Conformation pattern changes in R1-pS262 tau peptide induced endogenous tau aggregation, synaptic damage, and cognitive impairments.

Background: To date, the effect of tau phosphorylation at different amino acid sites on the conformation and function of tau is still unclear in Alzheimer's disease (AD). Protein fingerprinting, also known as the protein folding shape code (PFSC) method, is a protein structure prediction technique based on protein sequence, which can reveal proteins' most likely spatial conformation.

Objective: To investigate the effect of phosphorylation on tau protein conformation using PFSC technology and further analyze the differences in the effect of phosphorylation on tau aggregation at specific sites.

Methods: We performed a conformational analysis of wild-type and simulated mutant hTau441 using the PFSC method and synthesized the phosphorylated and non-phosphorylated tau fragments by the chemical solid phase method.

Results: We found that the number of Ser262 protein fingerprints increased from six in tau S262A to nine in tau S262E, together with increased conformational changes and enhanced flexibility. The in vitro Thioflavin S assay showed that phosphorylated tau fragments R1-pS262 possessed a stronger activity of inducing tau aggregation. In contrast to the non-phosphorylated tau fragment R1-nS262, R1-pS262 promoted endogenous tau aggregation and decreased synaptic proteins. In rats, R1-pS262 caused cognitive impairments and neuronal loss in addition to endogenous tau aggregation and synaptic damage.

Conclusions: Our study firstly reports that tau phosphorylation at Ser262 induces tau aggregation, and phosphorylated tau fragments R1-pS262 directly result in neuropathological changes. These provide new clues to the pathogenesis of tauopathy, such as AD, and a new molecular target for possible intervention.