# Synaptotoxic effects of extracellular tau are mediated by its microtubule-binding region

## TL;DR

This study shows that targeting a specific region of extracellular tau protein can prevent synaptic dysfunction linked to Alzheimer's disease.

## Contribution

The study identifies the microtubule-binding region of extracellular tau as a key driver of synaptotoxicity and a potential therapeutic target.

## Key findings

- Extracellular tau fragments containing the MTBR/R’ region disrupt synaptic plasticity in live rats.
- Antibodies targeting the MTBR/R’ region neutralize synaptotoxic effects of patient-derived tau.
- A recombinant tau fragment (tau297-391) mimics the synaptotoxic effects of AD brain extracts.

## Abstract

Immunotherapies targeting extracellular tau share the premise that interrupting cell-to-cell spread of tau pathology in Alzheimer’s disease (AD) will slow dementia pathogenesis. Whether these interventions affect the actions of synaptotoxic, extracellular tau species that may contribute to cognitive impairment is relatively unknown. Here, we assayed synaptic plasticity disruption in anaesthetised live rats caused by intracerebral injection of synaptotoxic tau present either in (a) secretomes of induced pluripotent stem cell-derived neurons (iNs) from people with Trisomy 21, the most common genetic cause of AD, or (b) aqueous extracts of human AD brain. Extracellular tau in iN secretomes was found to include fragments that contain the extended microtubule-binding regions of tau, MTBR/R’ and adjacent C-terminal sequences. Immunodepletion or co-injection with antibodies targeting epitopes within these fragments prevented the acute disruption of synaptic plasticity by these patient-derived synaptotoxic tau preparations. Moreover, a recombinant human tau fragment encompassing the core MTBR/R’-region present in tau fibrils, tau297-391, potently mimicked the deleterious action of patient-derived tau. MTBR/R’-directed antibodies also rapidly reversed a very persistent synaptotoxic effect of soluble brain tau. Our findings reveal a hitherto relatively unexplored potential benefit of targeting extracellular MTBR/R’ tau on correcting synaptic dysfunction.

The online version contains supplementary material available at 10.1007/s00401-025-02897-0.