Alzheimer’s disease (AD), the most common chronic neurodegenerative disorder, has complex neuropathology. The principal neuropathological hallmarks of the disease are the deposition of extracellular β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) comprised of hyperphosphorylated tau (p-tau) protein. These changes occur with neuroinflammation, a compromised blood-brain barrier (BBB) integrity, and neuronal synaptic dysfunction, all of which ultimately lead to neuronal cell loss and cognitive deficits in AD. Aβ_1–42 was stereotaxically administered bilaterally into the CA1 region of the hippocampi of 18-month-old male C57BL/6 mice. This study aimed to characterize, utilizing immunohistochemistry and behavioral testing, the spatial and temporal effects of Aβ_1–42 on a broad set of parameters characteristic of AD: p-tau, neuroinflammation, vascular pathology, pyramidal cell survival, and behavior. Three days after Aβ_1–42 injection and before significant neuronal cell loss was detected, acute neuroinflammatory and vascular responses were observed. These responses included the up-regulation of glial fibrillary acidic protein (GFAP), cell adhesion molecule-1 (PECAM-1, also known as CD31), fibrinogen labeling, and an increased number of activated astrocytes and microglia in the CA1 region of the hippocampus. From day 7, there was significant pyramidal cell loss in the CA1 region of the hippocampus, and by 30 days, significant localized up-regulation of p-tau, GFAP, Iba-1, CD31, and alpha-smooth muscle actin (α-SMA) in the Aβ_1–42-injected mice compared with controls. These molecular changes in Aβ_1–42-injected mice were accompanied by cognitive deterioration, as demonstrated by long-term spatial memory impairment. This study is reporting a comprehensive examination of a complex set of parameters associated with intrahippocampal administration of Aβ_1–42 in mice, their spatiotemporal interactions and combined contribution to the disease progression. We show that a single Aβ injection can reproduce aspects of the inflammatory, vascular, and p-tau induced pathology occurring in the AD human brain that lead to cognitive deficits.

阿尔茨海默病 (AD) 是最常见的慢性神经退行性疾病，具有复杂的神经病理学。该疾病的主要神经病理学特征是细胞外 β-淀粉样蛋白 (Aβ) 斑块和由过度磷酸化 tau (p-tau) 蛋白组成的神经原纤维缠结 (NFT) 的沉积。这些变化伴随着神经炎症、血脑屏障 (BBB) 完整性受损和神经元突触功能障碍而发生，所有这些最终导致 AD 中的神经元细胞丢失和认知缺陷。将 Aβ _1-42立体定向注射到 18 个月大的雄性 C57BL/6 小鼠的双侧海马 CA1 区域。本研究旨在利用免疫组织化学和行为测试来表征 Aβ _1-42对 AD 的一系列广泛特征参数的空间和时间影响：p-tau、神经炎症、血管病理学、锥体细胞存活和行为。注射 Aβ _1-42三天后，在检测到显着的神经元细胞损失之前，观察到急性神经炎症和血管反应。这些反应包括神经胶质纤维酸性蛋白 (GFAP)、细胞粘附分子 1 (PECAM-1，也称为 CD31)、纤维蛋白原标记的上调，以及神经胶质细胞 CA1 区域中活化星形胶质细胞和小胶质细胞数量的增加。海马体。从第 7 天开始，海马 CA1 区域出现显着的锥体细胞损失，到 30 天，p-tau、GFAP、Iba-1、CD31 和 α-平滑肌肌动蛋白 (α-与对照组相比，注射 Aβ _{1-42 的}小鼠中的 SMA）。 注射 Aβ _1-42的小鼠的这些分子变化伴随着认知恶化，如长期空间记忆障碍所证明的那样。这项研究报告了对与小鼠海马内 Aβ _1-42给药相关的一组复杂参数、它们的时空相互作用以及对疾病进展的综合贡献的全面检查。我们证明，单次 Aβ 注射可以重现 AD 人脑中发生的炎症、血管和 p-tau 诱导病理，从而导致认知缺陷。