# Tau oligomers modulate synapse fate by eliciting progressive bipartite synapse dysregulation and synapse loss

## TL;DR

This study shows how tau oligomers cause synapse dysfunction and loss in Alzheimer's disease by disrupting both presynaptic and postsynaptic components over time.

## Contribution

The study introduces a proximity labeling tool to map postsynaptic proteome changes and reveals a bipartite synapse deterioration mechanism triggered by tau oligomers.

## Key findings

- Tau oligomers cause immediate downregulation of Myosin-Va and Myosin IIb, impairing AMPAR trafficking.
- Postsynaptic sites are lost before presynaptic terminals, with long-term AMPAR downregulation and reduced vesicle release.
- Two synapse fates emerge: persistent weakening or complete loss, driven by progressive dysregulation.

## Abstract

Synapse function is critical for cognition, and synapse loss is highly correlated with cognitive decline in Alzheimer’s disease and related dementias. Tau oligomers, which accumulate in the brain in Alzheimer’s disease, can acutely inhibit synaptic plasticity and cause synapse loss. Coordinated presynaptic and postsynaptic function is essential for effective synaptic transmission, and both compartments can be dysregulated by pathogenic tau. However, the series of pathophysiological events triggered by tau oligomers to cause the dysfunction and deterioration of presynaptic terminals and postsynaptic sites remain unclear.

We developed a proximity labeling tool to map the postsynaptic proteome by fusing PSD-95 with APEX2 (APEX2-PSD-95) which was expressed in human induced pluripotent stem cell (iPSC)-derived neurons. We used APEX2-PSD-95 to map the dynamic changes in the postsynaptic proteome with precise temporal resolution after an acute exposure of human iPSC-derived neurons to recombinant tau oligomers for 30 min. Leveraging immunocytochemistry, electrophysiology and electron microscopy, we further delineated the impact of the acute tau oligomer exposure on presynaptic and postsynaptic compartments over time for up to 14 days.

The brief exposure of human iPSC-derived neurons to tau oligomers caused a progressive deterioration of synapses, marked by both presynaptic and postsynaptic dysregulation. Postsynaptic proteome mapping revealed an immediate tau oligomer-triggered downregulation of the postsynaptic actin motor proteins Myosin-Va and Myosin IIb, which coincided with impaired AMPA receptor (AMPAR) trafficking during synaptic plasticity. This was followed 24 h later by the upregulation of disease-related proteins, including GSK3β, at postsynaptic sites. The loss of PSD-95-labeled postsynaptic sites at 7 days after tau oligomer exposure preceded the loss of Synapsin-labeled presynaptic terminals at 14 days. The postsynaptic sites that remained exhibited a long-term downregulation of postsynaptic AMPAR levels and sustained synaptic plasticity impairment. Moreover, the remaining presynaptic terminals contained less clusters of vesicles at the presynaptic active zone which was associated with reduced vesicle release probability at synapses.

Our findings reveal the series of events underlying tau oligomer-induced bipartite synapse deterioration. The progressive decline of synapses involves the emergence of two synapse fates. One synapse fate involves the persistent weakening of both presynaptic and postsynaptic function, and the other results in synaptic loss.

The online version contains supplementary material available at 10.1186/s13024-026-00928-2.