Post-stroke hippocampal neurogenesis is impaired by microvascular dysfunction and PI3K signaling in cerebral amyloid angiopathy
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.
Authors
- Michał Toborek (ORCID: https://orcid.org/0000-0003-4475-2119)
- Daniel Bilbao (ORCID: https://orcid.org/0000-0003-1630-8811)
- Olivia Osborne (ORCID: https://orcid.org/0000-0002-8289-8429)
- Derek M. Dykxhoorn (ORCID: https://orcid.org/0000-0002-4998-9943)
- Samantha A. Brooks (ORCID: https://orcid.org/0000-0002-4500-2689)
- Christian Mason
- Alexander V. Margetts (ORCID: https://orcid.org/0000-0003-4568-2693)
- Luis M. Tuesta (ORCID: https://orcid.org/0000-0003-1610-8553)
- Silvia Torices
- Brett Colbert (ORCID: https://orcid.org/0000-0002-9668-0674)
- Oandy Naranjo (ORCID: https://orcid.org/0000-0002-4223-6869)
- Regina Vontell (ORCID: https://orcid.org/0000-0002-2664-8265)
- Malek Bashti
- Manav Daftari (ORCID: https://orcid.org/0009-0002-4206-6262)
- Anthony J. Griswold (ORCID: https://orcid.org/0000-0003-1925-7810)
- Elizabeth Lewis (ORCID: https://orcid.org/0000-0002-7471-9988)
- Adarsh N. Johar
- Jet Sendaydiego
- Gillian Drexler
Institutions
- University of Miami (US)
- Dr. John T. Macdonald Foundation (US)
- Sylvester Comprehensive Cancer Center (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-10-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.114848
- Citations
- 4
- Primary Topic
- Neurogenesis and neuroplasticity mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 1.64
Funders
- University of Miami
- Sylvester Comprehensive Cancer Center, University of Miami Health Systems
- National Institutes of Health
- Leonard M. Miller School of Medicine
- National Institute on Aging
- National Heart, Lung, and Blood Institute
- National Institute of Mental Health
- National Institute on Drug Abuse
- National Cancer Institute
- National Institute of Allergy and Infectious Diseases
- National Institute of Neurological Disorders and Stroke