pubmed.ncbi.nlm.nih.gov

Alzheimer Disease - PubMed

Review

Alzheimer Disease

Estela Area-Gomez et al. Adv Exp Med Biol. 2017.

Abstract

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.

Keywords: ApoE; Cholesterol; Cholesteryl esters; Endoplasmic reticulum; Lipid rafts; MAM; Membranes; Mitochondria; Mitochondria-associated ER membranes; Neurodegeneration; Phospholipids.

PubMed Disclaimer

Cited by

Connexin43 Contributes to Alzheimer's Disease by Promoting the Mitochondria-Associated Membrane-Related Autophagy Inhibition.
Yu W, Li Y, Li Y, Hu J, Wu J, Chen X, Huang Y, Shi X. Yu W, et al. Mol Neurobiol. 2025 Apr;62(4):4319-4337. doi: 10.1007/s12035-024-04536-3. Epub 2024 Oct 23. Mol Neurobiol. 2025. PMID: 39438345 Free PMC article.
A Review of the Role of Endo/Sarcoplasmic Reticulum-Mitochondria Ca²⁺ Transport in Diseases and Skeletal Muscle Function.
Zhang SS, Zhou S, Crowley-McHattan ZJ, Wang RY, Li JP. Zhang SS, et al. Int J Environ Res Public Health. 2021 Apr 7;18(8):3874. doi: 10.3390/ijerph18083874. Int J Environ Res Public Health. 2021. PMID: 33917091 Free PMC article. Review.
Towards a Unitary Hypothesis of Alzheimer's Disease Pathogenesis.
Area-Gomez E, Schon EA. Area-Gomez E, et al. J Alzheimers Dis. 2024;98(4):1243-1275. doi: 10.3233/JAD-231318. J Alzheimers Dis. 2024. PMID: 38578892 Free PMC article.
Effect of Chronic Stress Present in Fibroblasts Derived from Patients with a Sporadic Form of AD on Mitochondrial Function and Mitochondrial Turnover.
Drabik K, Malińska D, Piecyk K, Dębska-Vielhaber G, Vielhaber S, Duszyński J, Szczepanowska J. Drabik K, et al. Antioxidants (Basel). 2021 Jun 10;10(6):938. doi: 10.3390/antiox10060938. Antioxidants (Basel). 2021. PMID: 34200581 Free PMC article.
Protect Effects of Seafood-Derived Plasmalogens Against Amyloid-Beta (1-42) Induced Toxicity via Modulating the Transcripts Related to Endocytosis, Autophagy, Apoptosis, Neurotransmitter Release and Synaptic Transmission in SH-SY5Y Cells.
Feng J, Song G, Shen Q, Chen X, Wang Q, Guo S, Zhang M. Feng J, et al. Front Aging Neurosci. 2021 Nov 26;13:773713. doi: 10.3389/fnagi.2021.773713. eCollection 2021. Front Aging Neurosci. 2021. PMID: 34899276 Free PMC article.

Alzheimer Disease - PubMed