Apolipoprotein E4 targets mitochondria and the mitochondria-associated membrane complex in neuropathology, including Alzheimer's disease
Open accessAbstract
Apolipoprotein (apo) E4 sets the stage for neuropathology in Alzheimer's disease (AD) by causing mitochondrial dysfunction and altering mitochondria-associated membranes. Contact and apposition of mitochondrial-endoplasmic reticulum membranes are enhanced in brain cells in AD and associated with increases in tethering and spacing proteins that modulate many cellular processes. Contact site protein levels are higher in apoE4 cells. In apoE4 neurons, the NAD + /NADH ratio is lowered, reactive oxygen species are increased, and NAD/NADH pathway components and redox proteins are decreased. Oxidative phosphorylation is impaired and reserve ATP generation capacity is lacking. ApoE4 neurons have ∼50% fewer respiratory complex subunits (e.g., ATP synthase) and may increase translocase levels of the outer and inner mitochondrial membranes to facilitate delivery of nucleus-encoded complex subunits. Respiratory complex assembly relies on mitochondrial cristae organizing system subunits that are altered in apoE4 cells, and apoE4 increases mitochondrial proteases that control respiratory subunit composition for complex assembly.
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Neuron-specific proteolysis of APOE4, resulting in APOE4 fragments in the cytosol, caused toxic effects such as tau phosphorylation, alterations in cytoskeleton, and mitochondrial dysfunctions.
“Neuron-specific proteolysis of APOE4, resulting in APOE4 fragments in the cytosol, caused toxic effects such as tau phosphorylation, alterations in cytoskeleton, and mitochondrial dysfunctions [34,35].”
From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [34]
Inhibitory neurons express higher levels of APOE4.
“However, it has been shown that inhibitory neurons express higher levels of APOE4, and the proportion of inhibitory interneurons could be correlated with AD disease progression [4,34,48]”
From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [34]
The proportion of inhibitory interneurons could be correlated with AD disease progression.
“However, it has been shown that inhibitory neurons express higher levels of APOE4, and the proportion of inhibitory interneurons could be correlated with AD disease progression [4,34,48]”
From APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons (2024) · cites this paper as [34]
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APOE4 Increases Energy Metabolism in APOE-Isogenic iPSC-Derived Neurons
Budny, V., Knöpfli, Y., Meier, D., Zürcher, K., Bodenmann, C., Peter, S. L., Müller, T., Tardy, M., Cortijo, C., & Tackenberg, C. (2024) · Cells · doi:10.3390/cells13141207 · Cited by 15 · see citing works
- Authors
- Mahley, R. W.
- Affiliations
- Gladstone Institutes (US)
- Corresponding author
- Mahley, Robert W.
- ORCID
- Mahley, Robert W.
- Venue
- Current Opinion in Neurobiology
- Publisher
- Elsevier BV
- Published
- 2023-04
- Volume
- 79
- Pages
- 102684
- ISSN
- 0959-4388 (ISSN-L)
- OpenAlex
- W4319302769
- Cited by
- 43
- References
- 15
- Citations by year
- 2026: 17 · 2025: 8 · 2024: 12 · 2023: 6
- FWCI
- 1.11
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Current Opinion in Neurobiology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (1RF1AG059751)
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- APOE ε4, Alzheimer's disease, mitochondrial dysfunction, NAD+/NADH ratio, reactive oxygen species, oxidative phosphorylation, ATP synthase, mitochondrial protease, translocase, redox proteins, neuropathology
- MeSH terms
- Adenosine Triphosphate, Alzheimer Disease, Humans, Mitochondria, NAD, Nervous System Diseases, Apolipoprotein E4
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