Qi Guibo, Tang Han, Gong Pifang, Liu Yitong, He Chenzhao, Hu Jianian, Kang Siying, Chen Liang, Qin Song
Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China.
State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai, 200032, China.
Cell Biosci. 2024 Sep 13;14(1):120. doi: 10.1186/s13578-024-01295-5.
Amyloid toxicity and glucose metabolic disorders are key pathological features during the progression of Alzheimer's disease (AD). While the hypothalamus plays a crucial role in regulating systemic energy balance, the distribution of amyloid plaques in the preoptic, anterior, tuberal, and mammillary regions of the hypothalamus in AD mice, particularly across both sexes, remains largely unclear. Our ongoing research aims to explore hypothalamic neuropathology and glucose metabolic disturbances in a well-described APP/PS1 mouse model of AD.
Immunocytochemical staining revealed that Old-AD-Female mice exhibited a greater hypothalamic Amyloid β (Aβ) burden than their Old-AD-Male counterparts, with the mammillary bodies showing the most severe accumulation. Analysis of ionized calcium binding adaptor molecule 1 (IBA1) immunoreactivity and Iba1 mRNA indicated differential microgliosis based on sex, while tanycytic territory and ZO-1 tight junction protein expression remained stable in AD mice. Moreover, sex-specific peripheral glucose metabolic parameters (random and fasting blood glucose) seemed to be exacerbated by age. Old AD mice of both sexes exhibited limited hypothalamic activation (c-Fos + cells) in response to blood glucose fluctuations. Hypothalamic Glut 1 expression decreased in young but increased in old female AD mice compared with age-matched male AD mice. Pearson correlation analysis further supported a negative correlation between hypothalamic Aβ load and random blood glucose in old AD groups of both genders, shedding light on the mechanisms underlying this amyloidosis mouse model.
Aged APP/PS1 mice exhibit sex-specific hypothalamic neuropathology and differential glucose metabolism, highlighting distinct pathological mechanisms within each gender.
淀粉样蛋白毒性和葡萄糖代谢紊乱是阿尔茨海默病（AD）进展过程中的关键病理特征。虽然下丘脑在调节全身能量平衡中起着至关重要的作用，但AD小鼠下丘脑视前区、前部、结节部和乳头体区域淀粉样斑块的分布情况，尤其是在两性中的分布，仍 largely不清楚。我们正在进行的研究旨在探索在一个描述详尽的AD小鼠APP/PS1模型中的下丘脑神经病理学和葡萄糖代谢紊乱情况。
免疫细胞化学染色显示，老年AD雌性小鼠下丘脑淀粉样β（Aβ）负荷比老年AD雄性小鼠更大，乳头体显示出最严重的积聚。对离子钙结合衔接分子1（IBA1）免疫反应性和Iba1 mRNA的分析表明，基于性别存在不同的小胶质细胞增生，而AD小鼠中的伸长细胞区域和ZO-1紧密连接蛋白表达保持稳定。此外，性别特异性外周葡萄糖代谢参数（随机和空腹血糖）似乎因年龄而加剧。两性的老年AD小鼠对血糖波动的下丘脑激活（c-Fos +细胞）有限。与年龄匹配的雄性AD小鼠相比，年轻雌性AD小鼠下丘脑葡萄糖转运蛋白1（Glut 1）表达降低，但老年雌性AD小鼠中升高。Pearson相关分析进一步支持了老年AD组中下丘脑Aβ负荷与随机血糖之间的负相关，揭示了这种淀粉样变性小鼠模型的潜在机制。
老年APP/PS1小鼠表现出性别特异性下丘脑神经病理学和不同的葡萄糖代谢，突出了每种性别内独特的病理机制。
