Chaigneau Thomas, Sha Sha, Roux Candice M, Aïd Saba, Faucher Alice, Chantran Yannick, Dorothée Guillaume, Krantic Slavica
Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, Neuroimmunology, Inflammation and Therapeutics Laboratory, Hôpital Saint-Antoine, Paris, France.
Department of Physiology, Nanjing Medical University, Nanjing, China.
Glia. 2025 Aug;73(8):1727-1745. doi: 10.1002/glia.70029. Epub 2025 Apr 30.
Growing evidence highlights sex-related differences in the pathogenesis of Alzheimer's disease (AD). Yet, early impact of sex on neuronal activity and microglia in the hippocampus, a main site of memory formation and one of the most vulnerable brain areas in AD, remains poorly understood. We thus assessed these issues by using APPPS1 mouse model of AD-like amyloid pathology at a pre-symptomatic stage (5-6 months). Our electrophysiological data point to opposite alterations in hippocampal CA1 neurons' basal glutamatergic neurotransmission and response to excitatory inputs between male and female APPPS1 mice. These complex changes in neuronal activity are likely to precede plasticity impairments, which do not yet translate into sexual dimorphism of Long-Term Potentiation (LTP) at the studied age. Alteration in synaptic transmission in males coincides with an increased number and coverage of microglia, together with increased plaque coverage, as compared to the female hippocampus. Such increased microgliosis in males is accompanied by complex sex-related differences in the expression of specific transcriptomic markers Disease-Associated Microglia (DAM)/Microglial neurodegenerative phenotype (MGnD), whereas homeostatic (M0) markers were unaffected. Our data show for the first time that subtle alterations in hippocampal neuronal activity coincide with early sex-related differences in amyloidosis and microglia already at the pre-symptomatic stage of AD-like pathology.
越来越多的证据凸显了阿尔茨海默病（AD）发病机制中的性别差异。然而，性别对海马体中神经元活动和小胶质细胞的早期影响仍知之甚少，海马体是记忆形成的主要部位，也是AD中最脆弱的脑区之一。因此，我们通过使用处于症状前期（5 - 6个月）的AD样淀粉样病理的APPPS1小鼠模型来评估这些问题。我们的电生理数据表明，雄性和雌性APPPS1小鼠海马体CA1神经元的基础谷氨酸能神经传递以及对兴奋性输入的反应存在相反的改变。这些神经元活动的复杂变化可能先于可塑性损伤，在所研究的年龄阶段，可塑性损伤尚未转化为长时程增强（LTP）的性别二态性。与雌性海马体相比，雄性小鼠突触传递的改变与小胶质细胞数量和覆盖范围的增加以及斑块覆盖范围的增加相一致。雄性小鼠中这种小胶质细胞增生增加伴随着疾病相关小胶质细胞（DAM）/小胶质细胞神经退行性表型（MGnD）特定转录组标记物表达的复杂性别差异，而稳态（M0）标记物未受影响。我们的数据首次表明，在AD样病理的症状前期，海马体神经元活动的细微改变就与淀粉样变性和小胶质细胞的早期性别差异同时出现。
