Zhang Lihang, Xu Juan, Gao Jinchao, Chen Peiqing, Yin Ming, Zhao Wenjuan
School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240 China.
Immun Ageing. 2019 Jan 25;16:2. doi: 10.1186/s12979-018-0142-7. eCollection 2019.
Apolipoprotein E4 (APOE4) and ageing are the most important known risk factors for late-onset Alzheimer's disease (AD). In the present study, we determined the alterations of IgG, CD19, and Aβ in various brain regions of uninfected male and female APOE3- and APOE4-TR mice at the age of 3 and 10 months to elucidate impacts of AD risk factors on alterations of brain IgG.
Positive staining for IgG was distributed across the brain, including neocortex, entorhinal cortex, hippocampus, thalamus and cerebellum. IgG positive staining was mainly located on microglia, but not astrocytes. Some IgG positive neurons were also observed, but only in mediodorsal thalamic nucleus. Compared with APOE3-TR mice, 10-month-old female APOE4-TR mice had lower IgG level in AD susceptible brain regions such as neocortex, entorhinal cortex and hippocampus, but no significant changes in thalamus and cerebellum, two regions nearly intact in AD. In addition, the expression of CD19, a specific marker for mature B cells, was significantly reduced in the hippocampus of 10-month-old female APOE4-TR mice. Although there were no obvious differences in plasma IgG levels between APOE4- and age matched female APOE3-TR mice, significant decreased B cell amount in blood of 10-month-old female APOE4-TR mice have also been found. Moreover, more obvious positive staining for Aβ was observed in the cortex of 10-month-old female APOE4-TR mice than other groups.
Our study demonstrated that AD risk factors were associated with IgG alterations in various brain regions, which might result from the defects of humoral immunity and lead to the impairment of IgG-mediated clearance of Aβ by microglia, therefore facilitated AD progression.
载脂蛋白E4（APOE4）和衰老为已知的晚发型阿尔茨海默病（AD）最重要的风险因素。在本研究中，我们测定了3月龄和10月龄未感染的雄性和雌性APOE3-和APOE4-转基因（TR）小鼠不同脑区中免疫球蛋白G（IgG）、CD19和β淀粉样蛋白（Aβ）的变化，以阐明AD风险因素对脑IgG变化的影响。
IgG阳性染色分布于整个大脑，包括新皮质、内嗅皮质、海马、丘脑和小脑。IgG阳性染色主要位于小胶质细胞，而非星形胶质细胞。也观察到一些IgG阳性神经元，但仅在丘脑背内侧核中。与APOE3-TR小鼠相比，10月龄雌性APOE4-TR小鼠在AD易感脑区如新皮质、内嗅皮质和海马中的IgG水平较低，但在丘脑和小脑（AD中几乎未受损的两个区域）无显著变化。此外，10月龄雌性APOE4-TR小鼠海马中成熟B细胞的特异性标志物CD19的表达显著降低。虽然APOE4-与年龄匹配的雌性APOE3-TR小鼠之间血浆IgG水平无明显差异，但也发现10月龄雌性APOE4-TR小鼠血液中的B细胞数量显著减少。此外，在10月龄雌性APOE4-TR小鼠的皮质中观察到比其他组更明显的Aβ阳性染色。
我们的研究表明，AD风险因素与不同脑区的IgG变化有关，这可能是由于体液免疫缺陷导致小胶质细胞对IgG介导的Aβ清除受损，从而促进了AD的进展。
