Kushwaha Srishti, Roy Choudhury Rupsa, Bhat Priyanka, Kumaran S Senthil, Karunakaran Smitha
Centre for Brain Research, Indian Institute of Science, Bangalore, India.
Manipal Academy of Higher Education, Manipal, India.
Alzheimers Dement. 2026 Feb;22(2):e71168. doi: 10.1002/alz.71168.
The locus coeruleus (LC) is an early site of Alzheimer's disease (AD) pathology, yet the role of brainstem astrocytes in early, sex-dependent vulnerability remains unclear.
In 2- to 3-month-old APP/PS1 mice, we combined in vivo proton magnetic resonance spectroscopy (MRS) of the brainstem with region-resolved molecular analyses, including quantitative real-time polymerase chain reaction, amyloid beta 42 (Aβ42) oligomers enzyme-linked immunosorbent assay, lactate assay, immunohistochemistry, immunoblotting, astrocyte isolation, and 3D structural assessment. Environmental enrichment (EE) served as a non-pharmacologic intervention.
Females exhibited higher brainstem Aβ42 oligomers and an astrocyte-weighted MRS profile. Pontine glial fibrillary acidic protein (GFAP), complement component 3, and nuclear factor kappa-light-chain-enhancer of activated B cells were selectively upregulated without pan-reactive astrocytic and microglial markers. LC-restricted GFAP elevation occurred without changes in astrocyte counts or morphology, indicating a "primed" state. Females also showed higher lactate levels, increased monocarboxylate transporter 2 expression, and elevations in selected oxidative phosphorylation-associated transcripts, and reduced astrocytic alpha 2A-adrenergic receptor expression. EE normalized noradrenergic and pontine astrocytic changes.
Female-biased, LC-centric astrocytic priming emerges early in this amyloid-driven model and is modifiable.
蓝斑（LC）是阿尔茨海默病（AD）病理变化的早期位点，但脑干星形胶质细胞在早期性别依赖性易损性中的作用尚不清楚。
在2至3个月大的APP/PS1小鼠中，我们将脑干的体内质子磁共振波谱（MRS）与区域分辨分子分析相结合，包括定量实时聚合酶链反应、淀粉样β蛋白42（Aβ42）寡聚体酶联免疫吸附测定、乳酸测定、免疫组织化学、免疫印迹、星形胶质细胞分离和三维结构评估。环境富集（EE）作为一种非药物干预措施。
雌性小鼠脑干Aβ42寡聚体水平较高，且具有星形胶质细胞加权的MRS谱。脑桥胶质纤维酸性蛋白（GFAP）、补体成分3和活化B细胞核因子κB选择性上调，而无泛反应性星形胶质细胞和小胶质细胞标志物。LC区域的GFAP升高，而星形胶质细胞数量或形态无变化，表明处于“预激发”状态。雌性小鼠还表现出较高的乳酸水平、单羧酸转运蛋白2表达增加、某些氧化磷酸化相关转录本升高，以及星形胶质细胞α2A肾上腺素能受体表达降低。EE使去甲肾上腺素能和脑桥星形胶质细胞变化恢复正常。
在这个淀粉样蛋白驱动的模型中，以LC为中心的雌性偏向性星形胶质细胞预激发在早期出现且可改变。
