Alzheimer?s disease (AD) is the most common neurodegenerative disorder in the aging population. It is characterized by the progressive and irreversible deafferentation of the limbic system, association neocortex, and basal forebrain (Perry et?al. ¹⁹⁷⁷; Hyman et?al. ¹⁹⁸⁴; Wilcock et?al. ¹⁹⁸⁸; Hof et?al. ¹⁹⁹⁰; Palmer and Gershon ¹⁹⁹⁰; Masliah et?al. ¹⁹⁹³), accompanied by the formation of neuritic amyloid plaques, amyloid angiopathy, neurofibrillary tangles (NFTs), and neuropil threads (Terry et?al. ¹⁹⁹⁴). This neurodegenerative process is followed by reactive astrogliosis (Dickson et?al. ¹⁹⁸⁸) and microglial cell proliferation (Rogers et?al. ¹⁹⁸⁸; Masliah et?al. ¹⁹⁹¹).

Loss of synapses (DeKosky and Scheff ¹⁹⁹⁰; Masliah ²⁰⁰¹; Scheff and Price ²⁰⁰¹) and axonal pathology (Raff et?al. ²⁰⁰²) are probably key neuropathological features leading to dementia in these neurodegenerative disorders. In addition, recent evidence suggests that alterations in the niches for neurogenesis in the adult brain might also contribute to the neurodegenerative process (Haughey et?al. ²⁰⁰²; Tatebayashi et?al. ²⁰⁰³; Dong et?al. ²⁰⁰⁴; Jin et?al. ²⁰⁰⁴; Wen et?al. ²⁰⁰⁴; Chevallier et?al. ²⁰⁰⁵; Donovan et?al. ²⁰⁰⁶). The unique patterns of cognitive impairment that characterize AD, in turn, depend on the neural circuitry specifically affected (Hof and Morrison ¹⁹⁹⁴), the extent of the synapto-dendritic damage, and the speed with which the injury propagates (Terry et?al. ¹⁹⁹¹; DeKosky et?al. ¹⁹⁹⁶). Recent evidence supports the contention that neuronal cell death might occur later in the progression of neurodegeneration and that damage to the synapto-dendritic apparatus might be one of the earliest pathological alterations (Masliah and Terry ¹⁹⁹³, ¹⁹⁹⁴; Masliah ¹⁹⁹⁸, ²⁰⁰¹; Honer ²⁰⁰³; Scheff and Price ²⁰⁰³). This is accompanied by the abnormal accumulation of neuronal proteins in the extracellular space (e.g., plaques, cerebral amyloid angiopathy [CAA]) or in intracellular compartments (e.g., tangles and Lewy bodies [LBs]). Abnormal accumulation and misfolding (toxic conversion) of these synaptic and cytoskeletal proteins are being explored as key pathogenic events leading to neurodegeneration (Koo et?al. ¹⁹⁹⁹; Ramassamy et?al. ¹⁹⁹⁹; Ferrigno and Silver ²⁰⁰⁰).

In AD, amyloid-? peptide 1?42 (A?_1?42), a proteolytic product of amyloid precursor protein (APP) metabolism (Fig.?1), accumulates in the neuronal endoplasmic reticulum (ER) (Cuello ²⁰⁰⁵) and extracellularly (Selkoe et?al. ¹⁹⁹⁶; Trojanowski and Lee ²⁰⁰⁰; Walsh et?al. ²⁰⁰⁰). The primary pathogenic event triggering synaptic loss and selective neuronal cell death in these disorders is not yet completely clear (Masliah ²⁰⁰⁰, ²⁰⁰¹), however, recent studies suggest that nerve damage might result from the conversion of normally non-toxic monomers to toxic oligomers (Volles et?al. ²⁰⁰¹; Volles and Lansbury ²⁰⁰²; Walsh and Selkoe ²⁰⁰⁴) (Fig.?2), whereas larger polymers and fibers that often constitute the plaques might not be as toxic (Lansbury ¹⁹⁹⁹; Walsh et?al. ²⁰⁰²). An example of a naturally occurring oligomer species is A?*56, which has been shown to promote age-dependent memory deficits (Lesne et?al. ²⁰⁰⁶). A?*56 and A? trimers secreted by cultured cells could share common synaptotoxic properties (Selkoe ²⁰⁰⁸). Previous studies have shown that the A? dimers, trimers, and higher-order oligomers secreted by cultured neurons inhibit LTP and damage spines (Klein et?al. ²⁰⁰¹; Walsh and Selkoe ²⁰⁰⁴; Townsend et?al. ²⁰⁰⁶; Selkoe ²⁰⁰⁸). Additional studies have shown that A? dimers derived from human CSF disrupt synaptic plasticity and inhibit hippocampal LTP in?vivo (Klyubin et?al. ²⁰⁰⁸). Together, these studies indicate that A? oligomers ranging in size from 2 to 12 subunits might be responsible for the synaptic damage and memory deficits associated with AD (Lacor et?al. ²⁰⁰⁷).

Thus, when developing transgenic (tg) models of AD it is important to consider the following outcome features: (1) targeting the selective neuronal populations in the neocortex and limbic system involved in learning and memory; (2) favoring production of high levels of A?_1?42 over A?_1?40; (3) promoting accumulation of A? oligomers; (4) inducing post-transcriptional modifications (e.g., pyroglutamate A?); (5) evaluating abnormal accumulation of intracellular A?; (6) evaluating development of amyloid plaques and CAA; (7) evaluating neurodegeneration with synaptic loss, axonal damage, and defects in neurogenesis; and (8) behavioral and electrophysiological impairments that correspond to the pattern of neurodegeneration.

Although dramatic progress has been made in understanding the pathogenesis of neurodegenerative conditions of the aged population, such as AD, Parkinson?s disease (PD), and Lewy body disease (LBD), most of these disorders remain incurable. Because of the near epidemic proportion in the aging population, these disorders pose a serious challenge to the health care system. Identification of new targets and development of biological mouse models holds the promise of better understanding their pathogenesis and discovering and testing new treatments.

Experimental models of AD could mimic individual or multiple alterations found in AD; however, to date not a single model mimics all the alterations observed in AD. The best model is probably the aged monkey (Price et?al. ¹⁹⁹⁴), however, because of the time and cost involved in utilizing this model, most studies have been focused on developing murine models. Most of the tg animal models of AD are based on the targeted overexpression of single or multiple mutant molecules associated with familial AD (FAD) (Table?1, Fig.?3). Currently, mutations in three genes have been described, namely APP, presenilin (PS)1, and PS2 (Hutton and Hardy ¹⁹⁹⁷; Cruts and Van Broeckhoven ¹⁹⁹⁸; Rocchi et?al. ²⁰⁰³; Bertoli-Avella et?al. ²⁰⁰⁴; Pastor and Goate ²⁰⁰⁴). Other APP and PS tg models have been developed in rats, drosophila, and C.?elegans, either using constitutively active or regulatable promoters, or viral vectors. The main focus of this review will be dedicated to murine APP tg models and the corresponding neurodegenerative pathology and alterations in neurogenesis, however, it is important to emphasize that this represents one aspect of the disease; other components, such as NFT pathology will be addressed by others.

In AD, APP mutations as well as mutations in PS1 and 2 and polymorphisms in apolipoprotein E (ApoE) have also been linked with AD (Fig.?2) and as such are important targets. Most efforts toward developing tg models have been focused on overexpression of mutant APP (Table?1) in combination with mutant PS1. A summary of the FAD mutations reproduced in tg mouse models is presented in Fig.?3. Previously developed tg animal models have shown that it is possible to reproduce certain aspects of AD pathology over a shorter period of time (Masliah et?al. ¹⁹⁹⁶; Games et?al. ¹⁹⁹⁷; Price et?al. ²⁰⁰⁰). In this model, the platelet-derived growth factor (? chain) (PDGF-?) promoter drives an alternatively spliced human APP (hAPP) minigene (PDAPP) encoding mutated (Indiana, V717F) hAPP695, 751, and 770 (Games et?al. ¹⁹⁹⁵; Rockenstein et?al. ¹⁹⁹⁵). This confers a high ratio of mRNA encoding mutated hAPP versus wild-type mouse APP (Rockenstein et?al. ¹⁹⁹⁵), which promotes development of typical amyloid plaques, dystrophic neurites, loss of presynaptic terminals, astrocytosis and microgliosis (Games et?al. ¹⁹⁹⁵, ¹⁹⁹⁷; Masliah et?al. ¹⁹⁹⁶).

Other models have expressed mutant hAPP under the regulatory control of either the human or murine (m)Thy1 promoter (Andra et?al. ¹⁹⁹⁶; Sturchler-Pierrat et?al. ¹⁹⁹⁷; Moechars et?al. ¹⁹⁹⁹; Bornemann and Staufenbiel ²⁰⁰⁰) or the prion protein (PrP) promoter (Hsiao et?al. ¹⁹⁹⁶; Borchelt et?al. ¹⁹⁹⁷). Amyloid deposition begins at 12?months of age; however, co-expression of mutant PS1 accelerates amyloid deposition, beginning at 4?months of age (Borchelt et?al. ¹⁹⁹⁶, ¹⁹⁹⁷; Holcomb et?al. ¹⁹⁹⁸). Another previously developed model, where hAPP is also expressed under the control of the PrP promoter, displays even earlier onset of amyloid deposition, starting at 3?months and progressing to mature plaques and neuritic pathology from 5?months of age, accompanied by high levels of A?_1?42 (Chishti et?al. ²⁰⁰¹). While the PrP promoter has provided several models that mimic aspects of FAD, other promoters targeting expression of APP to neurons provide alternative models demonstrating pathology that recapitulate similar and additional aspects of FAD. In this regard, we have generated lines of tg mice expressing hAPP751 cDNA containing the London (Lon, V717I) and Swedish (Swe, K670N/M671L) mutations under the regulatory control of the mThy1 gene (mThy1-hAPP751) (Rockenstein et?al. ²⁰⁰¹; Fig.?4). While expression of mutant hAPP under the PDGF-? promoter results in the production of diffuse (and some mature) plaques (Games et?al. ¹⁹⁹⁵; Mucke et?al. ²⁰⁰⁰), tg expression of mutant hAPP under the mThy1 (Andra et?al. ¹⁹⁹⁶) and PrP (Hsiao et?al. ¹⁹⁹⁶; Borchelt et?al. ¹⁹⁹⁷) promoters favors the formation of mature plaques in the hippocampus and neocortex. This suggests that the differential patterns of A? deposition might be dependent on the specific neuronal populations selected by the promoter, levels of expression and topographical distribution of the transgene, and levels of A?_1?40 and A?_1?42. Consistent with this, in FAD and Down syndrome, production of high levels of A?_1?42 results in early plaque formation (Citron et?al. ¹⁹⁹⁷). This suggests that early age of onset and plaque formation depends on high levels of A?_1?42 production (Rockenstein et?al. ²⁰⁰¹). Finally, of considerable interest and wide attention is the triple tg mouse model developed by LaFerla et?al. (²⁰⁰⁷) (3xTg-AD) that involves overexpression of mutant APP (Swe) and Tau (P301L) under the Thy1.2 promoter in homozygous mutant PS1 (M146V) knockin mice. These mice develop neurological deficits, amyloid deposition, and tangle-like pathology in the hippocampus (Oddo et?al. ^2003a, ^b).

Models with accumulation of intracellular A? have also been developed. Among the most interesting ones is a rat tg model that expresses Swe/Ind mutant hAPP751 (K670N/M671L, V717F) alone or with mutant PS1 (M146L) under the control of the PDGF-? promoter (Echeverria et?al. ^2004a, ^b). These animals are characterized by extensive intracellular amyloid accumulation, CREB activation, and tau pathology (Echeverria et?al. ^2004a, ^b). Other APP tg rat models express mutant hAPP695 (K670N/M671L) under the control of the ubiquitin-C (UbC) promoter, which shows a similar ubiquitous expression pattern as the human APP promoter (Folkesson et?al. ²⁰⁰⁷); (Agca et?al. ²⁰⁰⁸). These animals have been shown to develop extracellular amyloid deposits at 15?18?months. A third rat line carrying both mutant APP (K670N/M671L) and a human PS1 transgene with the FAD M146V mutation under the control of the rat synapsin 1 promoter develops plaques at 7?months of age (Flood et?al. ²⁰⁰⁹). While these models show promising results recapitulating the intracellular accumulation of A? that is observed in AD patients, more detailed neuropathological examination is necessary to fully characterize these models. Interestingly, the 3xTg-AD model described earlier has also been shown to accumulate intraneuronal A?, and more recent studies have focused on this as a mouse model of intracellular A? deposition. In these animals, accumulation of intraneuronal A? leads to progressive degeneration and death of neurons in the brains of tg mice (LaFerla et?al. ²⁰⁰⁷).

Remarkably, post-transcriptionally modified A? also accumulates in substantial quantities intraneuronally (Fig.?5). In particular, pyroglutamate A?_3?42 triggers a lethal phenotype with neurodegeneration in a mouse model that expresses A?_3?42 peptides under the control of the Thy1 promoter (TBA2 tg) (Wirths et?al. ²⁰⁰⁹). This model expresses A? with N-terminal glutamine (A?3Q-42) as a fusion protein with the murine thyrotropin-releasing hormone (mTRH), for transport via the secretory pathway (Cynis et?al. ²⁰⁰⁶). The levels of converted A? (3(pE)-42) in TBA2 mice are comparable to the APP/PS1 knockin mouse model (Casas et?al. ²⁰⁰⁴), with extensive neuron loss and associated behavioral deficits (Wirths et?al. ²⁰⁰⁹). Eight weeks after birth, TBA2 mice develop neurological impairments together with abundant loss of Purkinje cells (Wirths et?al. ²⁰⁰⁹). Although the TBA2 model lacks important AD-typical neuropathological features like tangles and hippocampal degeneration, it clearly demonstrates that intraneuronal A? (3(pE)-42) is neurotoxic in?vivo (Wirths et?al. ²⁰⁰⁹).

To further understand the mechanisms involved in A? deposition and clearance, a unique model of neuronal APP expression has been developed that expresses mutant (Swe/Ind) hAPP695 under the control of a tetracycline-sensitive promoter (Jankowsky et?al. ²⁰⁰⁵). This approach allows the instantaneous abolition (95%) of hAPP expression upon treatment with doxycycline. Animals were treated with antibiotic after plaques were already formed and in this model, very little new hAPP?and subsequently, A??is produced after antibiotic treatment, so the natural rate of A? clearance can be assessed. Notably, even after 12?months of suppression of APP production, amyloid deposits in the brains of treated mice remained abundant (Jankowsky et?al. ²⁰⁰⁵). This indicates that, once formed, amyloid plaques are highly resistant to dissolution in the brain, and further suggests that therapeutic approaches based solely on reducing amyloid production may not be effective, and may need to be combined with clearance-based treatments.

While most animal models of AD involve ectopic expression or overexpression of FAD-related genes, some pathological features of AD have been recapitulated in mutant and knockin animals in which FAD-causing mutations are targeted into their endogenous genes. One advantage to gene-targeted and knockin models is that developmental and tissue-specific expression patterns of human A? are relatively preserved because the gene encoding the mutant precursor protein remains in its normal chromosomal location. One of the first models to express mutant APP in its endogenous location in the mouse genome used site-specific mutagenesis to transform murine APP into ?humanized? APP bearing the Swe mutation (K670N/M671L) (Reaume et?al. ¹⁹⁹⁶). In this model, amyloidogenic processing was somewhat enhanced and measurable increases in A? production were detected (Siman et?al. ²⁰⁰⁰), however, the effects were not as robust as in APP tg models. Interestingly, in the gene-targeted mutant APP animals, the pathological process is markedly enhanced upon introduction of a PS1 P264L knockin mutation in these mutant APP animals, characterized by a large increase in A?_1?42 levels and an acceleration of age-dependent onset of amyloid pathology (Siman et?al. ²⁰⁰⁰).

It is still controversial which A? species is responsible for the neurodegenerative process in AD. While most recent studies support a role for small oligomers (dimers, trimers, up to dodecamers) (Walsh and Selkoe ²⁰⁰⁴; Glabe ²⁰⁰⁵; Glabe and Kayed ²⁰⁰⁶), others emphasize an important role for the accumulation of intracellular A? and for post-transcriptional modifications, such as pyroglutamate changes (Cynis et?al. ²⁰⁰⁸; Schilling et?al. ²⁰⁰⁸). Models reproducing the formation of A? oligomers include those expressing APP bearing the Arctic mutation (E22G) under the control of the PDGF-? promoter (Cheng et?al. ²⁰⁰⁴). This mutation is highly fibrillogenic in?vivo, and these mice rapidly develop extensive plaque formation (Cheng et?al. ²⁰⁰⁴). Mutations that increase oligomers and protofibril formation include the E22G (Arctic), E22K (Italian), E22Q (Dutch), and the D23N (Iowa) amino acid substitutions (Demeester et?al. ²⁰⁰¹; Lashuel et?al. ²⁰⁰³; Betts et?al. ²⁰⁰⁸; Fig.?3). Interestingly, all of these mutations are located within the A?-containing sequence of APP, and in addition to the apparent oligomer-promoting effect of these mutations, it has been proposed that the pathogenic effect may also be related to a resistance in proteolysis of A? (Tsubuki et?al. ²⁰⁰³). In support of this possibility, another familial APP mutation, A21G (Flemish), exhibits a significantly reduced rate of proteolysis by the A?-degrading enzyme Neprilysin (Betts et?al. ²⁰⁰⁸).

Most emphasis has been placed on the amyloid deposition in the intracellular compartment and in the plaques. However, patients with AD also develop amyloid deposition around blood vessels, a process that ultimately leads to a condition known as cerebral amyloid angiopathy (CAA). This can cause vascular fragility and hemorrhages (reviewed in Pezzini et?al. (²⁰⁰⁹)), and it is important to note that therapeutic anti-A? vaccination strategies may increase susceptibility to developing CAA (Boche et?al. ²⁰⁰⁸). Patients who have hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) generate both wild-type A? and E22Q-mutant A? (A? Dutch) (van Duinen et?al. ¹⁹⁸⁷; Levy et?al. ¹⁹⁹⁰). The brains of patients with HCHWA-D show CAA with very little parenchymal amyloid deposition (Herzig et?al. ²⁰⁰⁶). To date, there are several mouse models that deposit amyloid in the blood vessels, including some models more widely used to study parenchymal A? accumulation, such as the Tg2576 mouse (Hsiao et?al. ¹⁹⁹⁶; Frackowiak et?al. ²⁰⁰³). The only mouse model that develops significant cerebrovascular amyloid with virtually no parenchymal amyloid is the APPDutch mouse, which overexpresses hAPP751 bearing the E693Q (E22Q in A?) mutation under the control of the Thy1 promoter (Herzig et?al. ²⁰⁰⁴). More recently, the same group has also developed a new model of CAA by crossing the APPDutch mutant mice with APP23 mice that express mutant hAPP751 (Swe) under the control of the Thy1 promoter (Herzig et?al. ²⁰⁰⁹). While the classical APP23 mice display extracellular A? plaques, double-tg APP23/APPDutch mice co-deposited A? Dutch (mainly A? Dutch1-40) and wild-type A? at twofold levels in the vasculature, with reduced parenchymal deposition (Herzig et?al. ²⁰⁰⁹). Hemorrhages were also significantly increased in the double-tg mice. These studies suggest that A? Dutch1-40 increases vascular deposits and reduces parenchymal amyloidosis similar to HCHWA-D patients.

For a comprehensive review of these and additional tg models of neurodegenerative disease, please visit the Alzheimer?s forum website at: http://www.alzforum.org/res/com/tra.

The most significant correlate to the severity of the cognitive impairment in AD is the loss of synapses in the frontal cortex and limbic system (DeKosky and Scheff ¹⁹⁹⁰; Terry et?al. ¹⁹⁹¹; Masliah and Terry ¹⁹⁹⁴; DeKosky et?al. ¹⁹⁹⁶; Figs.?2, 4). The pathogenic process in AD involves alterations in synaptic plasticity that include changes in formation of synaptic contacts, changes in spine morphology, and abnormal area of synaptic contact (Scheff and Price ²⁰⁰³). However, other cellular mechanisms necessary to maintain synaptic plasticity might also be affected in AD (Cotman et?al. ¹⁹⁹³; Masliah ²⁰⁰⁰; Masliah et?al. ²⁰⁰¹). Recent studies indicate that neurogenesis in the mature brain plays an important role maintaining synaptic plasticity and memory formation in the hippocampus (van Praag et?al. ²⁰⁰²). In the adult nervous system, motor activity and environmental enrichment (EE) have been shown to stimulate neurogenesis in the hippocampal dentate gyrus (DG) (Gage et?al. ¹⁹⁹⁸; van Praag et?al. ²⁰⁰²). Physiological neurogenesis in the adult brain is regulated by numerous cell extrinsic and intrinsic factors, including local cytokine/chemokine signals and intracellular signal transduction (Johnson et?al. ²⁰⁰⁹). In this context, recent studies have shown that, among other pathways, the Notch (Breunig et?al. ²⁰⁰⁷; Crews et?al. ²⁰⁰⁸), cyclin-dependent kinase-5 (CDK5) (Jessberger et?al. ²⁰⁰⁸; Lagace et?al. ²⁰⁰⁸), and wnt/bone morphogenetic protein (BMP) (Lim et?al. ²⁰⁰⁰; Lie et?al. ²⁰⁰⁵) cascades are involved in regulating adult neurogenesis. Interestingly, studies of human brains (Tatebayashi et?al. ²⁰⁰³) and tg animal models have demonstrated significant alterations in the process of adult neurogenesis in the hippocampus in AD (Dong et?al. ²⁰⁰⁴; Jin et?al. ²⁰⁰⁴; Wen et?al. ²⁰⁰⁴; Chevallier et?al. ²⁰⁰⁵; Donovan et?al. ²⁰⁰⁶). The deficient neurogenesis in the subgranular zone (SGZ) of the DG found in our APP tg mice (Rockenstein et?al. ²⁰⁰⁷; Fig.?6) is consistent with studies of other lines of APP tg mice and other models of AD that have shown decreased markers of neurogenesis, such as bromo-deoxyuridine (BrdU)+, and doublecortin (DCX)+ cells, with an increase in the expression of markers of apoptosis (Feng et?al. ²⁰⁰¹; Haughey et?al. ²⁰⁰²; Dong et?al. ²⁰⁰⁴; Wang et?al. ²⁰⁰⁴).

A different study reported increased neurogenesis in the PDAPP model (Jin et?al. ²⁰⁰⁴). Another recent study showed that in 5-month-old APP23 tg mice prior to amyloid deposition, there was no robust difference in neurogenesis relative to wild-type control mice, but 25-month-old amyloid-depositing APP23 mice showed significant increases in neurogenesis compared to controls (Ermini et?al. ²⁰⁰⁸). In contrast, 8-month-old amyloid-depositing APP/PS1 tg mice revealed decreases in neurogenesis compared to controls. Furthermore, 8-month-old nestin-GFP???APP/PS1 mice exhibited decreases in quiescent nestin-positive astrocyte-like stem cells, while transient amplifying progenitor cells did not change in number (Ermini et?al. ²⁰⁰⁸). Strikingly, both astrocyte-like and transient-amplifying progenitor cells revealed an aberrant morphologic reaction toward congophilic amyloid deposits. A similar reaction toward the amyloid was no longer observed in doublecortin-positive immature neurons (Ermini et?al. ²⁰⁰⁸). These results provide evidence for a disruption to neuronal progenitor cells (NPCs) in an amyloidogenic environment and support findings that neurogenesis is differentially affected among various tg mouse models of AD, probably due to variations in promoter cell type specificity, expression levels, and other factors. A more comprehensive analysis of neurogenesis in APP tg mice showed that while in the molecular layer (ML) of the DG there is an increased number of NPC, in the SGZ markers of neurogenesis are decreased, indicating that in PDAPP animals there is altered migration and increased apoptosis of NPC that contributes to the deficits in neurogenesis (Donovan et?al. ²⁰⁰⁶).

The molecular mechanisms of aberrant neurogenesis in AD are unclear, however, several signaling pathways that control physiological adult neurogenesis are known to be dysregulated in AD. For example, CDK5 is hyperactivated in AD by A? peptide-mediated calcium influx (Lee et?al. ²⁰⁰⁰). In mature neurons, this contributes to neurodegeneration by promoting aberrant phosphorylation of downstream targets of CDK5 such as tau (Ahlijanian et?al. ²⁰⁰⁰), however, the direct effects on NPCs are unknown. It is possible that kinases, such as CDK5 that are disturbed in mature neurons in AD may also play a role in the mechanisms of disrupted neurogenesis in the adult AD brain.

While a considerable body of work is currently emerging on neurogenic alterations associated with the pathogenesis of AD, it is important to keep the role of neurogenesis in perspective given the relatively limited number of brain regions that are neurogenic. It is an exciting prospect that new neurons from progenitor cells in the hippocampus could replace cells damaged during the pathogenesis of AD. However, the extent to which progenitor cells might integrate into already-established neural circuitry is unclear, and the problem of re-establishing long inter-regional connections is considerable. Furthermore, taking into account the distribution of AD pathology among various non-neurogenic brain regions, such as the entorhinal cortex and neocortex, it is possible that neurogenesis may not be an ideal target for repairing global neuronal damage in the brain. However, given the critical role of the hippocampus in the processes of learning and memory, and the recent studies showing that neurogenesis plays an important part in these functions (van Praag et?al. ²⁰⁰²), it is possible that modulation of neurogenesis in this area might have therapeutic potential. Moreover, it is important to consider the interconnected circuitry that characterizes the brain?s architecture. Although AD pathology in the hippocampus primarily affects the non-neurogenic pyramidal cell layers, the granular cells extend processes into the pyramidal layers, and additionally affect the connectivity of the entorhinal cortex via the perforant pathway. Taken together, much further work will be necessary to fully understand the role of neurogenesis in the pathogenesis of AD and the therapeutic potential of harnessing the regenerative capacity of progenitor cells.

Alterations in synaptic plasticity in AD might involve not only direct damage to the synapses but also interference with adult neurogenesis (Fig.?2). The mechanisms of synaptic pathology in AD are the subject of intense investigation. Studies of experimental models of AD and in human brain support the notion that aggregation of A?, resulting in the formation of toxic oligomers rather than fibrils, might be ultimately responsible for the synaptic damage that leads to cognitive dysfunction in patients with AD (Walsh and Selkoe ²⁰⁰⁴; Glabe ²⁰⁰⁵; Glabe and Kayed ²⁰⁰⁶; Fig.?1). Supporting this notion, it has been shown that A? oligomers reduce synaptic transmission and dendritic spine movement (Lacor et?al. ²⁰⁰⁴; Moolman et?al. ²⁰⁰⁴; Walsh and Selkoe ²⁰⁰⁴), and interfere with axoplasmic flow and activate signaling pathways that might lead to synaptic dysfunction, tau hyperphosphorylation, and cell death. Moreover, a dodecameric A? complex denominated *56 has been recently characterized (Lesne et?al. ²⁰⁰⁶) in brains from APP tg mice and shown to contribute to the behavioral alterations in these animals. The differential effects of this and other toxic oligomeric species of A? in mature and developing neurons and synapses awaits further investigation.

The accumulation of A? in the CNS and the formation of toxic oligomers most likely depend on the rate of A? aggregation, synthesis, and clearance (Fig.?7). Although most effort has been concentrated at elucidating the mechanisms of A? production and aggregation (Luo et?al. ¹⁹⁹⁹; Sinha et?al. ¹⁹⁹⁹; Vassar et?al. ¹⁹⁹⁹; Selkoe ²⁰⁰⁰; Cai et?al. ²⁰⁰¹), less is known about the mechanisms of A? clearance. As previously discussed in the section on tg models, the conditional APP tg model showed that enhancing clearance of A? may actually be more critical than preventing its production when considering potential therapies. This is also important because while most familial forms of AD might result from mutations that affect the rate of A? synthesis and aggregation, sporadic AD might be the result of alterations in A? clearance (Fig.?7). Pathways involved in A? clearance include LDLR-related protein (LRP) ligands, such as apolipoprotein E (ApoE) (Holtzman et?al. ¹⁹⁹⁵, ¹⁹⁹⁹), lysosomal degradation (Nixon et?al. ¹⁹⁹², ²⁰⁰⁵) and cleavage by proteolytic enzymes, such as Neprilysin, insulin-degrading enzyme (IDE), endothelin-converting enzyme (ECE), angiotensin converting enzyme (ACE), and matrix metalloproteinase-9 (MMP9) (Iwata et?al. ²⁰⁰⁰, ²⁰⁰¹; Selkoe ²⁰⁰¹; Carson and Turner ²⁰⁰²; Leissring et?al. ²⁰⁰³; Marr et?al. ²⁰⁰⁴; Eckman and Eckman ²⁰⁰⁵; Saito et?al. ²⁰⁰⁵; Fig.?7).

The relationship among the patterns of A? production, 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 dropout in early stages of pathogenesis (Irizarry et?al. ^1997a, ^b). In fact, the earliest neuronal pathology before amyloid deposition is the loss of synapses and dendrites in the limbic system and neocortex (Hsia et?al. ¹⁹⁹⁹; Mucke et?al. ²⁰⁰⁰). This is accompanied by neurophysiological deficits and alterations in long-term potentiation (LTP) and field potential (Chapman et?al. ¹⁹⁹⁹; Hsia et?al. ¹⁹⁹⁹). Since the synaptic damage in these mice correlates better with the levels of soluble A?_1?42 than with plaques, it has been proposed that neurodegeneration might be associated more with the neurotoxic effects of A? oligomers than with fibrillar amyloid (Mucke et?al. ²⁰⁰⁰). In agreement with this possibility, studies of brain slices have shown that A? oligomers rather than fibrillar amyloid are toxic to synapses and depress LTP, leading to cognitive impairment (Walsh et?al. ²⁰⁰²).

Other recently developed models have also focused on defining the effects of APP and its products on functional markers, including behavioral performance and LTP. These studies have shown that overexpression of the C-terminal APP fragment C100 under the control of neurofilament (NF) promoter results in amyloid-like production and electrophysiological alterations (Nalbantoglu et?al. ¹⁹⁹⁷). 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 in the ability to overexpress high levels of mutant APP, which is in a way rather non-physiological event. With the exception of Down syndrome, in sporadic AD there is no evidence for upregulation of APP expression but rather a shift in the ratio between APP770 and 751 to APP695. In this regard, a previous study (van Leeuwen et?al. ¹⁹⁹⁸) has shown frame shift mutations in APP and ubiquitin genes are present in some AD patients. It is conceivable that future tg models might utilize this mechanism in an attempt to reflect the more common sporadic forms of the disease.

In summary, a number of known mutations in the APP gene associated with familial forms of amyloid disorders have made it possible to recapitulate several features of amyloid pathology in the brains of tg animal models. While other genes, such as PS1 and tau have been manipulated alone or in combination with APP mutations, a large portion of the current literature describing the AD-like neurodegenerative phenotypes in animal models has been based on animal models expressing high levels of mutant APP. While APP tg murine models with mutations in the N- and C-terminal flanking regions of A? are characterized by increased A? production with plaque formation, mutations in the mid-segment of A? result in increased formation of oligomers, and mutations toward the C-terminus (E22Q) segment results in amyloid angiopathy. Several lines of evidence suggest that formation of A? oligomers reduces neuroplasticity and contributes to neuronal degeneration and alterations in neurogenesis. Specifically targeting these toxic oligomeric species of A? with ?- and ?-secretase inhibitors, immunization, and neurogenesis-stimulating therapies may provide individual or combination treatments that ameliorate multiple features of AD pathology.

This work was supported by National Institutes of Health grants AG5131, AG11385, AG10435, NS44233 and AG18440.

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