Centre for Brain Research, Indian Institute of Science, Bangalore, 560012, India.
Centre for Neuroscience, Indian Institute of Science, Bangalore, 560012, India.
Transl Psychiatry. 2023 Apr 12;13(1):123. doi: 10.1038/s41398-023-02411-8.
Women carry a higher burden of Alzheimer's disease (AD) compared to men, which is not accounted entirely by differences in lifespan. To identify the mechanisms underlying this effect, we investigated sex-specific differences in the progression of familial AD in humans and in APPswe/PS1ΔE9 mice. Activity dependent protein translation and associative learning and memory deficits were examined in APPswe/PS1ΔE9 mice and wild-type mice. As a human comparator group, progression of cognitive dysfunction was assessed in mutation carriers and non-carriers from DIAN (Dominantly Inherited Alzheimer Network) cohort. Female APPswe/PS1ΔE9 mice did not show recall deficits after contextual fear conditioning until 8 months of age. Further, activity dependent protein translation and Akt1-mTOR signaling at the synapse were impaired in male but not in female mice until 8 months of age. Ovariectomized APPswe/PS1ΔE9 mice displayed recall deficits at 4 months of age and these were sustained until 8 months of age. Moreover, activity dependent protein translation was also impaired in 4 months old ovariectomized APPswe/PS1ΔE9 mice compared with sham female APPswe/PS1ΔE9 mice. Progression of memory impairment differed between men and women in the DIAN cohort as analyzed using linear mixed effects model, wherein men showed steeper cognitive decline irrespective of the age of entry in the study, while women showed significantly greater performance and slower decline in immediate recall (LOGIMEM) and delayed recall (MEMUNITS) than men. However, when the performance of men and women in several cognitive tasks (such as Wechsler's logical memory) are compared with the estimated year from expected symptom onset (EYO) we found no significant differences between men and women. We conclude that in familial AD patients and mouse models, females are protected, and the onset of disease is delayed as long as estrogen levels are intact.
女性患阿尔茨海默病（AD）的负担比男性高，而这并不能完全归因于寿命的差异。为了确定这种影响的机制，我们研究了人类家族性 AD 进展中的性别差异和 APPswe/PS1ΔE9 小鼠。我们研究了 APPswe/PS1ΔE9 小鼠和野生型小鼠的活性依赖性蛋白翻译以及联想学习和记忆缺陷。作为人类对照组，我们评估了 DIAN（显性遗传性阿尔茨海默病网络）队列中突变携带者和非携带者认知功能障碍的进展。雌性 APPswe/PS1ΔE9 小鼠在 8 个月大之前不会出现情景恐惧条件反射的回忆缺陷。此外，直到 8 个月大，雄性小鼠的活性依赖性蛋白翻译和突触处 Akt1-mTOR 信号才受到损害，但雌性小鼠没有。去卵巢 APPswe/PS1ΔE9 小鼠在 4 个月大时出现回忆缺陷，并持续到 8 个月大。此外，与假手术雌性 APPswe/PS1ΔE9 小鼠相比，4 个月大的去卵巢 APPswe/PS1ΔE9 小鼠的活性依赖性蛋白翻译也受到损害。使用线性混合效应模型分析 DIAN 队列中男性和女性的记忆障碍进展情况不同，其中无论研究开始时的年龄如何，男性的认知衰退都更为陡峭，而女性在即时回忆（LOGIMEM）和延迟回忆（MEMUNITS）方面的表现明显更好，衰退速度更慢。然而，当比较男性和女性在几个认知任务（如韦氏逻辑记忆）中的表现与从预计发病开始的估计年份（EYO）时，我们发现男性和女性之间没有显著差异。我们得出的结论是，在家族性 AD 患者和小鼠模型中，只要雌激素水平正常，女性就受到保护，疾病的发病时间会延迟。
