Menopause Diminishes Female Protection against Vascular Contributions to Cognitive Impairment and Dementia

• Published in: The FASEB journal 2022-05, Vol.36 (S1), p.n/a
• Main Authors: Gannon, Olivia J., Naik, Janvie S., Abi‐Ghanem, Charly, Mansour, Febronia, Salinero, Abigail E., Riccio, David, Kelly, Richard D., Brooks, Heddwen L., Zuloaga, Kristen L.
• Format: Article
• Language: English
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.2022.36.S1.L7592

Around mid‐life, ovarian production of estrogen stops in a sex‐specific endocrine transition called menopause. While most women who have dementia are post‐menopausal, menopause is seldom included in rodent models of dementia despite its significance in dementia risk factors in women. Before, but not after menopause, women are less likely than men to suffer from stroke, obesity, and diabetes: known risk factors for vascular contributions to cognitive impairment and dementia (VCID). Here, we aim to determine if and how menopause worsens VCID. We hypothesize that menopause will increase metabolic dysfunction, cognitive impairment, and brain pathology in a mouse model of VCID. To model menopause, we utilized 4‐vinylcyclohexene diepoxide to induce accelerated ovarian failure. To model VCID, we performed a unilateral common carotid artery occlusion surgery. We assessed cognitive deficits using behavioral tests: open field, novel object recognition, Barnes maze, and nest building. To track metabolic changes, we recorded weight gain, adiposity, and glucose tolerance. We found that menopause led to weight gain, increased visceral adiposity, impaired glucose tolerance and impaired episodic‐like memory (novel object test). While these mice did not have cognitive impairments due to VCID alone, there was a significant correlation between the degree of blood flow deficit and activities of daily living (nest building test). While we have found that menopause had negative metabolic and cognitive consequences, there were no effects of VCID alone on cognitive function in young female mice, potentially due to the protective effect of ovarian estrogen production. Deficits in episodic‐like memory and activities of daily living appeared when menopause and VCID co‐occurred. Additionally, we are examining changes to estrogen receptor expression in the brain and integrity of the brain’s white matter, as white matter is particularly vulnerable to damage due to hypoperfusion. Further investigation into pathological features (brain inflammation, white matter, and vascular damage) may uncover the mechanisms through which menopause impacts cognitive function.