Chapter 4: Transgenic Mice Overexpressing GSK-3β as Animal Models for Alzheimer's Disease

Alzheimer's disease (AD) is characterized by two neuropathological hallmarks, senile plaques and neurofibrillary tangles (NFT). Senile plaques are extracellular deposits of amyloid fibrils composed of the β-amyloid peptide. NFT are intraneuronally generated aggregates of paired helical filaments (PHF), which are assembled from hyperphosphorylated forms of the microtubule-associated protein tau. Glycogen synthase kinase-3β (GSK3β) has been proposed as the link between these two neuropathological hallmarks of AD and deregulation of GSK3β activity in neurons has been postulated as a key feature in AD pathogenesis. This is based on the interaction of GSK3 with many of the cellular components related to the neuropathology of AD, such as the amyloid precursor protein, the β-amyloid peptide, the metabolic pathway leading to acetylcholine synthesis, the presenilins, which are mutated in many cases of familial AD, and tau protein. In this chapter, a resume of transgenic GSK3 mice overexpressing wild-type and different mutant isoforms as well as the additional AD models that results from the breeding of these GSK3 mice with mice overexpressing proteins altered in AD are summarized. The possibility of using these animal models to test novel therapeutic interventions aimed at blocking GSK3 to ameliorate AD pathology is also discussed.