Ischemic stroke (IS) is a major risk factor for dementia and may accelerate Alzheimer’s disease (AD) progression, but the underlying mechanisms remain unclear. We investigated whether cortical IS influences AD-related pathology, including hippocampal gliosis, neurogenesis, and amyloid deposition, and whether it worsens cognitive decline in a preclinical AD model. Permanent middle cerebral artery occlusion (pMCAO) was induced in 4-month-old wild-type (WT) and triple-transgenic AD (3xTg-AD) mice.
Stroke severity and motor function were assessed one week post-surgery, followed by behavioral and histological analyses at the age of 5–6 months. pMCAO produced comparable infarct size and motor outcomes in WT and 3xTg-AD mice, with lesions restricted to the sensorimotor cortex and sparing the hippocampus. Histological analyses revealed reduced hippocampal neurogenesis and mildly increased astrogliosis in 3xTg-AD mice, whereas pMCAO did not significantly affect microgliosis, neurogenesis, or amyloid burden in either genotype. Behaviorally, 3xTg-AD mice showed impaired remote contextual fear memory, consistent with early AD-related deficits.
In WT mice, pMCAO impaired contextual memory retrieval when conditioning occurred after stroke, but did not further worsen cognition in 3xTg-AD mice. At the time point examined, early cortical IS did not induce detectable additional AD-related pathology or cognitive impairment in 3xTg-AD mice. Cognitive impairments in 3xTg-AD mice coincided with reduced hippocampal neurogenesis.
Maria Angeles Moro (Neurovascular Pathophysiology group, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid) and colleagues for teaching the pMCAO model. Next, we want to express our gratitude to Gino De Smet and Anke De Smet for the technical assistance during the in vivo and ex vivo experiments. We also thank Brecht Ghesquire, Yves Heremans, prof.
Movahedi of the VUB’s Movahedi Lab and the VUB research core facilities for their aid in the (confocal) imaging as well as the SQUARE-group (VUB) for their help with the statistical analyses. The graphical abstract was created in BioRender. Figures were created with GraphPad Prism/Adobe Illustrator.
This work was supported by grants of FWO Research Foundation – Flanders (11F4223N), Vrije Universiteit Brussel (SRP85), Stichting Alzheimer Onderzoek (20200025), Boehringer Ingelheim Fonds (travel grant) and the Helaers Foundation (Helaers Research Prize for Stroke 2022). Research Group Experimental Pharmacology (EFAR), Department of Pharmaceutical and Pharmacological Sciences, Center for Neurosciences (C4N), Neuroprotection and Neuromodulation (NEUR) Research Group, Vrije Universiteit Brussel, Laarbeeklaan 103, Jette, Brussels, 1090, Belgium Robin Gens, Roxane Testaferrata, Ron Kooijman, Sebastiaan Engelborghs, Sylvie De Raedt & Dimitri De Bundel Department of Neurology and Bru-BRAIN, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, Jette, Brussels, 1090, Belgium Robin Gens, Sebastiaan Engelborghs & Sylvie De Raedt Department of Biomedical Sciences, University of Antwerp, Universiteitsplein 1, Wilrijk, Antwerp, 2610, Belgium Bio-Imaging Lab, University of Antwerp, Universiteitsplein 1, Wilrijk, 2610, Antwerp, Belgium µNeuro Center for Excellence, University of Antwerp, Universiteitsplein 1, Wilrijk, Antwerp, 2610, Belgium The authors declare no competing interests. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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