AD genetic risk factors and tau spreading

Development of tau pathology is associated with progressive neuronal loss and cognitive decline. In the brains of Alzheimer's disease (AD) patients, tau pathology propagates according to an anatomically defined pattern with relatively uniform distribution, and contributes to cognitive decline in age-associated tauopathy (Itraak and Braak, 1991; Saito et ad, 2004). Recently, it has been revealed that tau, which is an intracellular protein, can appear in the extracellular space, likely due to an exocytosis mechanism. Such extracellular tau could then be internalized into neighboring cells in at least two different ways depending on its aggregation state. In the case of soluble monomeric or small oligomeric tau protein, the endocytosis appears to be clathrin dependent (reviewed in, 2006). In contrast, larger aggregates of tau could bind heparin in the extracellular matrix and be internalized through macropinocytosis (I I olmes et ad, 2014). As a result of exocytosis and endocytosis, the spreading of tau can occur in various neurodegenerative diseases (tauopathies) including AD. In this opinion article we have focused on the endocytosis mechanism. Several genetic risk factors have been associated with a higher probability of developing sporadic Alzheimer's disease (SAD). The Alzheimer Association (http://www.alzforum.org/) has ranked the top six risk genes, shown in Table 1, based on genome-wide association studies (GWAS).