Treatment with an HDL mimetic peptide resembles the protective Christchurch variant in rescuing APOE4 secretion and lipidation deficits in primary and iPSC‐derived astrocytes
Open accessAbstract
Background: Apolipoprotein E (APOE) is the greatest genetic risk factor for Alzheimer's disease (AD) and in humans has 3 isoforms; APOE4 (E4) increases risk, APOE3 (E3) is neutral and APOE2 (E2) decreases risk. APOE is mainly produced and secreted by astrocytes, where it binds lipids to form HDL‐like particles. The lipidation state of APOE is crucial for maintaining lipid homeostasis and regulating Aβ aggregation and protein clearance. E4 is poorly lipidated compared to E2 and E3, contributing to cellular dysfunction. Emerging therapies aim to restore E4 lipidation levels to resemble E2 or E3. We previously showed that the HDL‐mimetic peptide 4F increases APOE secretion and lipidation in primary mouse and human astrocytes. Furthermore, recent evidence suggests that the protective APOE Christchurch (APOEch) mutation alters APOE properties to resemble E2. However, the effects of HDL mimetic peptides and APOEch on APOE4 astrocytes remain unclear. We hypothesize that both pharmacological (4F) and genetic (APOEch) interventions enhance APOE secretion and lipidation, and rescue E4‐related deficits. Method: We generated APOE4 Christchurch (E4ch) induced pluripotent stem cells (iPSCs) and knock‐in (KI) mice using CRISPR/Cas9. E3, E4 and E4ch isogenic iPSCs were differentiated into astrocytes. Primary astrocytes were isolated from E4 and E4ch KI mice. Astrocytes were incubated with aggregated Aβ42 and/or the HDL mimetic peptide 4F for 24 hours. Secreted media and cell lysates were subjected to non‐denaturing gradient gel electrophoresis and immunoblot analyses. Result: Compared to E4, E4ch primary and iPSC astrocytes enhanced APOE secretion and lipidation. Aβ42 inhibited APOE secretion in E4 astrocytes. Importantly, E4ch astrocytes were more resilient, maintaining elevated APOE secretion and lipidation levels in the presence of Aβ42. E4ch astrocytes also promoted lysosomal protein clearance more than E4 astrocytes. Remarkably, 4F treatment counteracted the inhibitory effects of Aβ42 and enhanced APOE secretion and lipidation in both primary and iPSC astrocytes. Conclusion: HDL mimetic peptide 4F treatment resembles the protective effects of E4ch and mitigates E4‐related deficits on APOE secretion and lipidation in astrocytes. These findings highlight the potential of targeting APOE secretion and lipidation as a therapeutic strategy for sporadic AD.
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Written from the paper’s full text.
TL;DR
This study tested whether an HDL mimetic peptide (4F) or the protective APOE Christchurch mutation rescues APOE4 secretion and lipidation deficits in astrocytes. It reports that E4ch and 4F both enhance APOE secretion and lipidation and counteract Aβ42 inhibition in primary and iPSC-derived astrocytes.
Key findings
- Compared with APOE4, APOE4 Christchurch (E4ch) primary and iPSC-derived astrocytes showed enhanced APOE secretion and lipidation.
- Aβ42 inhibited APOE secretion in E4 astrocytes; E4ch astrocytes were more resilient, maintaining elevated APOE secretion and lipidation in the presence of Aβ42.
- E4ch astrocytes also promoted lysosomal protein clearance more than E4 astrocytes.
- Treatment with the HDL mimetic peptide 4F counteracted the inhibitory effects of Aβ42 and enhanced APOE secretion and lipidation in both primary and iPSC astrocytes.
Methods
- The authors generated APOE4 Christchurch (E4ch) induced pluripotent stem cells (iPSCs) and knock-in (KI) mice using CRISPR/Cas9. E3, E4, and E4ch isogenic iPSCs were differentiated into astrocytes, and primary astrocytes were isolated from E4 and E4ch KI mice.
- Astrocytes were incubated with aggregated Aβ42 and/or the HDL mimetic peptide 4F for 24 hours. Secreted media and cell lysates were analyzed by non-denaturing gradient gel electrophoresis and immunoblot analyses.
Limitations
- The paper states no limitations.
- Evident from the text: this is a conference abstract with no figures or tables (Figure count: 0; Table count: 0) and no sample sizes, statistical tests, or effect sizes reported.
- Evident from the text: only astrocyte secretion, lipidation, and lysosomal clearance outcomes are described; no in vivo or clinical outcomes are reported in the abstract.
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Cites
Statistics
Claims the paper makes
- Findingown data§ Method
E4ch astrocytes maintained elevated APOE secretion levels in the presence of Aβ42.
“Importantly, E4ch astrocytes were more resilient, maintaining elevated APOE secretion and lipidation levels in the presence of Aβ42.”
Quote in the paperSubstantial claim - Findingown data§ Method
E4ch astrocytes maintained elevated APOE lipidation levels in the presence of Aβ42.
“Importantly, E4ch astrocytes were more resilient, maintaining elevated APOE secretion and lipidation levels in the presence of Aβ42.”
Quote in the paperSubstantial claim - Findingown data§ Method
4F treatment enhanced APOE lipidation in both primary and iPSC astrocytes.
“Remarkably, 4F treatment counteracted the inhibitory effects of Aβ42 and enhanced APOE secretion and lipidation in both primary and iPSC astrocytes.”
Quote in the paperSubstantial claim - Findingown data§ Method
4F treatment enhanced APOE secretion in both primary and iPSC astrocytes.
“Remarkably, 4F treatment counteracted the inhibitory effects of Aβ42 and enhanced APOE secretion and lipidation in both primary and iPSC astrocytes.”
Quote in the paperSubstantial claim - Findingown data§ Method
Aβ42 inhibited APOE secretion in APOE4 astrocytes.
“Aβ42 inhibited APOE secretion in E4 astrocytes.”
Quote in the paperSubstantial claim
- Findingown data§ Method
Compared to APOE4, APOE4 Christchurch (E4ch) primary and iPSC-derived astrocytes enhanced APOE lipidation.
“Compared to E4, E4ch primary and iPSC astrocytes enhanced APOE secretion and lipidation.”
Quote in the paperSubstantial claim - Findingown data§ Method
Compared to APOE4, APOE4 Christchurch (E4ch) primary and iPSC-derived astrocytes enhanced APOE secretion.
“Compared to E4, E4ch primary and iPSC astrocytes enhanced APOE secretion and lipidation.”
Quote in the paperSubstantial claim - Findingown data§ Method
4F treatment counteracted the inhibitory effects of Aβ42 on APOE secretion in astrocytes.
“Remarkably, 4F treatment counteracted the inhibitory effects of Aβ42 and enhanced APOE secretion and lipidation in both primary and iPSC astrocytes.”
Quote in the paperSubstantial claim - Findingown data§ Method
E4ch astrocytes promoted lysosomal protein clearance more than E4 astrocytes.
“E4ch astrocytes also promoted lysosomal protein clearance more than E4 astrocytes.”
Quote in the paperNot a substantial claim - Premiseown data§ Background
The HDL-mimetic peptide 4F increases APOE secretion and lipidation in primary mouse and human astrocytes (as shown previously by the authors).
“We previously showed that the HDL‐mimetic peptide 4F increases APOE secretion and lipidation in primary mouse and human astrocytes.”
Quote in the paperSubstantial claim - Interpretationown data§ Conclusion
4F treatment mitigates E4-related deficits on APOE secretion and lipidation in astrocytes.
“HDL mimetic peptide 4F treatment resembles the protective effects of E4ch and mitigates E4‐related deficits on APOE secretion and lipidation in astrocytes.”
Quote in the paperSubstantial claim- Rests on an assumption: APOE4 is poorly lipidated compared to APOE2 and APOE3.
- Rests on an assumption: Poor lipidation of APOE4 contributes to cellular dysfunction.
- Interpretationown data§ Conclusion
4F treatment resembles the protective effects of E4ch on APOE secretion and lipidation in astrocytes.
“HDL mimetic peptide 4F treatment resembles the protective effects of E4ch and mitigates E4‐related deficits on APOE secretion and lipidation in astrocytes.”
Quote in the paperSubstantial claim- Rests on an assumption: APOE4 is poorly lipidated compared to APOE2 and APOE3.
- Rests on an assumption: Poor lipidation of APOE4 contributes to cellular dysfunction.
- Interpretationreasoning§ Conclusion
Targeting APOE secretion and lipidation has potential as a therapeutic strategy for sporadic AD.
“These findings highlight the potential of targeting APOE secretion and lipidation as a therapeutic strategy for sporadic AD.”
Quote in the paperSubstantial claim- Rests on an assumption: APOE is the greatest genetic risk factor for Alzheimer's disease.
- Rests on an assumption: APOE4 is poorly lipidated compared to APOE2 and APOE3.
- Rests on an assumption: Poor lipidation of APOE4 contributes to cellular dysfunction.
- Interpretationown data§ Method
E4ch astrocytes were more resilient than E4 astrocytes in the presence of Aβ42.
“Importantly, E4ch astrocytes were more resilient, maintaining elevated APOE secretion and lipidation levels in the presence of Aβ42.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 1
Classified as probably not a substantial claim.
Premisecitation§ BackgroundThe protective APOE Christchurch (APOEch) mutation alters APOE properties to resemble APOE2.
“Furthermore, recent evidence suggests that the protective APOE Christchurch (APOEch) mutation alters APOE properties to resemble E2.”
Quote in the paperSubstantial claim
The paper relies on this without support.
APOE is the greatest genetic risk factor for Alzheimer's disease.
“Apolipoprotein E (APOE) is the greatest genetic risk factor for Alzheimer's disease (AD)”
The paper relies on this without support.
APOE has three isoforms in humans.
“in humans has 3 isoforms”
The paper relies on this without support.
APOE4 increases Alzheimer's disease risk.
“APOE4 (E4) increases risk”
The paper relies on this without support.
APOE3 is neutral for Alzheimer's disease risk.
“APOE3 (E3) is neutral”
The paper relies on this without support.
APOE2 decreases Alzheimer's disease risk.
“APOE2 (E2) decreases risk”
The paper relies on this without support.
APOE is mainly produced and secreted by astrocytes.
“APOE is mainly produced and secreted by astrocytes”
The paper relies on this without support.
APOE binds lipids to form HDL-like particles.
“where it binds lipids to form HDL‐like particles”
The paper relies on this without support.
The lipidation state of APOE is crucial for maintaining lipid homeostasis.
“The lipidation state of APOE is crucial for maintaining lipid homeostasis”
The paper relies on this without support.
The lipidation state of APOE is crucial for regulating Aβ aggregation and protein clearance.
“and regulating Aβ aggregation and protein clearance”
The paper relies on this without support.
APOE4 is poorly lipidated compared to APOE2 and APOE3.
“E4 is poorly lipidated compared to E2 and E3”
The paper relies on this without support.
Poor lipidation of APOE4 contributes to cellular dysfunction.
“contributing to cellular dysfunction”
The paper relies on this without support.
The effects of HDL mimetic peptides and APOEch on APOE4 astrocytes remain unclear.
“However, the effects of HDL mimetic peptides and APOEch on APOE4 astrocytes remain unclear.”
Cites
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- Authors
- Fredriksen, K., Joshi, S. S., Kim, M., & Li, L.
- Affiliations
- University of Minnesota (US)
- Corresponding author
- Fredriksen, Kristina
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2025-12
- Volume
- 21
- Issue
- S1
- Pages
- e102528-e102528
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC12727446
- OpenAlex
- W7117124522
- Semantic Scholar
- 1de219b60d6a55cc29df5929b69365fe8e1fa105
- Cited by
- 0
- References
- 0
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Keywords
- apolipoprotein E, APOE ε4
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Astrocytes, Humans, Mice, Transgenic, Amyloid beta-Peptides, Mice, Apolipoprotein E4, Induced Pluripotent Stem Cells
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