Micro-sub regional synapse weakening by mimicking the hyperphosphorylation of microtubule associated protein Tau in...

The role of microtubule associated protein Tau (Tau) in synaptic function is critical, yet many aspects remain unknown. However, increasing levels of tau phosphorylation has implications for physiological and pathophysiological plasticity. Utilizing human full-length (2N4R) phosphomimic Tau transfection in organotypic hippocampal slice culture, we revealed a regional specificity of synapse dysfunction in dendrites of Cornu Ammonis 1 (CA1) neurons. Specifically, phosphorylation mimic at S396/404 (Tau-PHF1E), a site important for pathophysiology, selectively weakened synapses in the distal portion of CA1 secondary apical dendrites within stratum radiatum, while the proximal region of the same dendrites remained unaltered. Furthermore, in the distal region, the expression of TauPHF1E impaired postsynaptic density-95 expression and dysregulated synaptic plasticity. This phenomenon was contingent on the presence of a key Tau-interactome and AMPA-receptor endocytosis-associated protein; PACSIN1. These findings illustrate that the posttranslational modification of Tau can play a key role in synapse weakening and further implicate the importance of the Tau-interactome PACSIN1 as a pivotal mediated in the process, which with further investigation could open new insights into Tau-associated pathophysiology.