桥接整合因子1(BIN1)是晚发性阿尔茨海默病的全基因组关联研究确定的第二个最普遍的遗传风险因素。BIN1编码一种衔接蛋白,可在胞吞和神经递质囊泡释放的情况下调节膜动力学。体外证据表明,BIN1可以直接结合胞质溶胶中的tau。此外,BIN1的功能通过胞吞作用和随后的繁殖限制了细胞外tau种子的摄取,并通过外泌体影响tau释放。然而,BIN1在tau发病机制和tau病介导的神经变性中的体内作用仍未表征。我们产生了条件性敲除小鼠,在P301S人tau转基因背景下,前脑兴奋性神经元和少突胶质细胞中Bin1表达选择性丧失(PS19线)。PS19小鼠出现年龄依赖性tau神经病理学和运动缺陷,通常用于研究阿尔茨海默病tau病理生理学。在前脑BIN1表达不同的实验小鼠和对照小鼠之间比较了运动缺陷和神经病理学的严重程度。通过生化方法和免疫染色量化BIN1在tau病理学和神经炎症中的参与。通过RNA测序分析对转录组变化进行剖析以获得分子见解。PS19小鼠前脑BIN1表达的缺失加剧了体感皮层的tau病理,丘脑,脊髓,和坐骨神经,加速疾病进展,并导致早逝。有趣的是,BIN1的缺失也减轻了部分区域的tau神经病理学,包括海马,内嗅/梨状皮质,和杏仁核,从而减轻海马突触的损失,神经元死亡,神经炎症,和脑萎缩.在分子水平上,前脑BIN1的丢失引起复杂的神经元和非神经元转录组变化,包括神经炎症基因表达的改变,伴随着小胶质细胞向疾病相关小胶质细胞表型的转化受损。这些结果为tau发病机制中体内BIN1功能提供了重要的新信息。我们得出结论,前脑神经元BIN1表达促进海马tau发病机制和神经炎症。我们的发现强调了神经元BIN1调节tau发病机制的令人兴奋的区域特异性,并揭示了BIN1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. BIN1 encodes an adaptor protein that regulates membrane dynamics in the context of endocytosis and neurotransmitter vesicle release. In vitro evidence 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, the in vivo roles of
BIN1 in tau pathogenesis and tauopathy-mediated neurodegeneration remain uncharacterized. We generated conditional knockout mice with a selective loss of Bin1 expression 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 on in vivo BIN1 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.