knowledge, five distinct hAPP transgenics considered compelling candidate genes for AD. have been developed: PDAPP, Tg2576, APP23, Especially interesting are the 13- and 3t-secretases, TgCRND8, and J20. Each transgenic has its own which catalyze the processing of APP to the various genetic characteristics (different mutations, different AI3 peptides, and a-secretase, which is part of the promoters, different background), which leads to non-amyloidogenic pathway. different expression levels and both qualitatively and quantitatively different levels of neuroana- tomical abnormalities. All have been tested secretase behaviorally; some extensively, others not. A close look at those lines that have been tested in great BACE1 is the most important 13-secretase in detail, such as PDAPP and Tg2576, demonstrates neurons. Both transgenic and knockout BACE1 that (genetically induced) high APP levels lead to mice have been developed and, interestingly, their GENETIC MOUSE MODELS OF ALZHEIMER'S DISEASE 305 phenotypic changes are opposite: The KOs are performance in the object recognition test, but not more anxious than controls and transgenics are in the water-navigation task, suggesting changes of bolder. This observation suggests the involvement PSI to affect non-hippocampal memory systems of BACE in anxiety and not so much in cognition (Huang et al., 2003; Janus et al., 2000). PS2 KOs as might have been expected. The next step in are both viable and fertile and do not appear to elucidating the role of 13-secretase in AD was the show any neurobehavioral abnormalities, whereas development of double transgenics, in this case the PS2 transgenics and KIs perform more poorly in crossbreeding of mice overexpressing hAPP with the water-navigation task. those either lacking or overexpressirlg BACE1 Following an experimental concept similar to (BACE/Tg2576 and hBACE/Tg2576, respectively). that of the hAPP x BACE1, both double trans- As expected, double transgenics (hBACE/Tg2576) genics and cPS//APP have been developed. Com- have accelerated amyloid pathology, high levels of pared with controls, double transgenics accumulate both total A[3 and AI342, and greater numbers of AI3 quicker and at higher levels and, consequently, plaques than hAPP mice alone. The removal of perform poorer in a multitude of cognitive tests BACE1 in the presence of hAPP, however, rescues (see Kobayashi &Chen, 2005). Mechanistically in certain of the cognitive deficits associated with line with the hAPP x PS findings is the (for re ferences, see Kobayashi & Chen, 2005). observation that cPS//APP mice, which carry a conditional postnatal -specific cre/lox KO version of the PSI gene, develop no amyloid T-secretase plaques and behave normally in an object recognition task (Dewachter et al., 2002), The secondary cleavage in the processing from suggesting /-secretase inhibition is a promising APP to AB42 requires the activity of the y- target for putative treatment strategies. secretase enzyme. In fact, functional /-secretase is a complex holoenzyme consisting of several indi- vidual enzymes, including PSI, PS2, Nicastrin, -secretase Aph-1, and Pen-2 (De Strooper & Woodgett, 2003; Francis et al., 2002). Especially the presenilins The third secretase involved in APP processing (PS1, PS2) have been the target of intense is the {x-secretase, which metabolizes about 90% of investigation. KOs, transgenics, and KIs have been APP. To a certain extent, the {x-secretase can be used, as well as double and even triple transgenics. considered the 'good' secretase as it produces Although PS KO mice are not viable (Shen et al., peptides not--or far less than the AI3s-associated 1997), this problem was circumvented by the with amyloid toxicity (see Fig. 2). Thus, although development of conditional KOs (cKO), in which the P3 fragment is also a component of certain the loss of the gene was limited to the postnatal amyloid plaques in AD, there have been very few forebrain. PSlcKO animals showed modest cogni- reports of P3 having apoptotic or any other kind of tive impairments in long-term spatial reference deleterious activity in neurons. As a result, the memory and retention (Yu et al., 2001). secretase-processing pathway has been described Mice overexpressing PS1 (hPS1), however, as the non-amyloidogenic pathway (Naslund et al., show only minor behavioral disturbances. Interest- 1994; Wei et al., 2002). A number of enzymes can ingly, KIs with a directed missense mutation in the act as t-secretase in the brain, including the ADAM endogenous murine PSI overproduce AI342, but proteins (ADAM9, ADAM10, and ADAM17). develop no plaques. These mice show poorer ADAM stands for A Disintegrin and Metallo- 306 Y.S. MINEUR ET AL. proteinase; its members have apparently redundant overexpress human wild-type tau and/or mutated a-secretase cleavage activities but differential ex- forms of human tau known to be associated with pression patterns (Buxbaum et al., 1998; Kark- frontotemporal dementia and parkinsonism kainen et al., 2000; Lammich et al., 1999). (abbreviated FDTP. In humans, tau proteins are ADAM 10 and ADAM 17 single knockouts encoded by a single gene on chromosome 17. have been shown to be lethal embryonically, Alternative splicing of the mRNA generates six whereas ADAM9 knockouts are viable and show different brains isoforms, which can be divided in no apparent abnormalities. While overexpression two classes: proteins that contain three C-terminal of a-secretase, i.e. ADAM 10, itself is not harmful, imperfect repeat domains (3R) and proteins that it restores basic neural function in a transgenic contain 4 repeats (4R). Most transgenic models model of AD. Thus in an extensive study Postina overexpress the mutated 4R tau form in one way or et al. (2004) showed that enhanced a-secretase another, varying from 'normal' 4R tau to one expression prevents the development of plaques in mutated form (P301L, P301S, V337M) to multiple old animals overexpressing hAPP. In contrast, mutations. Although numerous tau pathologies overexpression of a largely inactive ADAM10 on have been found in the brains of these transgenics an APP background exacerbates amyloid deposi- (for reviews see Brandt et al., 2005; Lee et al., tion. The authors also tested these animals in the 2000), few studies have exposed these mice to water navigation task and observed deficits in the extensive behavioral testing. acquisition phase of place learning and in the Interestingly, Tanemura et al. (2002) found 11- probe trial, whereas the double transgenicsmboth mo-old transgenics overexpressing the V337 overexpressing ADAM 10 and hAPP--performed mutant gene to be less anxious than control litter- as well as control animals. Long term potentiation mates on the elevated-plus maze, whereas no (LTP) was also improved in the double transgenics difference was observed in the water-navigation as opposed to single APP transgenics, suggesting a task. This result suggests the presence of a very fundamental rescue of synaptic function via the specific (non-spatial) cognitive deficit in which Tg increased activity of t-secretase. Their results on mice may not be able to discriminate fearful con- ,the neuroprotective role of a-secretase are in line ditions from fearless ones. Supporting this inter- with previous findings from Moechars et al. (1996) pretation, the transgenics showed little habituation on a double transgenic overexpressing hAPP with to the elevated plus maze and open field, whereas a disturbed a-secretase cleavage site. The resulting control animals showed clear habituation patterns. APP/RK mice had increased APP expression in Further studies on neurodegeneration in the hippo. their brains with a shift toward 13-site cleavage campus of these transgenicsmirregular shaping o amyloid peptides and had shorter life spans than 30% to 70% of the neurons, as well as diminishe control animals (Moechars et al., 1999). APP/RK neural responses recorded from hippocampa mice also showed neuroanatomical abnormalities in slicesmmight shed some light on the differentia the amygdala, cortex, and hippocampus and were functional (spatial vs. non-spatial) implications. observed to be more aggressive and hyperactive. The same laboratory also tested the behavic of mice overexpressing another mutated 4R ta gene, R406W, which in humans causes a tau Tall pathy that clinically resembles AD. Within 48

In addition to these 'AI3 transgenics', various see again http://www.molgen.ua.ac.be/AD Mutations for mc transgenic mouse models have been developed that information GENETIC MOUSE MODELS OF ALZHEIMER'S DISEASE 307 after conditioning, the transgenics showed reduced the absence of structural changes, in cognitive levels of fear response during the cued but not the decline in AD. Recently, 3xTg mice have also been contextual testing in comparison with control studied for their cognitive behavior at different littermates at an age of 16-23 months. Fifteen days time points (Billings et al., 2005). The earliest after conditioning, the animals also showed lower cognitive impairment manifests at 4 months as a levels of fear response during the contextual testing, deficit in long-term retention and correlates with suggesting that memory loss may be more. pro- the accumulation of intraneuronal A[3 in the nounced in longer retention delays in aged trans- hippocampus and amygdala. No plaques or tangles genics. Taken together, the results of that study are apparent at this age, suggesting that they suggest the presence of associative memory im- contribute to cognitive dysfunction at later time pairments in mice overexpressing the mutated tau points. Clearance of the intraneuronal A[3 pathology gene. This effect seems to be rather specific as by immunotherapy rescues the early cognitive transgenics either did not differ or differed only deficits on a hippocampal-dependent task, whereas slightly from controls with regard to other behav- reemergence of the A[3 pathology again leads to ioral and sensorimotor tests. Neuroanatomically, cognitive deficits. Triple-transgenic mice are now transgenics are characterized by congophilic tau being investigated at various, different levels and inclusions, predominantly in the hippocampus, are likely to provide more insight on the exact amygdala, and neocortex, areas that are well sequence of pathological events leading to established to be involved in memory formation Alzheimer (LaFerla & Oddo, 2005). (Tatebayashi et al., 2002).

CONCLUSIONS Triple Transgenics The use of genetic mouse models has certainly To study the interaction between A[3 and tau, been effective in research on the pathogenesis of Oddo et al. (2003) went one step further and AD and has led to important insights into the developed a triple-transgenic using a novel strategy underlying pathological processes. In comparison in which two transgenes, Tg2576 and tauP301L, to 10 years ago, genetic mouse models have were microinjected into single-cell embryos evolved both in a qualitative and in a quantitative obtained from homozygous PSl-knockin mice. way and seem to mimic AD neuropathology better Triple-transgenic (3xTg) mice develop age-related than the first genetically altered models. For and progressive neuropathologies, including plagues instance, the generation of the 3xTg-AD mice is a and tangles. The pattern of progression--A[3 first step forward in animal modeling because such in cortical regions, then later in hippocampus and transgenics develop both plaques and tangles in amygdala; tau the other way around--closely the same order as AD patients do. The 3xTg-AD mimics that observed in AD. One of the main model strongly implicates intraneuronal AI3 in the findings in their study is that presynaptic dys- onset of cognitive dysfunction, which might function, including LTP deficits, precede the facilitate therapeutic evaluations. accumulation of extracellular A[3 deposits, which, Another interesting line of research is the in tum, precede tau alterations, the latter sequence inclusion of environmental factors in a genetic of events being in line with the amyloid cascade design, which allows for the detection of gene- hypothesis. Moreover, the results of this study environment interactions. 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