Menopause causes metabolic and cognitive impairments in a chronic cerebral hypoperfusion model of vascular contributions to cognitive impairment and dementia

Biology of Sex Differences

Research

Charly Abi-Ghanem¹  Janvie S. Naik¹  David Riccio¹  Richard D. Kelly¹  Kristen L. Zuloaga¹  Febronia M. Mansour¹  Abigail E. Salinero¹  Olivia J. Gannon¹  Heddwen L. Brooks² 

[1] Department of Neuroscience and Experimental Therapeutics, Albany Medical College, 47 New Scotland Avenue, MC-136, 12208, Albany, NY, USA;Department of Physiology, University of Arizona College of Medicine, 85724, Tucson, AZ, USA;

关键词: Neuroscience;    Vascular;    Dementia;    Menopause;    Cognitive impairment;    Hypoperfusion;    Estrogen;    Metabolic;    Myelin;    Neuroinflammation;   

DOI  :  10.1186/s13293-023-00518-7

 received in 2023-02-09, accepted in 2023-05-08,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundThe vast majority of women with dementia are post-menopausal. Despite clinical relevance, menopause is underrepresented in rodent models of dementia. Before menopause, women are less likely than men to experience strokes, obesity, and diabetes—known risk factors for vascular contributions to cognitive impairment and dementia (VCID). During menopause, ovarian estrogen production stops and the risk of developing these dementia risk factors spikes. Here, we aimed to determine if menopause worsens cognitive impairment in VCID. We hypothesized that menopause would cause metabolic dysfunction and increase cognitive impairment in a mouse model of VCID.MethodsWe performed a unilateral common carotid artery occlusion surgery to produce chronic cerebral hypoperfusion and model VCID in mice. We used 4-vinylcyclohexene diepoxide to induce accelerated ovarian failure and model menopause. We evaluated cognitive impairment using behavioral tests including novel object recognition, Barnes maze, and nest building. To assess metabolic changes, we measured weight, adiposity, and glucose tolerance. We explored multiple aspects of brain pathology including cerebral hypoperfusion and white matter changes (commonly observed in VCID) as well as changes to estrogen receptor expression (which may mediate altered sensitivity to VCID pathology post-menopause).ResultsMenopause increased weight gain, glucose intolerance, and visceral adiposity. VCID caused deficits in spatial memory regardless of menopausal status. Post-menopausal VCID specifically led to additional deficits in episodic-like memory and activities of daily living. Menopause did not alter resting cerebral blood flow on the cortical surface (assessed by laser speckle contrast imaging). In the white matter, menopause decreased myelin basic protein gene expression in the corpus callosum but did not lead to overt white matter damage (assessed by Luxol fast blue). Menopause did not significantly alter estrogen receptor expression (ERα, ERβ, or GPER1) in the cortex or hippocampus.ConclusionsOverall, we have found that the accelerated ovarian failure model of menopause caused metabolic impairment and cognitive deficits in a mouse model of VCID. Further studies are needed to identify the underlying mechanism. Importantly, the post-menopausal brain still expressed estrogen receptors at normal (pre-menopausal) levels. This is encouraging for any future studies attempting to reverse the effects of estrogen loss by activating brain estrogen receptors.

【 授权许可】

CC BY   
© The Author(s) 2023

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