PICALM Genetic Variant Alters mRNA Expression Without Affecting Protein Levels or Tau Spreading in Alzheimer’s Disease

Phosphatidylinositol-binding clathrin assembly protein (PICALM) is a clathrin adaptor essential for clathrin-mediated endocytosis. Genome-wide association studies (GWAS) have consistently identified <i>PICALM</i> as one of the most significant genetic susceptibility loci for late-onset sporadic Alzheimer's disease (AD). However, the functional impact of the most validated AD-associated variant, rs3851179, remains unclear. Here, we examined <i>PICALM</i> mRNA and protein expression in <i>post-mortem</i> AD brains with reference to rs3851179 genotype. We found that <i>PICALM</i> mRNA levels were significantly increased in AD brains compared with controls, and that the protective rs3851179T allele was associated with reduced <i>PICALM</i> mRNA levels relative to the non-protective rs3851179C allele. In contrast, PICALM levels were significantly reduced in AD brain lysates compared with controls. PICALM expression did not significantly differ between carriers of the protective and non-protective alleles. Analysis of the mRNA-to-protein ratio revealed a significant dissociation between transcript and protein levels, suggesting relatively reduced protein expression efficiency in cases carrying the non-protective CC genotype. To assess whether reduced <i>PICALM</i> levels influence tau pathology, we used Picalm heterozygous knockout (Picalm+/-) mice, which express approximately 50% of the wild-type Picalm protein. Following stereotaxic injection of pathological tau extracted from AD brains, both wild-type and Picalm+/- mice developed tau pathology; however, the extent of tau accumulation did not significantly differ between genotypes. Together, these findings indicate that although PICALM protein level is reduced in AD, this reduction does not appear to affect tau propagation in this model. Therefore, the AD susceptibility associated with <i>PICALM</i> variant likely arises from mechanisms other than tau spread, possibly involving other aspects of autophagy, endocytic or vascular function.