ALZHEIMER RISK FACTOR PICALM IS INVOLVED IN TAU PATHOLOGY IN ALZHEIMER AND OTHER TAUOPATHIES

Recently, genome-wide association studies identified single nucleotide polymorphisms in the gene of PICALM as genetic risk factors for late-onset Alzheimer disease (LOAD). PICALM is ubiquitously expressed and plays a key role for Clathrin-mediated endocytosis. The role of PICALM in AD pathogenesis, however, remained elusive. In this study, we analysed the level and expression of PICALM in AD brains and in other neurodegenerative diseases in order to understand how PICALM is involved in AD aetiology. Western blotting and immunohistochemistry on human post-mortem brain tissues. In vitro assay for calpain and caspase activation. Co-immunoprecipitation. By western blotting of control and AD samples, we found that level of PICALM full-length protein was significantly decreased in AD T1 isocortex and that PICALM was also cleaved into smaller fragments. By in vitro cleavage assay, we demonstrated that PICALM was cleaved by both caspase and calpain. Immunohistochemistry revealed that PICALM was associated with neurofibrillary tangles of LOAD, familial AD and Down syndrome cases. Hyperphosphorylated tau co-immunoprecipitated with PICALM. We further analysed the involvement of PICALM in other neurodegenerative diseases and found that PICALM was associated with tau positive inclusions of several tauopathies such as Pick's disease and Progressive supranuclear palsy (PSP). Taken together, our results indicate that PICALM processing is modified in AD and is associated to tau pathology in AD and in some other tauopaties.