Alzheimer's disease (AD) is characterized by a sequential progression of amyloid plaques (A), neurofibrillary tangles (T) and neurodegeneration (N), constituting ATN pathology. While microglia are considered key contributors to AD pathogenesis, their contribution in the combined presence of ATN pathologies remains incompletely understood. As sensors of the brain microenvironment, microglial phenotypes and contributions are importantly defined by the pathologies in the brain, indicating the need for their analysis in preclinical models that recapitulate combined ATN pathologies, besides their role in A and T models only. Here, we report a new tau-seed model in which amyloid pathology facilitates bilateral tau propagation associated with brain atrophy, thereby recapitulating robust ATN pathology. Single-cell RNA sequencing revealed that ATN pathology exacerbated microglial activation towards disease-associated microglia states, with a significant upregulation of Apoe as compared to amyloid-only models (A). Importantly, Colony-Stimulating Factor 1 Receptor inhibition preferentially eliminated non-plaque-associated versus plaque associated microglia. The preferential depletion of non-plaque-associated microglia significantly attenuated tau pathology and neuronal atrophy, indicating their detrimental role during ATN progression. Together, our data reveal the intricacies of microglial activation and their contributions to pathology in a model that recapitulates the combined ATN pathologies of AD. Our data may provide a basis for microglia-targeting therapies selectively targeting detrimental microglial populations, while conserving protective populations.

中文翻译：

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CSF1R 抑制可在 A/T/N 模型中挽救具有联合 AD 病理的 tau 病理和神经变性，同时保留斑块相关的小胶质细胞

阿尔茨海默病 (AD) 的特征是淀粉样斑块 (A)、神经原纤维缠结 (T) 和神经变性 (N) 的连续进展，构成 ATN 病理。虽然小胶质细胞被认为是 AD 发病机制的关键因素，但它们在 ATN 病理共同存在下的作用仍未完全了解。作为大脑微环境的传感器，小胶质细胞表型和贡献由大脑中的病理学定义重要，这表明除了它们仅在 A 和 T 模型中的作用之外，还需要在概括 ATN 病理学的临床前模型中对其进行分析。在这里，我们报告了一种新的 tau 种子模型，其中淀粉样蛋白病理促进了与脑萎缩相关的双侧 tau 传播，从而重现了强大的 ATN 病理。单细胞 RNA 测序显示 ATN 病理加剧了小胶质细胞对疾病相关小胶质细胞状态的激活，与仅淀粉样蛋白模型相比，Apoe 显着上调 (A)。重要的是，与斑块相关的小胶质细胞相比，集落刺激因子 1 受体抑制优先消除了非斑块相关的小胶质细胞。非斑块相关小胶质细胞的优先消耗显着减轻了 tau 病理和神经元萎缩，表明它们在 ATN 进展过程中的不利作用。总之，我们的数据揭示了小胶质细胞激活的复杂性及其在概括 AD 组合 ATN 病理的模型中对病理学的贡献。我们的数据可能为选择性靶向有害小胶质细胞群的小胶质细胞靶向疗法提供基础，