PreprintCited by 1Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Differential Regulation of APOE4-Mediated Astrocytic Lipid Metabolism by BMP Signaling Exacerbates Alzheimer’s Disease Pathologies in Neurons

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Linden, Anne K., Affaneh, Amira, Aylward, Aimee, Wong, Yvette, Kessler, John A., Peng, Chian-Yu·2025·bioRxiv (Cold Spring Harbor Laboratory)

Abstract

The two greatest risk factors for Alzheimer’s Disease (AD) are aging and Apolipoprotein E4 (APOE4) polymorphism, yet how these factors interact remain unclear. In this study, we investigate how bone morphogenetic protein (BMP) signaling, which increases with age, contributes to APOE4-induced lipid metabolic dysfunctions using induced-pluripotent stem cell (iPSC)-derived astrocytes and cocultured neurons. Surprisingly, BMP signaling differentially altered lipid droplet formation, cholesterol synthesis and breakdown, and fatty acid-oxidation in APOE4 compared to APOE3 astrocytes, and increased secretion of oxidized LDL (oxLDL). Furthermore, neurons cocultured with BMP4-treated APOE4 astrocytes showed altered transcriptomic profiles based on scRNA-seq as well as increased tau phosphorylation (p-tau). oxLDL treatment similarly increased p-tau and reduced neuronal survival. Conversely, lipid uptake inhibition in neurons rescued the BMP4/APOE4 astrocyte-induced neuronal phenotype. These data demonstrate key interactions between APOE4 and aging-associated molecular signaling in AD pathogenesis and establish a causal linkage between astrocytic lipid metabolism and neuronal tau hyperphosphorylation.

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Crossref · 10.64898/2025.12.14.694212

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Research works printed but not linked: 3

  1. 2001, Oxidative stress in human aging and mitochondrial disease-consequences of defective mitochondrial respiration and impaired antioxidant enzyme system, Chin J Physiol, 44, 1
  2. 10.1016/j.cell.2019.1004.1001 · DOI
  3. 2015, Tau Hyperphosphorylation and Oxidative Stress, a Critical Vicious Circle in Neurodegenerative Tauopathies?, Oxid Med Cell Longev, 2015, 151979

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Authors
Linden, A. K., Affaneh, A., Aylward, A., Wong, Y., Kessler, J. A., & Peng, C.-Y.
Affiliations
Northwestern University (US)
Corresponding author
Peng, Chian-Yu
Venue
bioRxiv (Cold Spring Harbor Laboratory)
Publisher
openRxiv
Published
2025-12-14
OpenAlex
W4417315477
Cited by
1
References
90
Citations by year
2026: 1
Type
posted content
Language
en
Open access
Locations
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
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
Alzheimer's disease, APOE ε4, BMP signaling, BMP4, astrocytes, astrocyte-neuron co-culture, lipid metabolism, lipid droplets, cholesterol metabolism, fatty acid oxidation, oxidized LDL, tau phosphorylation, neuronal survival, aging, iPSC-derived astrocytes, lipid uptake

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