[Drug development for tauopathy and Alzheimer's disease]

Neurofibrillary tangles (NFTs), which consist of a fibrillar aggregate of hyperphosphorylated tau, are commonly seen in aging brains and those with Alzheimer's disease. Based on Braak staging of NFTs, NFTs are first observed in the entorhinal cortex. Then, NFTs spread from the entorhinal cortex to the limbic and neocortex. NFT the formation in the entorhinal cortex may be correlated with memory loss in brain aging, because entorhinal cortex is involved in memory formation, and NFTs in the limbic and neocortex may cause dementia in AD, because the limbic and neocortex serve higher order brain functions. These suggest that regional development of NFTs is correlated with decline of brain functions in aging and AD. Recent reports suggested that the process of NFT formation, but not NFT itself, is involved in neuronal dysfunction. We found that there are three tau aggregation forms, soluble tau oligomer, granular tau, and fibrilar tau, before NFT formation. From the analysis of tau Tg mice, it was indicated that soluble oligomer tau may be involved in synapse loss, and insoluble granular tau aggregates may play a role in neuronal death. Therefore, inhibition of oligomer tau, and granular tau aggregation is expected to block the progression of AD symptoms by preventing synapse loss and neuronal loss.