Toxic tau aggregation in AD.

The pathological hallmarks of Alzheimer’s disease (AD) are extracellular β-amyloid deposition and intracellular tau inclusions. While β-amyloid deposition does not correlate with clinical progression of AD, the diffusion of neurofibrillary tangles (NFTs) from the entorhinal cortex to the neocortex, followed by neuronal and synapse loss, matches well with the clinical progression of AD symptomatology. Therefore, blocking the formation of NFTs is considered to be a promising approach to halt the progression of AD dementia. Our analysis of the temporal formation of Tau fibrils in vitro showed that there are different and distinct forms of tau aggregates (soluble tau oligomer, and granular tau oligomer) that precede Tau fibril formation. Analysis of our P301L-Tau Tg mouse model suggested that toxicity of Tau aggregates could be attributed to granular tau. To test this further, we attempted to reduce formation of granular tau oligomer by screening the chemical compound X1 that was shown to inhibit the formation of granular tau. Interestingly, oral administration of X1 to P301L-Tau mice resulted in reduced neuronal loss, accompanied by a reduction of the levels of sarkosyl-insoluble tau, as compared to control vehicle treatment. Together, these studies offer novel insights into Tau aggregation pathology; they strongly suggest that granular tau oligomers represent a toxic tau aggregate and that X1 may be a promising compound for blocking AD progression.