Apolipoprotein E4 genotype compromises brain exosome production
Open accessAbstract
In addition to being the greatest genetic risk factor for Alzheimer's disease, expression of the ɛ4 allele of apolipoprotein E can lead to cognitive decline during ageing that is independent of Alzheimer's amyloid-β and tau pathology. In human post-mortem tissue and mouse models humanized for apolipoprotein E, we examined the impact of apolipoprotein E4 expression on brain exosomes, vesicles that are produced within and secreted from late-endocytic multivesicular bodies. Compared to humans or mice homozygous for the risk-neutral ɛ3 allele we show that the ɛ4 allele, whether homozygous or heterozygous with an ɛ3 allele, drives lower exosome levels in the brain extracellular space. In mice, we show that the apolipoprotein E4-driven change in brain exosome levels is age-dependent: while not present at age 6 months, it is detectable at 12 months of age. Expression levels of the exosome pathway regulators tumor susceptibility gene 101 (TSG101) and Ras-related protein Rab35 (RAB35) were found to be reduced in the brain at the protein and mRNA levels, arguing that apolipoprotein E4 genotype leads to a downregulation of exosome biosynthesis and release. Compromised exosome production is likely to have adverse effects, including diminishing a cell's ability to eliminate materials from the endosomal-lysosomal system. This reduction in brain exosome levels in 12-month-old apolipoprotein E4 mice occurs earlier than our previously reported brain endosomal pathway changes, arguing that an apolipoprotein E4-driven failure in exosome production plays a primary role in endosomal and lysosomal deficits that occur in apolipoprotein E4 mouse and human brains. Disruption of these interdependent endosomal-exosomal-lysosomal systems in apolipoprotein E4-expressing individuals may contribute to amyloidogenic amyloid-β precursor protein processing, compromise trophic signalling and synaptic function, and interfere with a neuron's ability to degrade material, all of which are events that lead to neuronal vulnerability and higher risk of Alzheimer's disease development. Together, these data suggest that exosome pathway dysfunction is a previously unappreciated component of the brain pathologies that occur as a result of apolipoprotein E4 expression.
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APOE isoforms influence EV biogenesis and cargo through effects on lipid membrane dynamics and endosomal trafficking.
“APOE isoforms influence EV biogenesis and cargo through effects on lipid membrane dynamics and endosomal trafficking. 28 , 29”
From Plasma extracellular vesicles from <i>APOE3</i> Christchurch carriers display a protective phenotype in early stages of autosomal dominant Alzheimer's disease (2026) · cites this paper as [29]
The Results (page not provided) report altered extracellular-vesicle lipid composition in APOE4 versus APOE3 mice, and the paper reports lower brain exosome levels with APOE4. The Discussion (page not provided) proposes that altered cholesterol metabolism and endosomal pathways may link APOE4 to reduced exosome production, but it presents that mechanism as a suggestion rather than an established causal pathway. (LLM, conf=0.84)
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“Since neurons upregulate the secretion of exosomes to mitigate lysosomal lipid and cargo burden [56], the inhibitory effect of APOE4 expression in exosomes release [70] may also contribute to neuronal vulnerability.”
BackgroundLarramona-Arcas, R., González-Arias, C., Perea, G., Gutiérrez, A., Vitorica, J., García-Barrera, T., Gómez-Ariza, J. L., Pascua-Maestro, R., Ganfornina, M. D., Kara, E., et al. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00382-8 · Cited by 56 · see citing works
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- Authors
- Peng, K. Y., Pérez-González, R., Alldred, M. J., Goulbourne, C. N., Morales-Corraliza, J., Saito, M., Saito, M., Ginsberg, S. D., Mathews, P. M., & Levy, E.
- Affiliations
- Nathan Kline Institute for Psychiatric Research (US)
- Center for Dementia Research, Nathan S. Kline Institute, Orangeburg, New York, USA
- Corresponding author
- Mathews, Paul M
- Levy, Efrat
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-11-27
- Volume
- 142
- Issue
- 1
- Pages
- 163-175
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC6308312
- OpenAlex
- W2905324087
- Cited by
- 109
- References
- 58
- Citations by year
- 2026: 11 · 2025: 9 · 2024: 8 · 2023: 8 · 2022: 22 · 2021: 22 · 2020: 17 · 2019: 11 · 2018: 1
- FWCI
- 8.48
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Brain (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- NIH (P01 AG017617, R01 AG057517, R01 AG043375, P01 AG014449, T32-GM066704, T32-AG052909, AG025688)
- Drs Thomas Wisniewski and Helen Scharfman
- Sackler Institute of Graduate Biomedical Sciences
- New York University School of Medicine
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- APOE ε4, Alzheimer's disease, TSG101, Rab35, multivesicular bodies, endosomal-lysosomal system, cognitive decline, synaptic function, neuronal vulnerability
- MeSH terms
- Tsg101 Protein, Aged, Aged, 80 and over, Aging, Alleles, Animals, Brain, DNA-Binding Proteins, Extracellular Space, Female, Genotype, Humans, Male, Mice, Transgenic, Middle Aged, Transcription Factors, Down-Regulation, rab GTP-Binding Proteins, Lipid Metabolism, Mice, Apolipoprotein E3, Apolipoprotein E4, Exosomes, Endosomal Sorting Complexes Required for Transport
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