Animal and Cellular Models of Alzheimer’s Disease: Progress, Promise, and Future Approaches

Abstract

Alzheimer’s disease (AD) is an incurable neurodegenerative disease affecting over 45 million people worldwide. Transgenic mouse models have made remarkable contributions toward clarifying the pathophysiological mechanisms behind the clinical manifestations of AD. However, the limited ability of these in vivo models to accurately replicate the biology of the human disease have precluded the translation of promising preclinical therapies to the clinic. In this review, we highlight several major pathogenic mechanisms of AD that were discovered using transgenic mouse models. Moreover, we discuss the shortcomings of current animal models and the need to develop reliable models for the sporadic form of the disease, which accounts for the majority of AD cases, as well as human cellular models to improve success in translating results into human treatments.

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“…For the purpose of designing therapeutics or disease modifying agents for AD treatment, a wide variety of animal models have been developed to replicate the human environment of the disease [ 70 , 71 , 72 , 73 , 74 ]. In particular, the first aim of most AD animal models is to develop the neuropathological features that precede the cognitive dysfunction [ 75 , 76 , 77 ].…”

“…The transgenic mice are important models for deciphering familial AD pathology pathways. These models do not display all the anomalies found in human AD and do not duplicate the sporadic forms of AD, because they only reproduce the pathological features of AD common mutated genes [ 77 ]. However, transgenic innovation gives special opportunity to replicate the cause of familial AD by transfecting a mutant human APP [ 74 , 75 ].…”

“…Transgenic mice models developed by over-expression of mutated human PS1, APP and tau, are the majority of these animal models. The triple-transgenic 3xTg-AD mice contains three mutated genes (human PS1M146V, APPSwe and tauP301L) and develops increasing age-dependent amyloid plaques and NFTs as well as memory deficits [ 76 , 77 , 78 ] ( Table 1 ).…”

“…On the other hand, many of the signature features of AD are reproduced by the injection of pharmacological or chemical agents into the brain or by the activation of lesions in specific brain regions [ 76 , 77 , 78 ]. For instance, the injection of Aβ peptide into the brain of rat or rhesus monkey has been used in several studies.…”

“…In general, interventional models will be effective for detecting symptomatic or therapeutic interventions as a disease model. These models can include valuable observations such as the streptozotocin (STZ)-induced AD model, scopolamine-mediated amnesia model that led to learning and memory loss and cognition dysfunction [ 76 , 77 , 78 , 79 , 80 ]. For instance, in scopolamine-induced amnesia models, inflammation is activated by endotoxins and the brain metabolism interacts with other chemical action models [ 73 ].…”