Kodali Maheedhar, Madhu Leelavathi N, Somayaji Yogish, Attaluri Sahithi, Huard Charles, Panda Prashanta Kumar, Shankar Goutham, Rao Shama, Shuai Bing, Gonzalez Jenny J, Oake Chris, Hering Catherine, Babu Roshni Sara, Kotian Sanya, Shetty Ashok K
bioRxiv. 2024 Jul 16:2024.07.11.603157. doi: 10.1101/2024.07.11.603157.
Chronic neuroinflammation represents a prominent hallmark of Alzheimer's disease (AD). While moderately activated microglia are pivotal in clearing amyloid beta (Aβ), hyperactivated microglia perpetuate neuroinflammation. Prior investigations have indicated that the elimination of ∼80% of microglia through a month-long inhibition of the colony-stimulating factor 1 receptor (CSF1R) during the advanced stage of neuroinflammation in 5xFamilial AD (5xFAD) mice mitigates synapse loss and neurodegeneration without impacting Aβ levels. Furthermore, prolonged CSF1R inhibition diminished the development of parenchymal plaques. Nonetheless, the immediate effects of short-term CSF1R inhibition during the early stages of neuroinflammation on residual microglial phenotype or metabolic fitness are unknown. Therefore, we investigated the effects of 10-day CSF1R inhibition in three-month-old female 5xFAD mice, a stage characterized by the onset of neuroinflammation and minimal Aβ plaques. We observed ∼65% microglia depletion in the hippocampus and cerebral cortex. The leftover microglia demonstrated a noninflammatory phenotype, with highly branched and ramified processes and reduced NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome complexes. Moreover, plaque-associated microglia were reduced in number with diminished Clec7a (dectin-1) expression. Additionally, both microglia and neurons displayed reduced mechanistic target of rapamycin (mTOR) signaling and autophagy. Biochemical assays validated the inhibition of NLRP3 inflammasome activation, decreased mTOR signaling, and enhanced autophagy. However, short-term CSF1R inhibition did not influence Aβ plaques, soluble Aβ-42 levels, or hippocampal neurogenesis. Thus, short-term CSF1R inhibition during the early stages of neuroinflammation in 5xFAD mice promotes the retention of homeostatic microglia with diminished inflammasome activation and mTOR signaling, alongside increased autophagy.
慢性神经炎症是阿尔茨海默病（AD）的一个显著特征。虽然适度激活的小胶质细胞在清除β淀粉样蛋白（Aβ）方面起着关键作用，但过度激活的小胶质细胞会使神经炎症持续存在。先前的研究表明，在5xFamilial AD（5xFAD）小鼠神经炎症晚期，通过为期一个月的集落刺激因子1受体（CSF1R）抑制作用消除约80%的小胶质细胞，可减轻突触损失和神经退行性变，而不影响Aβ水平。此外，长期抑制CSF1R可减少实质斑块的形成。然而，在神经炎症早期短期抑制CSF1R对残余小胶质细胞表型或代谢适应性的即时影响尚不清楚。因此，我们研究了在3个月大的雌性5xFAD小鼠中进行10天CSF1R抑制的效果，这个阶段的特征是神经炎症开始且Aβ斑块极少。我们观察到海马体和大脑皮层中的小胶质细胞减少了约65%。剩余的小胶质细胞表现出非炎症表型，具有高度分支和分叉的突起，且含NOD、LRR和pyrin结构域的蛋白3（NLRP3）炎性小体复合物减少。此外，与斑块相关的小胶质细胞数量减少，Clec7a（树突状细胞相关C型凝集素-1）表达降低。另外，小胶质细胞和神经元均表现出雷帕霉素机制性靶标（mTOR）信号传导和自噬减少。生化分析证实了NLRP3炎性小体激活受到抑制、mTOR信号传导降低以及自噬增强。然而，短期抑制CSF1R并未影响Aβ斑块、可溶性Aβ-42水平或海马体神经发生。因此，在5xFAD小鼠神经炎症早期短期抑制CSF1R可促进稳态小胶质细胞的保留，同时减少炎性小体激活和mTOR信号传导，并增加自噬。
