EMBO Journal 2012-11-05

Upregulated function of mitochondria-associated ER membranes in Alzheimer disease.

Estela Area-Gomez, Maria Del Carmen Lara Castillo, Marc D Tambini, Cristina Guardia-Laguarta, Ad J C de Groof, Moneek Madra, Junichi Ikenouchi, Masato Umeda, Thomas D Bird, Stephen L Sturley, Eric A Schon

Index: EMBO J. 31 , 4106-23, (2012)

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Abstract

Alzheimer disease (AD) is associated with aberrant processing of the amyloid precursor protein (APP) by γ-secretase, via an unknown mechanism. We recently showed that presenilin-1 and -2, the catalytic components of γ-secretase, and γ-secretase activity itself, are highly enriched in a subcompartment of the endoplasmic reticulum (ER) that is physically and biochemically connected to mitochondria, called mitochondria-associated ER membranes (MAMs). We now show that MAM function and ER-mitochondrial communication-as measured by cholesteryl ester and phospholipid synthesis, respectively-are increased significantly in presenilin-mutant cells and in fibroblasts from patients with both the familial and sporadic forms of AD. We also show that MAM is an intracellular detergent-resistant lipid raft (LR)-like domain, consistent with the known presence of presenilins and γ-secretase activity in rafts. These findings may help explain not only the aberrant APP processing but also a number of other biochemical features of AD, including altered lipid metabolism and calcium homeostasis. We propose that upregulated MAM function at the ER-mitochondrial interface, and increased cross-talk between these two organelles, may play a hitherto unrecognized role in the pathogenesis of AD.