P1‐136: Phosphorylation of truncated tau is driven by its aberrant conformation

Neurofibrillary tangles and neuropil threads, the main forms of tau lesions in AD, exhibit a characteristic temporal and spatial distribution pattern that strongly indicates a direct causal connection to the disease progression. In spite of intense research, however, the primary impetus that initiates formation of these insoluble lesions remains elusive. It is generally assumed that hyperphosphorylation of tau is an essential component of the pathological tau cascade and that it is brought about by an imbalance between kinases and phosphatases. In our work we tested the possibility that altered conformation of the substrate (truncated tau) influences its phosphorylation status. We used a rat model of tauopathy expressing a human truncated tau as a transgene. By western blotting we compared the phosphorylation levels of endogenous rat tau, truncated transgenic tau and the levels of the relevant tau kinases. The transgene, truncated tau in a rat model of tauopathies, exhibited high phosphorylation levels throughout the life of the animals, while the normal endogenous rat tau proteins were unaffected. Furthermore, transgenic animals did not exhibit elevated levels of most relevant tau kinases or their activated phospho-forms when compared with wild type animals. In vitro analysis of the phosphorylation rate of the recombinant human tau proteins in an in vitro kinase reaction revealed that truncated human tau becomes phosphorylated faster and to a higher degree than the full length tau protein at several phosphorylation sites relevant for AD pathology. We present evidence that conformational abnormalities of the truncated tau protein are sufficient to induce its abnormal phosphorylation and initiate the cascade of events leading to the formation of the insoluble misfolded forms.