Details

Autor(en) / Beteiligte

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

Titel

Upregulated function of mitochondria-associated ER membranes in Alzheimer disease

Ist Teil von

• The EMBO journal, 2012-11, Vol.31 (21), p.4106-4123

Ort / Verlag

Chichester, UK: John Wiley & Sons, Ltd

Erscheinungsjahr

2012

Link zum Volltext

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• 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. Alzheimer disease (AD) associated (gamma)‐secretase components presenilin‐1 and ‐2 accumulate in MAM, an LR‐like ER subcompartment connected to mitochondria. MAM function increases in patients with familial or sporadic AD and may be linked to AD pathogenesis.