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.

阿尔茨海默氏病（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）斑块和由高磷酸化tau（p-tau）蛋白组成的神经原纤维缠结（NFT）沉积。这些变化与神经炎症，受损的血脑屏障（BBB）完整性和神经元突触功能障碍有关，最终导致AD中的神经元细胞丢失和认知功能障碍。Aβ _1-42立体定位双侧给药到18个月大的雄性C57BL / 6小鼠的海马的CA1区域。这项研究旨在利用免疫组织化学和行为测试来表征_Aβ1–42的时空效应关于AD的一系列广泛参数：p-tau，神经炎症，血管病理学，锥体细胞存活和行为。注射_Aβ1–42后三天，在检测到明显的神经元细胞丢失之前，观察到急性神经炎症和血管反应。这些反应包括神经胶质原纤维酸性蛋白（GFAP），细胞粘附分子1（PECAM-1，也称为CD31）上调，纤维蛋白原标记，以及在CA1区的活化星形胶质细胞和小胶质细胞数量增加。海马。从第7天起，海马CA1区的锥体细胞大量丢失，到30天时，p-tau，GFAP，Iba-1，CD31和α-平滑肌肌动蛋白（α- SMA）在_Aβ1–42中注射的小鼠与对照。在_Aβ1–42注射的小鼠中，这些分子变化伴随着认知能力下降，长期空间记忆障碍证实了这一点。这项研究报告了对小鼠海马内施用_Aβ1–42的一组复杂参数，其时空相互作用以及对疾病进展的综合影响的综合检查。我们显示，单次Aβ注射可以重现AD人脑中发生的炎症，血管和p-tau诱导的病理，从而导致认知缺陷。