PICALM Rescues Endocytic Defects Caused by the Alzheimer’s Disease Risk Factor APOE4
Open accessAbstract
The ε4 allele of apolipoprotein E (APOE4) is a genetic risk factor for many diseases, including late-onset Alzheimer's disease (AD). We investigate the cellular consequences of APOE4 in human iPSC-derived astrocytes, observing an endocytic defect in APOE4 astrocytes compared with their isogenic APOE3 counterparts. Given the evolutionarily conserved nature of endocytosis, we built a yeast model to identify genetic modifiers of the endocytic defect associated with APOE4. In yeast, only the expression of APOE4 results in dose-dependent defects in both endocytosis and growth. We discover that increasing expression of the early endocytic adaptor protein Yap1802p, a homolog of the human AD risk factor PICALM, rescues the APOE4-induced endocytic defect. In iPSC-derived human astrocytes, increasing expression of PICALM similarly reverses endocytic disruptions. Our work identifies a functional interaction between two AD genetic risk factors-APOE4 and PICALM-centered on the conserved biological process of endocytosis.
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APOE4-bound cholesterol, taken up by the cell, is released from the receptor in the late endosome or lysosome, and aggregation of APOE4 has been shown to cause endosomal congestion and dysfunction.
“APOE4-bound cholesterol, taken up by the cell, is released from the receptor in the late endosome or lysosome, and aggregation of APOE4 has been shown to cause endosomal congestion and dysfunction (Narayan et al., 2020; Nuriel et al., 2017; Rawat et al., 2019).”
From APOE2, E3, and E4 differentially modulate cellular homeostasis, cholesterol metabolism, and inflammatory response in isogenic iPSC-derived astrocytes (2022) · cites this paper as Narayan et al., 2020
The Results section on iPSC-derived astrocytes reports that APOE4 disrupts early endocytosis, supporting the general claim of endocytic dysfunction. It does not describe APOE4-bound cholesterol being released from a receptor in late endosomes or lysosomes. The yeast-model Results section instead reports that APOE4 did not accumulate in protein aggregates and that the observed defects were not a response to aggregation. Page numbers were not available in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAPOE4 iPSCs exhibit defects in endocytosis.
“APOE4 iPSCs also exhibit defects in endocytosis (Narayan et al., 2020).”
From APOE traffics to astrocyte lipid droplets and modulates triglyceride saturation and droplet size (2024) · cites this paper as Narayan et al., 2020
The Results section (‘APOE4 disrupts endocytosis in iPSC-derived astrocytes’) reports reduced early endocytosis in APOE4 astrocytes compared with APOE3 astrocytes. The tested cells were derived from iPSCs; the cited passages do not establish an endocytic defect in undifferentiated APOE4 iPSCs themselves. (LLM, conf=0.87)
Experimental — accuracy not yet measuredA person with one copy of the APOE ε4 allele is more likely to be affected than a person with two copies.
“A person with one copy of this allele is more likely to be affected than a person with two copies [42,43,44].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [42]
The APOE ε4 allele greatly increases AD risk.
“The AD risk is greatly increased by the APOE ε4 allele.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [42]
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Lysosomal proteomics reveals mechanisms of neuronal APOE4-associated lysosomal dysfunction
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Alzheimer’s disease basics: we all should know
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The Cross-Talk Between the Peripheral and Brain Cholesterol Metabolisms
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PICALM exerts a role in promoting CRC progression through ERK/MAPK signaling pathway
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Apolipoprotein E intersects with amyloid-β within neurons
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Modulating lipid droplet dynamics in neurodegeneration: an emerging area of molecular pharmacology
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Altered Mitochondrial Morphology and Bioenergetics in a New Yeast Model Expressing Aβ42
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The Strategies for Treating “Alzheimer’s Disease”: Insulin Signaling May Be a Feasible Target
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Building in vitro models of the brain to understand the role ofAPOEin Alzheimer’s disease
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Coupling of Alzheimer’s Disease Genetic Risk Factors with Viral Susceptibility and Inflammation
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APOE3 astrocytes can rescue lipid abnormalities and dystrophic neurites of APOE4 human neurons
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Alzheimer’s Disease: Significant Benefit from the Yeast-Based Models
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Neuronal endolysosomal alterations induced by Apolipoprotein E4 emerge over time in primary neurons
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ApoE4-carrying Human Astrocytes Oversupply Cholesterol into Neurons and Promote Aβ GenerationPreprint
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Meta-analysis on the association between rs11868035, rs823144, rs3851179 and Parkinson's disease
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Organoids: the third dimension of human brain development and disease
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PICALM as a Novel Prognostic Biomarker and Its Correlation with Immune Infiltration in Breast Cancer
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APOE4 and INPP5D converge on membrane mechanics to regulate endocytosis in human astrocytesPreprint
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Self-citation
- Authors
- Narayan, P., Sienski, G., Bonner, J. M., Lin, Y.-T., Seo, J., Baru, V., Haque, A., Milo, B., Akay, L. A., Graziosi, A., Freyzon, Y., Landgraf, D., Hesse, W. R., Valastyan, J., Barrasa, M. I., Tsai, L.-H., & Lindquist, S.
- Affiliations
- National Institutes of Health (US)
- Whitehead Institute for Biomedical Research (US)
- Massachusetts Institute of Technology (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Tsai, Li-Huei
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2020-10
- Volume
- 33
- Issue
- 1
- Pages
- 108224
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC8190562
- OpenAlex
- W3092088846
- Cited by
- 75
- References
- 50
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 16 · 2023: 15 · 2022: 15 · 2021: 12 · 2020: 2
- FWCI
- 6.61
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- Howard Hughes Medical Institute
- American Parkinson's Disease Foundation
- Helen Hay Whitney Foundation
- National Institute of Diabetes and Digestive and Kidney Diseases (R01AG058002, U54-HG008097, RF1AG062377)
- University of California, San Francisco
- AstraZeneca
- EMBO (ALTF 829-2015)
- Edward N. and Della L. Thome Memorial Foundation
- European Molecular Biology Organization (NIA AG055697-03)
- JPB Foundation
- Robert A. and Renee E. Belfer Family Foundation
- National Institutes of Health (R21 NS087557)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- PICALM, APOE ε4, Alzheimer's disease, endocytosis, astrocytes, iPSC-derived astrocytes, genetic modifiers, yeast model
- MeSH terms
- Alzheimer Disease, Endocytosis, Humans, Risk Factors, Apolipoprotein E4
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