Lohkamp Klara J, Timmer Nienke, Solé Guardia Gemma, Shenk Justin, Verweij Vivienne, Geenen Bram, Dederen Pieter J, Bakker Lieke, Egitimci Cansu, Yoldas Rengin, Verhaeg Minou, Kothuis Josine, Nieuwenhuis Desirée, Wiesmann Maximilian, Kiliaan Amanda J
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.
Alzheimer Center Limburg, Department of Psychiatry and Neuropsychology, Mental Health and Neuroscience Research Institute (MHeNs), European Graduate School of Neuroscience (EURON), Faculty of Health, Medicine and Life Sciences (FHML), Maastricht University, 6229 ER Maastricht, The Netherlands.
Life (Basel). 2025 Feb 21;15(3):333. doi: 10.3390/life15030333.
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 (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.
中风对阿尔茨海默病（AD）进展的长期影响，尤其是性别差异方面，仍不清楚。我们采用纵向研究设计，对3.5月龄的APP/PS1（淀粉样前体蛋白/早老素1）小鼠和野生型小鼠进行短暂性大脑中动脉闭塞实验。在体内，我们通过神经影像学评估行为、脑血流量（CBF）和结构完整性，以及死后的髓鞘完整性（偏振光成像，PLI）、神经炎症和β淀粉样蛋白（Aβ）沉积。APP/PS1小鼠表现出认知能力下降、白质退化（通过扩散张量成像（DTI）降低分数各向异性（FA））以及通过PLI显示髓鞘密度降低。尽管早期出现高血压，但APP/PS1小鼠仅表现出散发性灌注不足。皮质增厚和海马体肥大可能是由Aβ积累和神经炎症引起的。中风处理后的小鼠尽管由于脑血管适应性改变导致皮质变薄和海马体萎缩，但仍保持认知能力，包括海马体和丘脑的CBF增加。中风并未使AD病理恶化，AD也未加重中风后果。发现了性别差异：雌性APP/PS1小鼠有更严重的Aβ沉积、多动、体重降低和CBF减少，但神经炎症较少，提示可能存在神经保护作用。这些发现突出了白质退化和Aβ病理是AD认知能力下降的关键驱动因素，中风相关的缺陷可通过（脑血管）适应性改变得到缓解。针对性别的治疗对AD和中风至关重要。
