Based on genetic links identified from the human population associated with developing AD, several transgenic mouse models have been generated to recapitulate specific aspects of AD pathology. Interestingly, rare mutations appear capable of producing the full scope of AD pathology in humans, but when expressed in mice, these transgenes recapitulate only specific aspects of AD (reviewed in (Ashe and Zahs, 2010
). Despite their shortcomings, AD animal models have been extraordinarily instructive. Given that aberrant APP processing is suggested to temporally precede tau alterations and has been directly linked with spine degeneration (Selkoe, 2002
), this review will emphasize animal models that mimic amyloidogenesis.
Due to the profound memory loss associated with AD, it is necessary to test AD mouse models for behavioral deficits indicative of cognitive impairment, especially impairment in reference memory and working memory. Many models display memory impairment as well as aberrant LTP expression (Ashe and Zahs, 2010
). Additionally, the prominent synapse pathology observed in AD patients has prompted the investigation of spine morphology and density in AD models. The widely used Tg2576 mouse model (Hsiao et al., 1996
), which expresses human APP containing mutations identified in a large Swedish family, display decreased spine density in CA1 and DG much before the formation of amyloid plaques, supporting a role for Aβ oligomers in mediating at least some AD-related pathology (Jacobsen et al., 2006
; Lanz et al., 2003
). Interestingly, cognitive impairment also becomes evident in these mice prior to plaque development but around the time when spines become depleted, suggesting that synapse loss can drive cognitive decline. Expressing mutations in APP
in mice leads to neurons with fewer large spines and various dendritic abnormalities (Knafo et al., 2009
). Such dendritic abnormalities include shaft atrophy, neurite breakage, and greater reductions in spine density near amyloid deposits (Grutzendler et al., 2007
; Tsai et al., 2004
). Similarly, amyloid plaques in Tg2576 mice alter neurites and reduce spine density on dendrites nearby (Spires et al., 2005
). Taken together, these studies suggest that both soluble and insoluble amyloid can have deleterious effects on neurons by perturbing synaptic connections as well as dendritic projections. It should be noted, though, that substantial synapse degeneration appears to take place prior to plaque deposition. It will thus be important to explore dendrite and spine phenotypes in newly generated animal models and at time-points before widespread deposition of amyloid plaques. Many AD animal models support the concept that synaptic degeneration is central to the disease and may serve as a driving force, rather than a byproduct, of AD pathology that leads to memory impairment. Importantly, structural alterations have been reported to be reversible pharmacologically, opening new therapeutic directions in AD (Smith et al., 2009
Despite major advances made possible by the use of animal models, the available models are incomplete and the findings they produce should be taken in conjunction with the limitations of each model. Most models mimic only one or a few components of AD, thus they provide insight about a narrow aspect of the disease, not necessarily the disease as a whole. While genetic manipulations in animals may help identify the role of individual proteins in AD pathogenesis, they could also elucidate important common pathways affected in the disease. Determining the specific pathways disrupted in AD and understanding how they contribute to AD pathology is thus an important next step.