2. Academic Validation
  3. Post-stroke hippocampal neurogenesis is impaired by microvascular dysfunction and PI3K signaling in cerebral amyloid angiopathy

Post-stroke hippocampal neurogenesis is impaired by microvascular dysfunction and PI3K signaling in cerebral amyloid angiopathy

  • Cell Rep. 2024 Oct 22;43(10):114848. doi: 10.1016/j.celrep.2024.114848.
Olivia M Osborne 1,  Manav Daftari 2,  Oandy Naranjo 2,  Adarsh N Johar 2,  Samantha Brooks 2,  Brett M Colbert 3,  Silvia Torices 2,  Elizabeth Lewis 2,  Jet Sendaydiego 2,  Gillian Drexler 2,  Malek Bashti 2,  Alexander V Margetts 4,  Luis M Tuesta 5,  Christian Mason 6,  Daniel Bilbao 7,  Regina Vontell 8,  Anthony J Griswold 9,  Derek M Dykxhoorn 9,  Michal Toborek 10
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address: omo17@miami.edu.
  • 2 Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 3 Medical Scientist Training Program, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 4 Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA; Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 5 Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, Miami, FL, USA; Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Neurology and Evelyn F. McKnight Brain Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 6 Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 7 Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 8 Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, FL, USA; Brain Endowment Bank, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 9 The Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA; John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
  • 10 Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address: mtoborek@med.miami.edu.
PMID: 39392753 DOI: 10.1016/j.celrep.2024.114848
Abstract

Ischemic stroke and cerebral amyloid angiopathy (CAA) pose significant challenges in an aging population, particularly in post-stroke recovery. Using the 5xFAD mouse model, we explore the relationship between CAA, ischemic stroke, and tissue recovery. We hypothesize that amyloid-beta accumulation worsens stroke outcomes by inducing blood-brain barrier (BBB) dysfunction, leading to impaired neurogenesis. Our findings show that CAA exacerbates stroke outcomes, with mice exhibiting constricted BBB microvessels, reduced cerebral blood flow, and impaired tissue recovery. Transcriptional analysis shows that endothelial cells and neural progenitor cells (NPCs) in the hippocampus exhibit differential gene expression in response to CAA and stroke, specifically targeting the phosphatidylinositol 3-kinase (PI3K) pathway. In vitro experiments with human NPCs validate these findings, showing that disruption of the CXCL12-PIK3C2A-CREB3L2 axis impairs neurogenesis. Notably, PI3K pathway activation restores neurogenesis, highlighting a potential therapeutic approach. These results suggest that CAA combined with stroke induces microvascular dysfunction and aberrant neurogenesis through this specific pathway.

Keywords

CAA; CP: Cell biology; CP: Neuroscience; PI3K; hippocampus; neurogenesis; stroke.

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