Loss of forebrain BIN1 attenuates hippocampal pathology and neuroinflammation in a tauopathy model.
Loss of forebrain BIN1 attenuates hippocampal pathology and neuroinflammation in a tauopathy model.
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前脑 BIN1 的缺失会减轻 tau 蛋白病模型中的海马病理学和神经炎症。
DOI：
10.1093/brain/awac318
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Thinakaran,Gopal
中科院分区：
文献类型：
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作者：
Ponnusamy,Moorthi;Wang,Shuai;Yuksel,Melike;Hansen,MitchellT;Blazier,DanielleM;McMillan,JosephD;Zhang,Xiaolin;Dammer,EricB;Collier,Lisa;Thinakaran,Gopal
桥接整合子1（BIN 1）是全基因组关联研究（GWAS）发现的晚发性阿尔茨海默病的第二大遗传危险因子，BIN 1编码一种衔接蛋白，在胞吞和神经递质囊泡释放过程中调节膜动力学。此外，BIN 1的功能限制了细胞外tau种子通过内吞作用的摄取和随后的增殖，以及影响tau通过外泌体的释放。然而，BIN 1在tau蛋白发病机制和tau蛋白病介导的神经变性中的作用仍不明确。我们在P301 S人tau蛋白转基因背景下（系PS19）产生了选择性丧失Bin 1在前脑兴奋性神经元和少突胶质细胞中表达的条件性敲除小鼠。PS19小鼠发展年龄依赖性tau神经病理学和运动缺陷，并且通常用于研究阿尔茨海默病tau病理生理学。在前脑BIN 1表达不同的实验小鼠和对照小鼠之间比较运动缺陷和神经病理学的严重程度。通过生物化学方法和免疫染色定量BIN 1参与tau病理学和神经炎症。通过RNA测序分析来分析转录组变化以获得分子见解。PS19小鼠前脑BIN 1表达的缺失加剧了躯体感觉皮层、丘脑、脊髓和坐骨神经中的tau病理学，加速了疾病进展并导致早期死亡。有趣的是，BIN 1的丢失也减轻了选定区域中的tau神经病理学，包括海马、内嗅/梨状皮质和杏仁核，从而减弱了海马突触丢失、神经元死亡、神经炎症和脑萎缩。在分子水平上，前脑BIN 1的丢失引起复杂的神经元和非神经元转录组学变化，包括改变神经炎性基因表达，伴随着受损的小胶质细胞向疾病相关的小胶质细胞表型的转变。这些结果提供了在tau蛋白发病机制中体内BIN 1功能的重要新信息。我们得出结论，前脑神经元BIN 1表达促进海马tau蛋白发病机制和神经炎症。我们的研究结果突出了神经元BIN 1调节tau发病机制的令人兴奋的区域特异性，并揭示了参与BIN 1调节tau神经病理学的细胞自主和非细胞自主机制。
Bridging integrator 1 (BIN1) is the second most prevalent genetic risk factor identified by genome-wide association studies (GWAS) for late-onset Alzheimer’s disease.BIN1encodes an adaptor protein that regulates membrane dynamics in the context of endocytosis and neurotransmitter vesicle release.In vitroevidence suggests that BIN1 can directly bind to tau in the cytosol. In addition, BIN1’s function limits extracellular tau seed uptake by endocytosis and subsequent propagation as well as influences tau release through exosomes. However, thein vivoroles of BIN1 in tau pathogenesis and tauopathy-mediated neurodegeneration remain uncharacterized.We generated conditional knockout mice with a selective loss ofBin1expression in the forebrain excitatory neurons and oligodendrocytes in P301S human tau transgenic background (line PS19). PS19 mice develop age-dependent tau neuropathology and motor deficits and are commonly used to study Alzheimer’s disease tau pathophysiology. The severity of motor deficits and neuropathology was compared between experimental and control mice that differ with respect to forebrain BIN1 expression. BIN1’s involvement in tau pathology and neuroinflammation was quantified by biochemical methods and immunostaining. Transcriptome changes were profiled by RNA-sequencing analysis to gain molecular insights.The loss of forebrain BIN1 expression in PS19 mice exacerbated tau pathology in the somatosensory cortex, thalamus, spinal cord and sciatic nerve, accelerated disease progression and caused early death. Intriguingly, the loss of BIN1 also mitigated tau neuropathology in select regions, including the hippocampus, entorhinal/piriform cortex, and amygdala, thus attenuating hippocampal synapse loss, neuronal death, neuroinflammation and brain atrophy. At the molecular level, the loss of forebrain BIN1 elicited complex neuronal and non-neuronal transcriptomic changes, including altered neuroinflammatory gene expression, concomitant with an impaired microglial transition towards the disease-associated microglial phenotype. These results provide crucial new information onin vivoBIN1 function in the context of tau pathogenesis.We conclude that forebrain neuronal BIN1 expression promotes hippocampal tau pathogenesis and neuroinflammation. Our findings highlight an exciting region specificity in neuronal BIN1 regulation of tau pathogenesis and reveal cell-autonomous and non-cell-autonomous mechanisms involved in BIN1 modulation of tau neuropathology.