特雷姆2
小胶质细胞
单倍率不足
生物
免疫系统
发病机制
细胞生物学
阿尔茨海默病
神经科学
免疫学
医学
病理
炎症
疾病
生物化学
表型
基因
作者
Peter Bor‐Chian Lin,Andy Po‐Yi Tsai,Disha Soni,Audrey Lee‐Gosselin,Miguel Moutinho,Shweta S. Puntambekar,Gary E. Landreth,Bruce T. Lamb,Adrian L. Oblak
摘要
Abstract Introduction Inositol polyphosphate‐5‐phosphatase (INPP5D) is a microglia‐enriched lipid phosphatase in the central nervous system. A non‐coding variant (rs35349669) in INPP5D increases the risk for Alzheimer's disease (AD), and elevated INPP5D expression is associated with increased plaque deposition. INPP5D negatively regulates signaling via several microglial cell surface receptors, including triggering receptor expressed on myeloid cells 2 (TREM2); however, the impact of INPP5D inhibition on AD pathology remains unclear. Methods We used the 5xFAD mouse model of amyloidosis to assess how Inpp5d haplodeficiency regulates amyloid pathogenesis. Results Inpp5d haplodeficiency perturbs the microglial intracellular signaling pathways regulating the immune response, including phagocytosis and clearing of amyloid beta (Aβ). It is important to note that Inpp5d haploinsufficiency leads to the preservation of cognitive function. Spatial transcriptomic analysis revealed that pathways altered by Inpp5d haploinsufficiency are related to synaptic regulation and immune cell activation. Conclusion These data demonstrate that Inpp5d haplodeficiency enhances microglial functions by increasing plaque clearance and preserves cognitive abilities in 5xFAD mice. Inhibition of INPP5D is a potential therapeutic strategy for AD.
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