Increased ER-Mitochondrial Communnication in the Pathogenesis of Alzheimer Disease
Abstract
We discovered that PS1, PS2, and ?-secretase activity, are localized predominantly in mitochondria-associated ER membranes (MAM), a key regulator of phospholipid metabolism, cholesterol metabolism, and calcium homeostasis, all of which activities are perturbed in AD. In the past year, we published a paper showing that presenilins are negative regulators of MAM function, and that MAM function is upregulated not only in cells from FAD patients, but, remarkably, also in those with sporadic AD in which the presenilin genes are normal. We also published a "thought piece" discussing how we think perturbed MAM function causes AD. More recently, we have now discovered found that the "active," cleaved form of PS1 is localized to MAM, whereas the inactive, uncleaved form, is present in "bulk" ER. This finding supports a role for MAM in AD and explains why MAM is a key player in the disease pathogenesis. We are now pursuing this discovery on a number of fronts, including (1) analyzing human AD brain for MAM markers, (2) analyzing MAM function in human induced stem cells differentiated into neurons, and (3) making the appropriate "bifunctional" constructs that will tether ER to mitochondria, to ask how such apposition affects MAM function.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jun 25, 2021
- Source ID
- W911NF1210159
Entities
People
- Eric Schon
Organizations
- Army Contracting Command
- Columbia University
- United States Army