The impact of translational dysregulation in the pathogenesis of Alzheimer disease

     The objective of this work is to determine the extent to which pathological tau affects ribosomal efficiency and transport in neurons. Our lab recently determined in AD brains that pathological tau species (hyperphosphorylated and oligomeric) associate with ribosomes (Meier et al. j neurosci 2016) and stress granule proteins (in collaboration with Dr. Wolozin; Vanderwyde et al. Cell Rep 2016) and that this association reduces ribosomal efficiency. Importantly, we discovered that RNA translational selectivity is affected in tauopathies. In addition, de novo protein synthesis is necessary for memory formation and reconsolidation. Indeed, protein production is reduced in AD and other tauopathies. Finally, hyperphosphorylated tau associates with ribosomes, the hub of protein synthesis. Together, these findings suggest that the link between tau and memory impairment might reside in the inability to manufacture new and specific proteins. Therefore, we propose that tau impacts the dynamics of protein synthesis leading to memory decline.