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

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

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 APP<sub>swe</sub>/PS1<sub>dE9<...

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Main Authors: 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
Format: Article
Language:English
Published: MDPI AG 2025-02-01
Series:Life
Subjects:
Alzheimer’s disease
stroke
sex differences
MRI
cerebral blood flow
cognition neuroinflammation
Online Access:https://www.mdpi.com/2075-1729/15/3/333
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Summary: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 APP<sub>swe</sub>/PS1<sub>dE9</sub> (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.
ISSN:2075-1729

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