“A different way of thinking about Alzheimer disease”

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Date: January 14, 2021
Time: 11:00 a.m. - 12:00 p.m.
Location: Virtual event
Category: Seminar

Eric A. Schon, PhD, Lewis P. Rowland Professor of Neurology (in Genetics and Development), Columbia University

“A different way of thinking about Alzheimer disease”

Abstract: Alzheimer disease (AD) is characterized by neuronal loss, especially in the cortex and hippocampus, accompanied by accumulation in the brain of extracellular neuritic plaques containing -amyloid (A), and of intracellular neurofibrillary tangles consisting of hyperphosphorylated tau protein. The most widely accepted hypothesis of AD pathogenesis, called the "amyloid cascade," is aimed at explaining plaques and tangles as the proximal cause of the disease. However, it does not explain other features of AD that have received far less attention, including aberrant cholesterol, phospholipid, and calcium homeostasis, and altered mitochondrial function and dynamics. Another challenge in deducing the molecular mechanisms underlying AD is our lack of an understanding of the precise subcellular localization(s) of presenilin-1 (PS1) and presenilin-2 (PS2), the catalytic core of -secretase that processes the amyloid precursor protein (APP) to produce A. We have found that PS1 and PS2, and the 99-aa C-terminal fragment of APP that is the immediate substrate of -secretase, as well as -secretase activity itself, are all located predominantly in mitochondria-associated ER membranes (MAM), a lipid raft-like subdomain of the ER that communicates, both physically and biochemically, with mitochondria. Moreover, cells from AD patients have massively increased ER-mitochondrial connectivity and upregulated MAM activity, resulting in altered cholesterol, phospholipid, and calcium homeostasis, and in aberrant mitochondrial dynamics and function. These results may help explain not only the deposition of A in plaques, but also many of the seemingly unrelated biochemical and morphological features of the disease, including the bioenergetic defects. Based on these findings, we propose that ER-mitochondrial hyperconnectivity plays a fundamental role in the pathogenesis of AD (the "MAM hypothesis"), with major implications for both diagnosis and treatment of this devastating disorder.


Suzanne Shaw




Current students, Faculty