Phospholipid dysregulation contributes to ApoE4-associated cognitive deficits in Alzheimer’s disease pathogenesis
Open accessAbstract
Significance: The apolipoprotein E4 (ApoE4) genotype is the strongest genetic risk factor for developing Alzheimer’s disease (AD). However, the mechanisms that underlie this link between ApoE4 genotype and AD are not well understood. Our data in this paper are the first mechanistic studies to our knowledge that link ApoE4 genotype-specific changes in brain phospholipid homeostasis to ApoE4-increased susceptibility to develop AD. Our studies indicate previously unidentified therapeutic options for the treatment of AD, targeting ApoE4’s pathogenic nature.
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ApoE participates in brain phospholipid homeostasis in an isoform-dependent manner.
“ApoE participates in the brain phospholipid homeostasis in an isoform-dependent manner.”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [46]
In humans, ApoE knock-in mice, and primary neurons, ApoE3 regulates brain PIP2 via suppressing the level of synaptojanin 1.
“In a set of experiments in humans, ApoE knock-in mice, and primary neurons, ApoE3 regulates brain phosphoinositol biphosphate (PIP2) via suppressing the level of phosphoinositol phosphatase synaptojanin 1, a PIP2-degrading enzyme, while ApoE4 is dysfunctional in this process [46].”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [46]
In humans, ApoE knock-in mice, and primary neurons, ApoE4 is dysfunctional in the process of ApoE3 regulation of brain PIP2 via synaptojanin 1.
“In a set of experiments in humans, ApoE knock-in mice, and primary neurons, ApoE3 regulates brain phosphoinositol biphosphate (PIP2) via suppressing the level of phosphoinositol phosphatase synaptojanin 1, a PIP2-degrading enzyme, while ApoE4 is dysfunctional in this process [46].”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [46]
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Self-citation
- Authors
- Zhu, L., Zhong, M., Elder, G. A., Sano, M., Holtzman, D. M., Gandy, S., Cardozo, C., Haroutunian, V., Robakis, N. K., & Cai, D.
- Affiliations
- James J. Peters VA Medical Center (US)
- Westchester Medical Center (US)
- Washington University in St. Louis (US)
- Icahn School of Medicine at Mount Sinai (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2015-09-08
- Volume
- 112
- Issue
- 38
- Pages
- 11965-11970
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4586834
- OpenAlex
- W2134475193
- Cited by
- 160
- References
- 9
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 29 · 2023: 9 · 2022: 11 · 2021: 11 · 2020: 18 · 2019: 24 · 2018: 7 · 2017: 15 · 2016: 13 · 2015: 2
- FWCI
- 9.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer Association (NIRP14-304720)
- U.S. Department of Veterans Affairs (RR&D 1I21RX001558-01A1, BLRD Cai-CDA Spring 2010, B9212C)
- HHS | National Institutes of Health (1RO1AG048923-01, #2P50AG005138-28, R37 #AG017926), #2R01AG008200)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- APOE ε4, Alzheimer's disease, phospholipid homeostasis, SYNJ1, phosphoinositide phosphatase, cognitive impairment, loss of function, APOE3, postmortem brain
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Animals, Astrocytes, Brain, Cognition Disorders, Female, Homeostasis, Humans, Male, Nerve Tissue Proteins, Neurons, Phospholipids, Phosphoric Monoester Hydrolases, Cohort Studies, Phosphatidylinositol Phosphates, Disease Progression, Mice, Apolipoprotein E4, Gene Knock-In Techniques
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