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. AD patients also present with other features that have received less attention, including aberrant cholesterol, phospholipid, and calcium homeostasis, and altered mitochondrial function and dynamics. Presenilin-1 (PS1), presenilin-2 (PS2), and ?-secretase activity, which processes the amyloid precursor protein (APP) to generate A, are all located predominantly in a specialized subcompartment of the endoplasmic reticulum (ER) that is physically and biochemically connected to mitochondria, called mitochondria-associated ER membranes (MAM). MAM is involved in the regulation of cholesterol and phospholipid metabolism, calcium homeostasis, and in mitochondrial function and dynamics. Recently, we showed that MAM is lipid raft-like domain and that cells from AD patients have massively upregulated MAM activity and increased ER mitochondrial connectivity, resulting in altered cholesterol, phospholipid and calcium homeostasis, and aberrant mitochondrial dynamics, which may help explain many of the biochemical and morphological features of the disease. Based on these findings, we believe that MAM dysfunction and altered ER-mitochondrial connectivity are early causative events in the pathogenesis of AD. We now propose studies aimed at understanding MAM function from a basic science standpoint, with the ultimate goal of applying this knowledge translationally. Specifically, we will (1) analyze MAM function in cells and tissues that are more AD-relevant, including PS-deficient human neuroblastoma cells, human induced pluripotent stem cells differentiated into neurons, and tissues and neurons explanted from PS1 knock-in mice; (2) analyze presenilins and ?-secretase regulation in MAM versus other compartments, such as bulk ER or the plasma membrane, while also assessing the role of other components (e.g. APH-1, nicastrin, PEN2) and regulators (e.g. CD147, GSAP, and TMP21) of the ?-secretase complex; and (3) understand the role of ER-mitochondrial communication in the pathogenesis of AD, by tethering ER to mitochondria at various fixed distances, using novel ER-mitochondria crosslinking plasmids, in order to mimic ER-mitochondrial connectivity in a presenilin-independent manner.

Public Health Relevance

We have developed a novel hypothesis to explain the pathogenesis of Alzheimer Disease (AD), based on our observation of significant upregulation of the communication between the endoplasmic reticulum (ER) and mitochondria in AD cells, via ER-mitochondrial membranes, or MAM. We now propose to study MAM in greater detail, in order to obtain insight into how AD arises, with an ultimate goal of diagnosing and treating this devastating disorder.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
5K01AG045335-02
Application #
8915031
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Yang, Austin Jyan-Yu
Project Start
2014-09-01
Project End
2019-06-30
Budget Start
2015-07-15
Budget End
2016-06-30
Support Year
2
Fiscal Year
2015
Total Cost
$113,379
Indirect Cost
$8,398
Name
Columbia University (N.Y.)
Department
Neurology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Area-Gomez, Estela; de Groof, Ad; Bonilla, Eduardo et al. (2018) A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease. Cell Death Dis 9:335
Pera, Marta; Larrea, Delfina; Guardia-Laguarta, Cristina et al. (2017) Increased localization of APP-C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease. EMBO J 36:3356-3371
Area-Gomez, Estela; Schon, Eric A (2017) Alzheimer Disease. Adv Exp Med Biol 997:149-156
Area-Gomez, Estela; Schon, Eric A (2017) On the Pathogenesis of Alzheimer's Disease: The MAM Hypothesis. FASEB J 31:864-867
Servián-Morilla, Emilia; Takeuchi, Hideyuki; Lee, Tom V et al. (2016) A POGLUT1 mutation causes a muscular dystrophy with reduced Notch signaling and satellite cell loss. EMBO Mol Med 8:1289-1309
Area-Gomez, Estela; Schon, Eric A (2016) Mitochondria-associated ER membranes and Alzheimer disease. Curr Opin Genet Dev 38:90-96
Tambini, Marc D; Pera, Marta; Kanter, Ellen et al. (2016) ApoE4 upregulates the activity of mitochondria-associated ER membranes. EMBO Rep 17:27-36
Guardia-Laguarta, Cristina; Area-Gomez, Estela; Schon, Eric A et al. (2015) A new role for ?-synuclein in Parkinson's disease: Alteration of ER-mitochondrial communication. Mov Disord 30:1026-33
Gulati, Sonia; Balderes, Dina; Kim, Christine et al. (2015) ATP-binding cassette transporters and sterol O-acyltransferases interact at membrane microdomains to modulate sterol uptake and esterification. FASEB J 29:4682-94
Guardia-Laguarta, Cristina; Area-Gomez, Estela; Schon, Eric A et al. (2015) Novel subcellular localization for ?-synuclein: possible functional consequences. Front Neuroanat 9:17

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