Nuclear signalling by membrane protein intracellular domains: The AICD enigma

Alzheimer's disease (AD) is a neurodegenerative illness and the leading cause of dementia in the elderly. The accumulation of amyloid-β peptide (Aβ) is a well-known pathological hallmark associated with the disease. However, Aβ is only one of several metabolites produced by β- and γ-secretase actions on the transmembrane protein, the amyloid precursor protein (APP). A proteolytic fragment termed the APP intracellular domain (AICD) is also produced. By analogy with the Notch signalling pathway, AICD has been proposed as a transcriptional regulator although its mechanism of action and the complement of genes regulated remain controversial. This review will focus on the contributions that studies of APP processing have brought to the understanding of a novel nuclear signalling pathway that may contribute to the pathology of AD and may provide new therapeutic opportunities.

► The Alzheimer's amyloid precursor protein has a diverse metabolome.
► Its intracellular domain (AICD) selectively controls neuronal gene expression.
► Here we review pathways, regulation and controversies of AICD nuclear signalling.
► AICD biology may contribute to AD pathology and provide new therapeutic directions.