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

## TL;DR

This study shows that mimicking Tau phosphorylation weakens specific synapses in brain cells, revealing a key role for the protein PACSIN1 in this process.

## Contribution

The study identifies regional synapse weakening by phosphomimic Tau and highlights PACSIN1 as a critical mediator in this mechanism.

## Key findings

- Tau-PHF1E selectively weakens synapses in distal CA1 dendrites but not proximal regions.
- PACSIN1 is essential for the synapse weakening caused by Tau-PHF1E.
- Phosphomimic Tau impairs PSD-95 expression and synaptic plasticity in distal dendrites.

## Abstract

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.

Mitchell et al. report that phosphorylation-mimic Tau (TauPHF1E) selectively weakens synapses in distal CA1 dendrites, impairing PSD-95 expression, dynamics and synaptic plasticity. This effect depends on PACSIN1, a key Tau-interacting protein. Collectively highlighting that pTau-mediated synapse weakening is not uniform and the importance of the Tau interactome.

Graphical Abstract