The most widely accepted hypothesis to explain the pathogenesis of Alzheimer disease (AD) is the amyloid cascade, in which the accumulation of extraneuritic plaques and intracellular tangles plays a key role in driving the course and progression of the disease. However, there are other biochemical and morphological features of AD, including altered calcium, phospholipid, and cholesterol metabolism and altered mitochondrial dynamics and function that often appear early in the course of the disease, prior to plaque and tangle accumulation. Interestingly, these other functions are associated with a subdomain of the endoplasmic reticulum (ER) called mitochondria-associated ER membranes (MAM). MAM, which is an intracellular lipid raft-like domain, is closely apposed to mitochondria, both physically and biochemically. These MAM-localized functions are, in fact, increased significantly in various cellular and animal models of AD and in cells from AD patients, which could help explain the biochemical and morphological alterations seen in the disease. Based on these and other observations, a strong argument can be made that increased ER-mitochondria connectivity and increased MAM function are fundamental to AD pathogenesis.
KeywordsApoE Cholesterol Cholesteryl esters Endoplasmic reticulum Lipid rafts MAM Membranes Mitochondria Mitochondria-associated ER membranes Neurodegeneration Phospholipids
This work was supported by the US Department of Defense (W911F-15-1-0169), the Ellison Medical Foundation, and the J. Willard and Alice S. Marriott Foundation (to EAS) and by the US National Institutes of Health (K01-AG045335 to E.A.-G.).
- Area-Gomez E, Del Carmen Lara Castillo M, Tambini MD, Guardia-Laguarta C, de Groof AJC, Madra M, Ikenouchi J, Umeda M, Bird TD, Sturley SL et al (2012) Upregulated function of mitochondria-associated ER membranes in Alzheimer disease. EMBO J 31:4106–4123Google Scholar
- Beel AJ, Mobley CK, Kim HJ, Tian F, Hadziselimovic A, Jap B, Prestegard JH, Sanders CR (2008) Structural studies of the transmembrane C-terminal domain of the amyloid precursor protein (APP): does APP function as a cholesterol sensor? Biochemistry 47:9428–9446CrossRefPubMedPubMedCentralGoogle Scholar
- Hedskog L, Pinho CM, Filadi R, Ronnback A, Hertwig L, Wiehager B, Larssen P, Gellhaar S, Sandebring A, Westerlund M et al (2013) Modulation of the endoplasmic reticulum-mitochondria interface in Alzheimer’s disease and related models. Proc Natl Acad Sci USA 110:7916–7921CrossRefPubMedPubMedCentralGoogle Scholar
- Mattson MP (2010) ER calcium and Alzheimer’s disease: in a state of flux. Sci Signal 3:pe10Google Scholar
- Walter J, Capell A, Grunberg J, Pesold B, Schindzielorz A, Prior R, Podlisny MB, Fraser P, Hyslop PS, Selkoe DJ et al (1996) The Alzheimer’s disease-associated presenilins are differentially phosphorylated proteins located predominantly within the endoplasmic reticulum. Mol Med 2:673–691PubMedPubMedCentralGoogle Scholar