The amyloid precursor protein intracellular domain (AICD) as modulator of gene expression, apoptosis, and cytoskeletal dynamics—Relevance for Alzheimer's disease

Since the discovery of the amyloid precursor protein (APP) in 1987, extensive research has been conducted analyzing the APP-derived β-amyloid (Aβ) which is found in massive quantities in senile plaques of Alzheimer disease (AD) patients. Numerous studies over the last two decades have demonstrated the neurotoxic properties of Aβ. However, it is still unclear whether Aβ neurotoxicity is an initial cause or rather a late event in the pathophysiology of AD. The understanding of preclinical AD-related pathophysiological mechanisms is of significant interest in the identification of potential pharmacological targets. In this context another APP-derived cleavage product, the amyloid precursor protein intracellular domain (AICD), has sparked considerable research interest over the last 7 years. Different AICD levels as a result of γ-secretase activity may contribute to early pathophysiological mechanisms in AD. However, the relevance of AICD is being discussed highly controversially amongst AD researchers. This review summarizes recent findings in terms of the origin of AICD by regulated intramembrane proteolysis; its structure, binding factors, and post-translational modifications; and its putative role in gene transcription, apoptosis, and cytoskeletal dynamics.