Alzheimer disease (AD) is a neurodegenerative disease characterized by a cognitive decline leading to dementia. The most impactful genetic risk factor is apolipoprotein E (APOE). APOE-ε4 significantly increases AD risk, APOE-ε3 is the most common gene variant, and APOE-ε2 protects against AD. However, the underlying mechanisms of APOE-ε4 on AD risk remains unclear, with APOE-ε4 impacting many pathways. We investigated how the APOE isoforms associated with the neuroinflammatory state of the brain with and without AD pathology. Frozen brain tissue from the superior and middle temporal gyrus was analyzed from APOE-ε3/3 (n = 9) or APOE-ε4/4 (n = 10) participants with AD pathology and APOE-ε3/3 (n = 9) participants without AD pathology. We determined transcript levels of 757 inflammatory related genes using the NanoString Human Neuroinflammation Panel. We found significant pathways impaired in APOE-ε4/4-AD individuals compared to APOE-ε3/3-AD. Of interest, expression of genes related to microglial activation (SALL1), motility (FSCN1), epigenetics (DNMT1), and others showed altered expression. Additionally, we performed immunohistochemistry of P2RY12 to confirm reduced microglial activation. Our results suggest APOE-ε3 responds to AD pathology while potentially having a harmful long-term inflammatory response, while APOE-ε4 shows a weakened response to pathology. Overall, APOE isoforms appear to modulate the brain immune response to AD-type pathology.

中文翻译：

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阿尔茨海默病中炎症通路受损并与载脂蛋白 E 状态存在差异相关


阿尔茨海默病（AD）是一种神经退行性疾病，其特征是认知能力下降，导致痴呆。最有影响力的遗传风险因素是载脂蛋白 E (APOE)。 APOE-ε4 显着增加 AD 风险，APOE-ε3 是最常见的基因变异，APOE-ε2 可以预防 AD。然而，APOE-ε4 对 AD 风险的潜在机制仍不清楚，APOE-ε4 影响许多途径。我们研究了 APOE 异构体如何与有或没有 AD 病理的大脑神经炎症状态相关。对患有 AD 病理的 APOE-ε3/3 (n = 9) 或 APOE-ε4/4 (n = 10) 参与者和 APOE-ε3/3 (n = 9) 参与者的颞上回和颞中回的冷冻脑组织进行了分析无AD病理。我们使用 NanoString Human Neuroinflammation Panel 测定了 757 个炎症相关基因的转录水平。我们发现与 APOE-ε3/3-AD 相比，APOE-ε4/4-AD 个体的通路明显受损。有趣的是，与小胶质细胞激活 (SALL1)、运动性 (FSCN1)、表观遗传学 (DNMT1) 等相关的基因的表达显示出表达改变。此外，我们对 P2RY12 进行了免疫组织化学分析，以证实小胶质细胞活化减少。我们的结果表明 APOE-ε3 对 AD 病理有反应，同时可能产生有害的长期炎症反应，而 APOE-ε4 显示对病理的反应减弱。总体而言，APOE 亚型似乎可以调节大脑对 AD 型病理的免疫反应。