APOE genotype‐dependent effects of enhanced BMP signaling on astrocytes and co‐cultured neurons
Open accessAbstract
Background: Apolipoprotein E4 (E4) is the strongest genetic risk factor for sporadic Alzheimer’s Disease (AD), and aging is the greatest overall risk factor for AD. Many cellular and molecular changes occur within the brain throughout aging, one of which being the increased bone morphogenetic protein 4 (BMP4) signaling. As APOE and BMPs are known to interact in non‐neuronal organs, we hypothesized that enhanced BMP signaling in the brain may interact with APOE in a genotype‐dependent manner to initiate or exacerbate neuropathological cascades relevant to AD. Method: E4 patient‐derived IPSC, along with CRISPR‐corrected isogenic APOE3 (E3) controls, were virally induced into astrocytes with SOX9 and NFIB overexpression, or neurons with NGN2 overexpression, using previously published protocols. After maturation, astrocytes and neurons cultured alone or in co‐culture, were treated for 72 hours BMP4 or vehicle prior to collection to observe changes. Result: In the presence of BMP4, E4 astrocytes accumulated larger amounts of lipids in the cytoplasm compared to E3 astrocytes. This accumulation of lipids resulted from enhanced lipid generation, reduced lipid breakdown, and reduced efficiency of beta oxidation compared to E3 astrocytes treated with BMP4. Further, single cell transcriptomic analysis of astrocyte‐neuron co‐cultures revealed that BMP4 promotes astrocyte to neuron cholesterol signaling from E4 astrocytes more than E3 astrocytes, and BMP4 treatment reduces elevated TGFβ signaling from E4 astrocytes to co‐cultured neurons. These BMP4 induced changes coincide with enhanced phosphorylation of tau and reduced oxidative phosphorylation capacity in neurons cocultured with E4 astrocytes compared to E3 astrocytes. Conclusion: Increased BMP signaling alters the physiology of astrocytes in an APOE‐dependent manner, with E4 astrocytes exhibiting more abnormalities in lipid metabolism than E3 astrocytes. Specifically, BMP‐treated E4 astrocytes have greater lipid droplet accumulation due to increased lipid generation, reduced lipid breakdown, and lack of beta oxidation when compared to E3 astrocytes treated with BMP4. E4 astrocytes exert greater effects than E3 astrocytes on the disease phenotype of co‐cultured AD neurons, with increases in phosphorylated tau and decreases in oxidative phosphorylation efficiency. This suggests that enhanced BMP4 signaling in the aging brain may be one of the contributing factors to development of AD.
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TL;DR
This conference abstract reports that enhanced BMP4 signaling alters astrocyte physiology in an APOE genotype-dependent manner, with APOE4 astrocytes showing greater lipid abnormalities than isogenic APOE3 controls. Co-cultured neurons with E4 astrocytes showed increased phosphorylated tau and reduced oxidative phosphorylation capacity.
Key findings
- In the presence of BMP4, E4 astrocytes accumulated larger amounts of cytoplasmic lipids than E3 astrocytes; this resulted from enhanced lipid generation, reduced lipid breakdown, and reduced beta-oxidation efficiency relative to BMP4-treated E3 astrocytes.
- Single-cell transcriptomic analysis of astrocyte–neuron co-cultures showed BMP4 promotes astrocyte-to-neuron cholesterol signaling from E4 astrocytes more than from E3 astrocytes, and BMP4 treatment reduces elevated TGFβ signaling from E4 astrocytes to co-cultured neurons.
- These BMP4-induced changes coincided with enhanced tau phosphorylation and reduced oxidative phosphorylation capacity in neurons co-cultured with E4 astrocytes compared to E3 astrocytes.
Methods
- E4 patient-derived iPSCs and CRISPR-corrected isogenic APOE3 (E3) controls were virally induced into astrocytes (SOX9 and NFIB overexpression) or neurons (NGN2 overexpression) using previously published protocols.
- After maturation, astrocytes and neurons were cultured alone or in co-culture and treated with BMP4 or vehicle for 72 hours prior to collection.
- Analyses included assessment of lipid accumulation/metabolism and single-cell transcriptomic analysis of astrocyte–neuron co-cultures.
Limitations
- Not stated in the paper (the abstract reports no limitations).
- Evident from the text: this is a 2-page conference abstract with 0 figures and 0 tables, so quantitative effect sizes, sample sizes, replication, and statistical details are not provided; findings are described qualitatively.
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Claims the paper makes
- Findingown data§ Method
BMP4 treatment reduces elevated TGFβ signaling from E4 astrocytes to co-cultured neurons.
“Further, single cell transcriptomic analysis of astrocyte‐neuron co‐cultures revealed that BMP4 promotes astrocyte to neuron cholesterol signaling from E4 astrocytes more than E3 astrocytes, and BMP4 treatment reduces elevated TGFβ signaling from E4 astrocytes to co‐cultured neurons.”
Quote in the paperSubstantial claim - Findingown data§ Method
In astrocyte-neuron co-cultures, BMP4 promotes astrocyte to neuron cholesterol signaling from E4 astrocytes more than from E3 astrocytes.
“Further, single cell transcriptomic analysis of astrocyte‐neuron co‐cultures revealed that BMP4 promotes astrocyte to neuron cholesterol signaling from E4 astrocytes more than E3 astrocytes, and BMP4 treatment reduces elevated TGFβ signaling from E4 astrocytes to co‐cultured neurons.”
Quote in the paperSubstantial claim - Findingown data§ Method
In the presence of BMP4, E4 astrocytes exhibit reduced efficiency of beta oxidation compared to E3 astrocytes.
“This accumulation of lipids resulted from enhanced lipid generation, reduced lipid breakdown, and reduced efficiency of beta oxidation compared to E3 astrocytes treated with BMP4.”
- Also stated in: § Conclusion · plain
“Specifically, BMP‐treated E4 astrocytes have greater lipid droplet accumulation due to increased lipid generation, reduced lipid breakdown, and lack of beta oxidation when compared to E3 astrocytes treated with BMP4.”
Quote in the paperSubstantial claim - Also stated in: § Conclusion · plain
- Findingown data§ Method
In the presence of BMP4, E4 astrocytes accumulate larger amounts of lipids in the cytoplasm compared to E3 astrocytes.
“In the presence of BMP4, E4 astrocytes accumulated larger amounts of lipids in the cytoplasm compared to E3 astrocytes.”
- Also stated in: § Conclusion · plain
“Specifically, BMP‐treated E4 astrocytes have greater lipid droplet accumulation due to increased lipid generation, reduced lipid breakdown, and lack of beta oxidation when compared to E3 astrocytes treated with BMP4.”
Quote in the paperSubstantial claim - Also stated in: § Conclusion · plain
- Findingown data§ Method
In neurons co-cultured with E4 astrocytes compared to E3 astrocytes, BMP4-induced changes coincide with reduced oxidative phosphorylation capacity.
“These BMP4 induced changes coincide with enhanced phosphorylation of tau and reduced oxidative phosphorylation capacity in neurons cocultured with E4 astrocytes compared to E3 astrocytes.”
- Also stated in: § Conclusion · plain
“E4 astrocytes exert greater effects than E3 astrocytes on the disease phenotype of co‐cultured AD neurons, with increases in phosphorylated tau and decreases in oxidative phosphorylation efficiency.”
Quote in the paperSubstantial claim - Also stated in: § Conclusion · plain
- Findingown data§ Method
In neurons co-cultured with E4 astrocytes compared to E3 astrocytes, BMP4-induced changes coincide with enhanced phosphorylation of tau.
“These BMP4 induced changes coincide with enhanced phosphorylation of tau and reduced oxidative phosphorylation capacity in neurons cocultured with E4 astrocytes compared to E3 astrocytes.”
- Also stated in: § Conclusion · plain
“E4 astrocytes exert greater effects than E3 astrocytes on the disease phenotype of co‐cultured AD neurons, with increases in phosphorylated tau and decreases in oxidative phosphorylation efficiency.”
Quote in the paperSubstantial claim - Also stated in: § Conclusion · plain
- Findingown data§ Method
In the presence of BMP4, E4 astrocytes exhibit reduced lipid breakdown compared to E3 astrocytes.
“This accumulation of lipids resulted from enhanced lipid generation, reduced lipid breakdown, and reduced efficiency of beta oxidation compared to E3 astrocytes treated with BMP4.”
- Also stated in: § Conclusion · plain
“Specifically, BMP‐treated E4 astrocytes have greater lipid droplet accumulation due to increased lipid generation, reduced lipid breakdown, and lack of beta oxidation when compared to E3 astrocytes treated with BMP4.”
Quote in the paperSubstantial claim - Also stated in: § Conclusion · plain
- Findingown data§ Method
In the presence of BMP4, E4 astrocytes exhibit enhanced lipid generation compared to E3 astrocytes.
“This accumulation of lipids resulted from enhanced lipid generation, reduced lipid breakdown, and reduced efficiency of beta oxidation compared to E3 astrocytes treated with BMP4.”
- Also stated in: § Conclusion · plain
“Specifically, BMP‐treated E4 astrocytes have greater lipid droplet accumulation due to increased lipid generation, reduced lipid breakdown, and lack of beta oxidation when compared to E3 astrocytes treated with BMP4.”
Quote in the paperSubstantial claim - Also stated in: § Conclusion · plain
- Interpretationreasoning§ Conclusion
Enhanced BMP4 signaling in the aging brain may be one of the contributing factors to development of AD.
“This suggests that enhanced BMP4 signaling in the aging brain may be one of the contributing factors to development of AD.”
Quote in the paperSubstantial claim- Rests on an assumption: Increased bone morphogenetic protein 4 (BMP4) signaling occurs in the brain throughout aging.
- May combine two claims. 2
May combine two claims.
Interpretationown data§ ConclusionE4 astrocytes exert greater effects than E3 astrocytes on the disease phenotype of co-cultured AD neurons, with increases in phosphorylated tau and decreases in oxidative phosphorylation efficiency.
“E4 astrocytes exert greater effects than E3 astrocytes on the disease phenotype of co‐cultured AD neurons, with increases in phosphorylated tau and decreases in oxidative phosphorylation efficiency.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown data§ ConclusionIncreased BMP signaling alters the physiology of astrocytes in an APOE-dependent manner, with E4 astrocytes exhibiting more abnormalities in lipid metabolism than E3 astrocytes.
“Increased BMP signaling alters the physiology of astrocytes in an APOE‐dependent manner, with E4 astrocytes exhibiting more abnormalities in lipid metabolism than E3 astrocytes.”
Quote in the paperSubstantial claim
The paper relies on this without support.
Apolipoprotein E4 (E4) is the strongest genetic risk factor for sporadic Alzheimer’s Disease (AD).
“Apolipoprotein E4 (E4) is the strongest genetic risk factor for sporadic Alzheimer’s Disease (AD)”
The paper relies on this without support.
Increased bone morphogenetic protein 4 (BMP4) signaling occurs in the brain throughout aging.
“Many cellular and molecular changes occur within the brain throughout aging, one of which being the increased bone morphogenetic protein 4 (BMP4) signaling.”
The paper relies on this without support.
APOE and BMPs interact in non-neuronal organs.
“As APOE and BMPs are known to interact in non‐neuronal organs”
- Authors
- Linden, A. K., Affaneh, A., Kessler, J. A., & Yu Peng, C.
- Affiliations
- Northwestern University (US)
- Northwestern University, Chicago, IL USA
- Corresponding author
- Linden, Anne K
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2024-12
- Volume
- 20
- Issue
- S1
- Pages
- e090956-e090956
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC11710445
- OpenAlex
- W4406030174
- 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 Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- APOE ε4, APOE3
- MeSH terms
- Alzheimer Disease, Astrocytes, Brain, Cells, Cultured, Humans, Neurons, Signal Transduction, Coculture Techniques, Apolipoprotein E4, Bone Morphogenetic Protein 4, Induced Pluripotent Stem Cells
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