Upregulated function of mitochondria-associated ER membranes in Alzheimer disease

Alzheimer disease (AD) is associated with aberrant processing of the amyloid precursor protein (APP) by gamma-secretase, via an unknown mechanism. We recently showed that presenilin-1 and -2, the catalytic components of gamma-secretase, and gamma-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 gamma-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. The EMBO Journal (2012) 31, 4106-4123. doi: 10.1038/emboj.2012.202; Published online 14 August 2012