Picalm reduction exacerbates tau pathology in a murine tauopathy model

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.