Amyloid precursor protein ‐mediated mitochondrial regulation and Alzheimer's disease

Despite clear evidence of a neuroprotective physiological role of amyloid precursor protein (APP) and its non ‐amyloidogenic processing products, APP has been investigated mainly in animal and cellular models of amyloid pathology in the context of Alzheimer's disease. The rare familial mutations in APP and presenilin‐1/2, which sometimes drive increased amyloid beta (Aβ) production, may have unduly inf luenced Alzheimer's disease research. APP and its cleavage products play important roles in cellular and mitochondrial metabolism, but many studies focus solely on Aβ. Mitochondrial bioenergetic metabolism is essential for neuronal function, maintenance and survival, and multiple reports indicate m itochondrial abnormalities in patients with Alzheimer's disease. In this review, we focus on mitochondrial abnormalities reported in sporadic Alzheimer's disease patients, and the role of full‐length APP and its non‐amyloidogenic fragments, particularly soluble APP α (sAPPα), on mitochondrial bioenergetic metabolism. We do not review the plethora of animal andin vitro studies using mutant APP/presenilin constructs or experiments using exogenous A β. In doing so, we aim to invigorate research and discussion around non‐amyloidogenic APP processing products and the mechanisms linking mitochondria and complex neurodegenerative disorders such as sporadic Alzheimer's disease.
Source: British Journal of Pharmacology - Category: Drugs & Pharmacology Authors: Tags: REVIEW ARTICLE THEMED ISSUE Source Type: research