Preclinical models of Alzheimer’s disease for identification and preclinical validation of therapeutic targets: from fine-tuning strategies for validated targets to new venues for therapy

Abstract

Animal models recapitulate characteristic pathological features of Alzheimer’s disease and related tauopathies, in addition to several phenotypic traits reminiscent of the disease. These animal models have been used as a central tool in the identification of therapeutic targets and their preclinical validation. A major focus has been on therapies targeting amyloid-β (Aβ). However, clinical trials aiming at Aβ have led to the general view that once the disease process has started, multitargeted combined therapies are required for disease-modifying therapies, including downstream targets in the amyloid cascade. These include not only tau as a crucial executor of the pathogenesis, but also mechanisms involved in spreading of tau-pathology and in Aβ-induced tau-pathology. In this work, we review the use of preclinical models for identification of targets for disease-modifying therapies. We thereby focus on the initial validation of targets currently tested in clinical trials, their constraints and subsequent fine-tuning, and on new venues for future therapies currently under study in preclinical models.