Genome-wide association studies (GWAS) have identified PICALM as one of the most significant susceptibility loci for late-onset Alzheimer's disease (AD) after APOE and BIN1. PICALM is a clathrin-adaptor protein and plays critical roles in clathrin-mediated endocytosis and in autophagy. PICALM modulates brain amyloid ß (Aß) pathology and tau accumulation. We have previously reported that soluble PICALM protein level is reduced in correlation with abnormalities of autophagy markers in the affected brain areas of neurodegenerative diseases including AD, sporadic tauopathies and familial cases of frontotemporal lobar degeneration with tau-immunoreactive inclusions (FTLD-tau) with mutations in the microtubule-associated protein tau (MAPT) gene. It remains unclarified whether in vivo PICALM reduction could either trigger or influence tau pathology progression in the brain. In this study, we confirmed a significant reduction of soluble PICALM protein and autophagy deficits in the post-mortem human brains of FTLD-tau-MAPT (P301L, S364S and L266V). We generated a novel transgenic mouse line named Tg30xPicalm+/- by crossing Tg30 tau transgenic mice with Picalm-haploinsufficient mice to test whether Picalm reduction may modulate tau pathology. While Picalm haploinsufficiency did not lead to any motor phenotype or detectable tau pathology in mouse brains, Tg30xPicalm+/-  mice developed markedly more severe motor deficits than Tg30 by the age of 9 months. Tg30xPicalm+/-  had significantly higher pathological tau levels in the brain, an increased density of neurofibrillary tangles compared to Tg30 mice and increased abnormalities of autophagy markers. Our results demonstrate that Picalm haploinsufficiency in transgenic Tg30 mice significantly aggravated tau pathologies and tau-mediated neurodegeneration, supporting a role for changes in Picalm expression as a risk/sensitizing factor for development of tau pathology and as a mechanism underlying the AD risk associated to PICALM.

中文翻译：

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在鼠tauopathy模型中，减少Picalm会加剧tau病理。

全基因组关联研究（GWAS）已将PICALM确定为继APOE和BIN1之后的晚期阿尔茨海默氏病（AD）最重要的易感基因座之一。PICALM是一种网格蛋白适应蛋白，在网格蛋白介导的内吞作用和自噬中起关键作用。PICALM调节脑淀粉样蛋白ß（Aß）病理和tau积累。我们以前曾报道过，可溶性PICALM蛋白水平降低与神经退行性疾病（包括AD），散发性Tauopath病和额颞叶大叶变性伴tau免疫反应性包涵体（FTLD-tau）突变的家族性病例的受影响脑区自噬标记物异常相关在微管相关蛋白tau（MAPT）基因中。体内PICALM的降低是否会触发或影响脑内tau病理学进展尚不清楚。在这项研究中，我们证实了FTLD-tau-MAPT（P301L，S364S和L266V）的死后人类大脑中可溶性PICALM蛋白的显着减少和自噬缺陷。我们通过将Tg30 tau转基因小鼠与Picalm-haploinsufficient小鼠杂交来测试Picalm的减少是否可以调节tau病理学，从而生成了一种名为Tg30xPicalm +/-的新型转基因小鼠品系。虽然Picalm单倍体功能不全在小鼠脑中未导致任何运动表型或可检测的tau病理，但到9个月大时，Tg30xPicalm +/-小鼠比Tg30表现出更严重的运动缺陷。Tg30xPicalm +/-在大脑中的病理tau水平明显较高，与Tg30小鼠相比，神经原纤维缠结的密度增加，自噬标记物异常增加。我们的结果表明，转基因Tg30小鼠中Picalm单倍剂量不足会严重加重tau病理和tau介导的神经退行性变，支持Picalm表达的变化作为tau病理发展的风险/致敏因素，以及与PICALM相关的AD风险的潜在机制。