Cholesterol-mediated Lysosomal Dysfunction in APOE4 Astrocytes Promotes α-Synuclein Pathology in Human Brain Tissue

  • bioRxiv. 2025 Feb 14:2025.02.09.637107. doi: 10.1101/2025.02.09.637107.
Louise A Mesentier-Louro  1  2  3  4  5  6  7 ,  Camille Goldman  1  2  3  4  5  6  7 ,  Alain Ndayisaba  6  8  9  10 ,  Alice Buonfiglioli  1  2  3  4  5 ,  Rikki B Rooklin  1  2  3  4  5 ,  Braxton R Schuldt  1  2  3  4  5 ,  Abigail Uchitelev  1  2  3  4  5  11 ,  Vikram Khurana  6  8  9  10  12  13 ,  Joel W Blanchard  1  2  3  4  5  6  14
Affiliations
  • 1. Icahn School of Medicine, Mount Sinai, New York, NY, USA.
  • 2. Nash Family Department of Neuroscience, Mount Sinai, New York, NY, USA.
  • 3. Friedman Brain Institute, Mount Sinai, New York, NY, USA.
  • 4. Ronald M. Loeb Center for Alzheimer's Disease, Mount Sinai, New York, NY USA.
  • 5. Black Family Stem Cell Institute, Mount Sinai, New York, NY, USA.
  • 6. Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD 20815, USA.
  • 7. These authors contributed equally.
  • 8. Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA.
  • 9. Division of Movement Disorders, American Parkinson Disease Association (APDA) Center for Advanced Research and MSA Center of Excellence, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA.
  • 10. Harvard Medical School, Boston, MA, USA.
  • 11. Macaulay Honors College at Hunter College, New York, NY, USA.
  • 12. The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • 13. Harvard Stem Cell Institute, Cambridge, MA, USA.
  • 14. Lead contact.
PMID: 39975381 DOI: 10.1101/2025.02.09.637107
Abstract

The pathological hallmark of neurodegenerative disease is the aberrant post-translational modification and aggregation of proteins leading to the formation of insoluble protein inclusions. Genetic factors like APOE4 are known to increase the prevalence and severity of tau, amyloid, and α-synuclein inclusions. However, the human brain is largely inaccessible during this process, limiting our mechanistic understanding. Here, we developed an iPSC-based 3D model that integrates neurons, glia, myelin, and cerebrovascular cells into a functional human brain tissue (miBrain). Like the human brain, we found pathogenic phosphorylation and aggregation of α-synuclein is increased in the APOE4 miBrain. Combinatorial experiments revealed that lipid-droplet formation in APOE4 astrocytes impairs the degradation of α-synuclein and leads to a pathogenic transformation that seeds neuronal inclusions of α-synuclein. Collectively, this study establishes a robust model for investigating protein inclusions in human brain tissue and highlights the role of astrocytes and Cholesterol in APOE4-mediated pathologies, opening therapeutic opportunities.

Keywords
APOE4; Alzheimer’s Disease; Astrocytes; Cholesterol metabolism; Lewy Body Dementia; Lysosomal dysfunction; Neurodegeneration; iPSC-derived brain model; miBrain; α-Synuclein.
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