Upregulated function of mitochondria-associated ER membranes in Alzheimer disease
By E. Area‐Gomez, Maria del Carmen Lara Castillo, M. Tambini, C. Guardia-Laguarta, Ad J C de Groof, Moneek Madra, Junichi Ikenouchi, M. Umeda, T. Bird, S. Sturley and 1 more. EMBO Journal, 2012
620 citations recorded by the source corpus.
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.
Subfields: Molecular Biology, Physiology
View Paper: https://www.semanticscholar.org/paper/5fd563e57da335c1d95130926c52724ef437c8b3
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Molecular Biology
In Physiology
Citations in the corpus
- Endoplasmic Reticulum Stress and Associated ROS (2016, background): “Next, the mitochondrial membrane potential dissipates, further accumulating mitochondrial ROS [100].”
- Recent advances in Alzheimer’s disease: mechanisms, clinical trials and new drug development strategies (2024, background): “324 – 326 Under the in fl uence of A β , the expression of some MAM-related proteins, such as IP3Rs and VDAC1, is signi fi cantly increased, 325,327,328 leading to mitochondrial Ca 2 + overload, inhibition of normal ATP synthesis, and potential release of apoptotic signals.”