Sex-Specific Adaptations in Alzheimer’s Disease and Ischemic Stroke: A Longitudinal Study in Male and Female APP<sub>swe</sub>/PS1<sub>dE9</sub> Mice
Klara J. Lohkamp,
Nienke Timmer,
Gemma Solé Guardia,
Justin Shenk,
Vivienne Verweij,
Bram Geenen,
Pieter J. Dederen,
Lieke Bakker,
Cansu Egitimci,
Rengin Yoldas,
Minou Verhaeg,
Josine Kothuis,
Desirée Nieuwenhuis,
Maximilian Wiesmann,
Amanda J. Kiliaan
Affiliations
Klara J. Lohkamp
Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition & Behavior, Center for Medical Neuroscience, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, Nijmegen, The Netherlands
Nienke Timmer
Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition & Behavior, Center for Medical Neuroscience, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, Nijmegen, The Netherlands
Gemma Solé Guardia
Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition & Behavior, Center for Medical Neuroscience, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, Nijmegen, The Netherlands
Justin Shenk
Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition & Behavior, Center for Medical Neuroscience, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, Nijmegen, The Netherlands
Vivienne Verweij
Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition & Behavior, Center for Medical Neuroscience, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, Nijmegen, The Netherlands
Bram Geenen
Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition & Behavior, Center for Medical Neuroscience, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, Nijmegen, The Netherlands
Pieter J. Dederen
Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition & Behavior, Center for Medical Neuroscience, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, Nijmegen, The Netherlands
Lieke Bakker
Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition & Behavior, Center for Medical Neuroscience, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, Nijmegen, The Netherlands
Cansu Egitimci
Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition & Behavior, Center for Medical Neuroscience, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, Nijmegen, The Netherlands
Rengin Yoldas
Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition & Behavior, Center for Medical Neuroscience, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, Nijmegen, The Netherlands
Minou Verhaeg
Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition & Behavior, Center for Medical Neuroscience, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, Nijmegen, The Netherlands
Josine Kothuis
Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition & Behavior, Center for Medical Neuroscience, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, Nijmegen, The Netherlands
Desirée Nieuwenhuis
Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition & Behavior, Center for Medical Neuroscience, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, Nijmegen, The Netherlands
Maximilian Wiesmann
Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition & Behavior, Center for Medical Neuroscience, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, Nijmegen, The Netherlands
Amanda J. Kiliaan
Department of Medical Imaging, Anatomy, Radboud University Medical Center, Donders Institute for Brain, Cognition & Behavior, Center for Medical Neuroscience, Preclinical Imaging Center PRIME, Radboud Alzheimer Center, Nijmegen, The Netherlands
The long-term impact of stroke on Alzheimer’s disease (AD) progression, particularly regarding sex-specific differences, remains unknown. Using a longitudinal study design, we investigated transient middle cerebral artery occlusion in 3.5-month-old APPswe/PS1dE9 (APP/PS1) and wild-type mice. In vivo, we assessed behavior, cerebral blood flow (CBF), and structural integrity by neuroimaging, as well as post-mortem myelin integrity (polarized light imaging, PLI), neuroinflammation, and amyloid beta (Aβ) deposition. APP/PS1 mice exhibited cognitive decline, white matter degeneration (reduced fractional anisotropy (FA) via diffusion tensor imaging (DTI)), and decreased myelin density via PLI. Despite early hypertension, APP/PS1 mice showed only sporadic hypoperfusion. Cortical thickening and hippocampal hypertrophy likely resulted from Aβ accumulation and neuroinflammation. Stroke-operated mice retained cognition despite cortical thinning and hippocampal atrophy due to cerebrovascular adaptation, including increased CBF in the hippocampus and thalamus. Stroke did not worsen AD pathology, nor did AD exacerbate stroke outcomes. Sex differences were found: female APP/PS1 mice had more severe Aβ deposition, hyperactivity, lower body weight, and reduced CBF but less neuroinflammation, suggesting potential neuroprotection. These findings highlight white matter degeneration and Aβ pathology as key drivers of cognitive decline in AD, with stroke-related deficits mitigated by (cerebro)vascular adaptation. Sex-specific therapies are crucial for AD and stroke.
