Marongiu Roberta, Platholi Jimcy, Park Laibak, Yu Fangmin, Sommer Garrett, Woods Clara, Milner Teresa A, Glass Michael J
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, United States.
Neurological Surgery Department, Weill Cornell Medicine, New York, NY, United States.
Front Mol Biosci. 2025 May 14;12:1597130. doi: 10.3389/fmolb.2025.1597130. eCollection 2025.
Alzheimer's disease, the most common form of dementia, is characterized by age-dependent amyloid beta (Ab) aggregation and accumulation, neuroinflammation, and cognitive deficits. Significantly, there are prominent sex differences in the risk, onset, progression, and severity of AD, as well as response to therapies, with disease burden disproportionately affecting women. Although menopause onset (i.e., perimenopause) may be a critical transition stage for AD susceptibility in women, the role of early ovarian decline in initial disease pathology, particularly key neuroinflammatory processes, is not well understood.
To study this, we developed a unique mouse model of perimenopausal AD by combining an accelerated ovarian failure (AOF) model of menopause induced by 4-vinylcyclohexene diepoxide (VCD) with the 5xFAD transgenic AD mouse model. To target early stages of disease progression, 5xFAD females were studied at a young age (∼4 months) and at the beginning stage of ovarian failure analogous to human perimenopause (termed "peri-AOF"), and compared to age-matched males. Assessment of neuropathology was performed by immunohistochemical labeling of Ab as well as markers of astrocyte and microglia activity in the hippocampus, a brain region involved in learning and memory that is deleteriously impacted during AD.
Our results show that genotype, AOF, and sex contributed to AD-like pathology. Aggregation of Ab was heightened in female 5xFAD mice and further increased at peri-AOF, with hippocampal subregion specificity. Further, select increases in glial activation also paralleled Ab pathology in distinct hippocampal subregions. However, cognitive function was not affected by peri-AOF.
These findings align with the hypothesis that perimenopause constitutes a period of susceptibility for AD pathogenesis in women.
阿尔茨海默病是痴呆最常见的形式，其特征为与年龄相关的β淀粉样蛋白（Aβ）聚集和积累、神经炎症以及认知缺陷。值得注意的是，在阿尔茨海默病的风险、发病、进展和严重程度以及对治疗的反应方面存在显著的性别差异，疾病负担对女性的影响尤为严重。尽管绝经开始（即围绝经期）可能是女性患阿尔茨海默病易感性的关键过渡阶段，但早期卵巢功能衰退在疾病初始病理过程，特别是关键神经炎症过程中的作用尚不清楚。
为了研究这一问题，我们通过将4-乙烯基环己烯二环氧化物（VCD）诱导的绝经加速卵巢功能衰竭（AOF）模型与5xFAD转基因阿尔茨海默病小鼠模型相结合，开发了一种独特的围绝经期阿尔茨海默病小鼠模型。为了针对疾病进展的早期阶段，对年轻（约4个月）且处于类似于人类围绝经期的卵巢功能衰竭开始阶段（称为“围绝经期AOF”）的5xFAD雌性小鼠进行研究，并与年龄匹配的雄性小鼠进行比较。通过对Aβ以及海马体（参与学习和记忆的脑区，在阿尔茨海默病期间受到有害影响）中星形胶质细胞和小胶质细胞活性标志物进行免疫组织化学标记来评估神经病理学。
我们的结果表明，基因型、AOF和性别都对阿尔茨海默病样病理有影响。雌性5xFAD小鼠中Aβ的聚集增加，并在围绝经期AOF时进一步增加，具有海马亚区特异性。此外，在不同的海马亚区，胶质细胞活化的某些增加也与Aβ病理变化平行。然而，围绝经期AOF并未影响认知功能。
这些发现与围绝经期是女性阿尔茨海默病发病易感性时期的假设一致。
