Mitochondria in alzheimer’s disease

Abstract

The pathogenesis of Alzheimer disease (AD) is associated with aberrant proteolytic processing of the amyloid precursor protein (APP) - first by b-secretase to generate a 99-aa C-terminal fragment (C99) and then by g-secretase (containing presenilins-1 [PS1] or -2 [PS2]) that cleaves C99 to generate the APP intracellular domain and the b-amyloid (Ab) that is found in extraneuronal plaques - but the relationship of the former to the latter is unclear. Whereas plaques typically form late in disease progression, early events include aberrant lipid metabolism and mitochondrial dysfunction. We recently showed that PS1, PS2, and g-secretase activity itself are highly enriched in a subdomain of the endoplasmic reticulum (ER) that communicates with mitochondria, called mitochondria-associated ER membranes (MAM), and that ER-mitochondrial connectivity and MAM function are highly upregulated in presenilin-mutant cells and in cells from AD patients. However, the relationship of perturbed APP processing to MAM-related AD phenotypes has been unclear. MAM, which is a lipid raft rich in cholesterol and sphingomyelin, is a key regulator of lipid metabolism and of mitochondial dynamics, among other processes. We now show that C99 is highly enriched in the MAM, and that it plays a central role in regulating cellular cholesterol and sphingolipid homeostasis and mitochondrial bioenergetics. Furthermore, in cells from AD patients and in cell and animal models of AD, C99 levels are increased significantly, resulting in a disruption of lipid homeostasis that is triggered by the unregulated uptake of extracellular cholesterol, with downstream consequences that mimic the biochemical features of AD, including the bioenergetic deficits. We propose that MAM-localized C99 is a component of the cell's lipid sensing machinery and that its accumulation is a key and early event in AD pathogenesis that can explain many of the biochemical and morphological features of the disease.