β-淀粉样蛋白（β-amyloid, Aβ）相关神经退行性疾病主要包括阿尔茨 海默病（Alzheimer’s disease, AD）和淀粉样脑血管病（Cerebral amyloid angiopathy, CAA），是导致认知功能障碍和痴呆的主要原因之一，但其病因和发病机制仍未完 全阐明。Aβ 异常沉积可引发突触功能障碍、线粒体损伤以及神经炎症反应的激活 等多种病理改变，被认为是 Aβ 相关神经退行性疾病的核心病理特征之一。然而， Aβ 异常沉积如何触发神经炎症及其后续的神经退行性过程，仍然是当前研究的热 点和难点。免疫系统在神经退行性疾病中扮演了重要角色，中性粒细胞作为先天 免疫系统主要的效应细胞，其激活和浸润被认为是炎症的关键驱动因素。然而中 性粒细胞影响 Aβ 相关神经退行性疾病的具体机制以及它们对 Aβ 病理的具体影响 仍不明确。 本研究利用国家发育和功能人脑组织资源库 483 例人全脑样本，系统分析 了 Aβ 相关神经退行性疾病（AD 和 CAA）的检出率及其与认知功能障碍的相关性， 并进一步探究脑组织不同类型 Aβ 斑块与 Aβ 相关神经病理改变及认知功能障碍的 相关性。通过激光捕获显微切割技术和微量蛋白质组学分析了不同类型 Aβ 斑块的 组成成分。应用免疫染色技术研究了中性粒细胞、小胶质细胞和星形胶质细胞特 征性蛋白与 Aβ 沉积的共定位现象，并进一步分析其与 Aβ 相关神经退行性疾病病 理改变之间的相关性。以 7 月龄雄性 FAD4T转基因小鼠为研究对象，通过抗 Ly6G 单克隆抗体介导的中性粒细胞清除技术建立耗竭模型，进而阐明中性粒细胞在 Aβ 相关神经退行性疾病中的作用机制。 本研究发现 AD 和 CAA 在中国捐献者队列中的检出率分别为 36.4%和 31.3%，且两者存在显著的共患病现象，这种共患病状态与更严重的认知功能障碍 相关。致密核心 Aβ 斑块（Focal Aβ plaques, FAPs）的数量与 AD 和 CAA 的病理严 重程度呈显著正相关，而弥漫样 Aβ 斑块（Diffuse Aβ plaques, DAPs）的数量与 AD 和 CAA 的病理程度无显著相关性。斑块微量蛋白质组学显示，FAPs 及其周围 微环境主要富集免疫反应相关蛋白（包括中性粒细胞、小胶质细胞和星形胶质细 胞特征性蛋白）。中性粒细胞特征性蛋白髓过氧化物酶（myeloperoxidase, MPO） 和天青杀素（azurocidin, AZU1）在 FAPs 和血管 Aβ 沉积中显著富集，且与 AD 和 CAA 病理严重程度显著相关。FAD4T 转基因小鼠脑组织中性粒细胞特征性蛋白 MPO 和 AZU1 显著增加，并且和 Aβ 病理沉积呈现显著空间共定位。FAD4T转基因 小鼠中性粒细胞耗竭后显著改善认知功能障碍，并显著减轻脑组织 Aβ 病理负荷。 本研究首次报道 Aβ 相关神经退行性疾病（包括 AD 和 CAA）在中国捐献 者队列中的检出率，为理解 Aβ 相关神经退行性疾病流行病学特征提供了重要数据 支持。本研究揭示了中性粒细胞特征性蛋白在 Aβ 相关神经退行性疾病中的重要作 用，提示中性粒细胞可能通过 MPO、AZU1 等特征性蛋白促进 Aβ 病理进展并加剧 认知功能障碍。这些发现提示中性粒细胞及其特征性蛋白可能成为 Aβ 相关神经退 行性疾病的潜在治疗靶点，为针对 Aβ 相关神经退行性疾病的诊断及治疗策略提供 了新方向。

Background and Objectives: β-amyloid (Aβ) related neurodegenerative diseases mainly include Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA), which are among the main causes of cognitive impairment and dementia. However, the etiology and pathogenesis of these diseases remain largely unclear. Aβ abnormal deposition can trigger various pathological changes such as synaptic dysfunction, mitochondrial damage, and activation of neuroinflammatory responses, and is considered as one of the core pathological features of Aβ-related neurodegenerative diseases. However, how Aβ abnormal deposition triggers neuroinflammation and subsequent neurodegenerative processes remains a current research hotspot and challenge. The immune system plays an important role in neurodegenerative diseases, and neutrophils, as the main effector cells of the innate immune system, their activation and infiltration are considered as key drivers of inflammation. However, the specific mechanisms by which neutrophils affect Aβ-related neurodegenerative diseases and their specific impacts on Aβ pathology remain unclear. Methods: This study utilized 483 human whole-brain samples from the National Human Brain Bank for Development and Function to systematically analyze the prevalence of Aβ-related neurodegenerative diseases (AD and CAA) and their relationship with cognitive impairment, and further explored the relationship between different types of Aβ plaques in brain tissue and Aβ-related neuropathological changes and cognitive impairment. Laser capture microdissection technology and micro proteomics were used to analyze the composition of different types of Aβ plaques. Immunostaining techniques were applied to study the co-localization of neutrophil, microglial, and astrocyte characteristic proteins with Aβ deposition, and to further analyze their correlations with the pathology of Aβ-related neurodegenerative diseases. Using 7-month-old male FAD4T transgenic mice as the research subjects, a depletion model was established through anti Ly6G monoclonal antibody-mediated neutrophil depletion technology, and the role of neutrophils in Aβ-related neurodegenerative diseases was elucidated. Results: This study found that the detection rates of AD and CAA in the donor cohort from China were 36.4% and 31.3%, respectively, with a notable comorbidity observed between the two conditions. This comorbidity state was associated with more severe cognitive dysfunction. The quantity of focal Aβ plaques (FAPs) was significantly positively correlated with the severity of the pathology of AD and CAA, while the quantity of diffuse Aβ plaques (DAPs) was not significantly correlated with the severity of the pathology of AD and CAA. The micro proteomic analysis of plaques revealed that FAPs and their surrounding microenvironment mainly enriched immune response-related proteins (including characteristic proteins of neutrophils, microglial, and astrocytes). The characteristic proteins of neutrophils, myeloperoxidase (MPO) and azurocidin (AZU1), were significantly enriched in FAPs and vascular Aβ deposition, and were significantly correlated with the severity of AD and CAA pathology. In the brain tissues of FAD4T transgenic mice, the neutrophil characteristic proteins MPO and AZU1 were significantly upregulated and exhibited significant spatial co-localization with Aβ pathological deposition. Following the depletion of neutrophils in FAD4T transgenic mice, cognitive dysfunction was substantially ameliorated, and the pathological burden of Aβ in brain tissues was significantly diminished. Conclusions: This study is the first to report the detection rates of Aβ-related neurodegenerative diseases (including AD and CAA) in the donor cohort from China, providing important data support for understanding the epidemiological characteristics of Aβ-related neurodegenerative diseases. This study has revealed the significant role of neutrophil characteristic proteins in Aβ-related neurodegenerative diseases, suggesting that neutrophils may promote the pathological progression of Aβ and exacerbate cognitive dysfunction through characteristic proteins such as MPO and AZU1. These findings indicate that neutrophils and their characteristic proteins may become potential therapeutic targets for Aβ-positive neurodegenerative diseases, providing a new direction for the diagnosis and treatment strategies of Aβ-related neurodegenerative diseases