Skip to content
DraconiticResearch
Search Sources API
197,768 studies31 sourcesUpdated 36 min ago
Peer-reviewedCC BY-NC-NDCell

A pericyte-to-myofibroblast transition links APOE4 to cerebrovascular degeneration

  • Braxton R. Schuldt1,2,3
  • Dominic Haworth-Staines1,2,3
  • Andrea Perez-Arevalo1,2,3
  • Diede W.M. Broekaart1,2,4
  • Ashley Harlock1,2,3
  • Leon Wang1,2,3
  • Anna Bright1,2,3
  • Georgia Gallagher1,2,3
  • Grace Rabinowitz1,2,3
  • Alison M. Goate1,2,3
  • Towfique Raj1,2,3
  • Ana C. Pereira1,2,4
1 more authors
  • Joel W. Blanchard1,2,3
4 affiliations
  1. 1Nash Family Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  2. 2Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
  3. 3Institute for Regenerative Medicine, Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
  4. 4Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
Read full textDOICite

Abstract

Cerebrovascular disease is a major but poorly understood feature of Alzheimer's disease (AD). The strongest genetic AD risk factor, apolipoprotein E4 (APOE4), is associated with cerebrovascular degeneration, including vascular amyloid deposition and fibrosis. To uncover how APOE4 promotes cerebrovascular pathology, we assembled a single-cell transcriptomic atlas of human brain vasculature. In APOE4 carriers, pericyte abundance was significantly reduced and accompanied by the emergence of a myofibroblast-like cell population co-expressing contraction and extracellular matrix genes. Immunostaining confirmed non-vascular myofibroblasts in APOE4 human and mouse brains. We show that APOE4 pericytes transition into myofibroblasts that secrete fibronectin, which promotes vascular amyloid accumulation. Computational and experimental analyses identified elevated transforming growth factor β (TGF-β) signaling as the driver of this pericyte-to-myofibroblast transition. Inhibition of TGF-β restored pericyte coverage and reduced vascular fibrosis and amyloid to APOE3 levels, revealing a targetable mechanism linking APOE4 to cerebrovascular pathology in AD.

Related

  1. Editor’s Note: ‘Expression of Concern: MGST2hi PMNs mediate NETs and drive pericyte-to-myofibroblast transition in RA-ILD’
    American journal of respiratory cell and molecular biologyPeer-reviewedCC BY-NCFull textGeneral medicineEurope PMCPMC
  2. The role and mechanism of macrophage-to-myofibroblast transition in fibrotic diseases
    Hua Guo, Xiao Xiao Tang
    Frontiers in ImmunologyPeer-reviewedCC BY 4.0Full textCardiovascular medicineCrossrefEurope PMC
  3. Global brain activity links subcortical degeneration to cortical tau progressively across Braak regions over early Alzheimer's disease stages.
    Yutong Mao, Baizhou Pan, Xiao Liu
    Nature communicationsPeer-reviewedCC BY-NC-NDFull textPsychiatry & mental healthEurope PMC
  4. Mitochondrial ROS and Mitophagy in Intervertebral Disc Degeneration: Mechanistic Interplay and Links to Regulated Cell Death
    Lice Wang, Kai Cao, Haozhe Cheng +1
    International Journal of Molecular SciencesPeer-reviewedCC BY 4.0General medicineCrossref
  5. Daily affect profiles during addiction recovery: Transition dynamics and links to acute recovery outcomes
    Joseph H. Lancaster, Timothy R. Brick, Hannah B. Apsley +1
    Addictive behaviorsPeer-reviewedCC BYFull textEpidemiology & public healthPMC

Cite

BibTeXRIS
BibTeX
@article{schuldt2026pericytetomyofibroblast,
  title = {{A pericyte-to-myofibroblast transition links APOE4 to cerebrovascular degeneration}},
  author = {Braxton R. Schuldt and Dominic Haworth-Staines and Andrea Perez-Arevalo and Diede W.M. Broekaart and Ashley Harlock and Leon Wang and Anna Bright and Georgia Gallagher and Grace Rabinowitz and Alison M. Goate and Towfique Raj and Ana C. Pereira and Joel W. Blanchard},
  journal = {Cell},
  year = {2026},
  month = sep,
  doi = {10.1016/j.cell.2026.08.058},
  url = {https://doi.org/10.1016/j.cell.2026.08.058},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - A pericyte-to-myofibroblast transition links APOE4 to cerebrovascular degeneration
AU  - Braxton R. Schuldt
AU  - Dominic Haworth-Staines
AU  - Andrea Perez-Arevalo
AU  - Diede W.M. Broekaart
AU  - Ashley Harlock
AU  - Leon Wang
AU  - Anna Bright
AU  - Georgia Gallagher
AU  - Grace Rabinowitz
AU  - Alison M. Goate
AU  - Towfique Raj
AU  - Ana C. Pereira
AU  - Joel W. Blanchard
PY  - 2026
DA  - 2026/09/24
JO  - Cell
DO  - 10.1016/j.cell.2026.08.058
UR  - https://doi.org/10.1016/j.cell.2026.08.058
AB  - Cerebrovascular disease is a major but poorly understood feature of Alzheimer's disease (AD). The strongest genetic AD risk factor, apolipoprotein E4 (APOE4), is associated with cerebrovascular degeneration, including vascular amyloid deposition and fibrosis. To uncover how APOE4 promotes cerebrovascular pathology, we assembled a single-cell transcriptomic atlas of human brain vasculature. In APOE4 carriers, pericyte abundance was significantly reduced and accompanied by the emergence of a myofibroblast-like cell population co-expressing contraction and extracellular matrix genes. Immunostaining confirmed non-vascular myofibroblasts in APOE4 human and mouse brains. We show that APOE4 pericytes transition into myofibroblasts that secrete fibronectin, which promotes vascular amyloid accumulation. Computational and experimental analyses identified elevated transforming growth factor β (TGF-β) signaling as the driver of this pericyte-to-myofibroblast transition. Inhibition of TGF-β restored pericyte coverage and reduced vascular fibrosis and amyloid to APOE3 levels, revealing a targetable mechanism linking APOE4 to cerebrovascular pathology in AD.
SN  - 0092-8674
SN  - 1097-4172
ER  -