Amyloid precursor protein and tau transgenic models of Alzheimer's disease: insights from the past and directions for the future

Abstract

During the last 20 years, our understanding of the mechanisms underlying Alzheimer's disease (AD) has considerably improved, in part owing to both in vitro and in vivo model systems. Studies in mice expressing both human amyloid precursor protein and human tau have provided clear evidence that amyloid-beta and tau interact in the pathogenesis of AD. Moreover, amyloid-beta toxicity has been shown to be tau-dependent since reducing tau levels prevents behavioral deficits and sudden death in amyloid precursor protein transgenic mice. As tau pathology preferentially develops in specific sites and spreads in a predictable manner across the brain, understanding the mechanism underlying tau dysfunction should be a focus in AD mouse modeling. A defined effort must be made to develop therapies that directly address the impact of tau dysfunction in the pathogenesis of AD. Finally, early diagnosis of AD is essential and this must be made possible by identification of early biomarkers, behavioral changes or use of novel imaging techniques.

Figure 1. Disease cascades leading to amyloidosis and tauopathy in humans and mouse models

Mutations in APP and PSEN genes can lead to AD; however, the discovery of mutations within the MAPT gene encoding tau protein demonstrated that tau dysfunction alone could cause neurodegeneration, at least in FTDP-17. It is still unclear how amyloid influences the tau cascade to yield both amyloid and tau pathology within the same disease (AD). Given this, a number of Tg mice have been generated to provide models in which we can examine the origin of the main pathological features of these diseases and ultimately test therapeutics aimed at abrogating toxic species of amyloid or tau. A number of different models are listed under the cascade that they attempt to model. Tau levels are noted in each of these models where endogenous is represented as (+), overexpression is represented as (+++), and degree of tau deficiency is either (-) or (+/-). Salient features of AD or FTDP-17 that are recapitulated within each model are noted. Aβ: Amyloid β; AD: Alzheimer's disease; APP: Amyloid precursor protein; PSEN: Presenilin; FAD: Familial AD; FTDP: Frontotemporal Dementia with Parkinson's; tg: Transgenic.