TY - JOUR
T1 - Sex-Specific Adaptations in Alzheimer's Disease and Ischemic Stroke
T2 - A Longitudinal Study in Male and Female APPswe/PS1dE9 Mice
AU - Lohkamp, Klara J
AU - Timmer, Nienke
AU - Solé Guardia, Gemma
AU - Shenk, Justin
AU - Verweij, Vivienne
AU - Geenen, Bram
AU - Dederen, Pieter J
AU - Bakker, Lieke
AU - Egitimci, Cansu
AU - Yoldas, Rengin
AU - Verhaeg, Minou
AU - Kothuis, Josine
AU - Nieuwenhuis, Desirée
AU - Wiesmann, Maximilian
AU - Kiliaan, Amanda J
PY - 2025/2/21
Y1 - 2025/2/21
N2 - 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 /PS1 (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 (Aß) 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 Aß 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 Aß deposition, hyperactivity, lower body weight, and reduced CBF but less neuroinflammation, suggesting potential neuroprotection. These findings highlight white matter degeneration and Aß 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.
AB - 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 /PS1 (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 (Aß) 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 Aß 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 Aß deposition, hyperactivity, lower body weight, and reduced CBF but less neuroinflammation, suggesting potential neuroprotection. These findings highlight white matter degeneration and Aß 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.
KW - Alzheimer’s disease
KW - MRI
KW - cerebral blood flow
KW - cognition neuroinflammation
KW - neuropathology
KW - sex differences
KW - stroke
U2 - 10.3390/life15030333
DO - 10.3390/life15030333
M3 - Article
SN - 0024-3019
VL - 15
JO - Life
JF - Life
IS - 3
M1 - 333
ER -