A holistic inquiry into how toxic tau impacts synapses provides a new take on the processes that lead to neuronal dysfunction and memory loss in Alzheimer's disease. A tool, developed in the Tracy lab, enables researchers to track changes in the synaptic proteome, correlating changes to synaptic dysregulation and synapse loss over time. The results and the tool, which is available to all researchers, are now online at Molecular Neurodegeneration.
"Not enough people in the Alzheimer's disease field are working on synapses," says Buck Associate Professor Tara Tracy, PhD , senior scientist of the study. "We're hoping our tool and our new discoveries help change that."
Synapses are the junctions between nerve cells, a minute gap through which impulses are signaled via the diffusion of neurotransmitters. The process by which those signals move involves both pre ("sending") and post ("receiving") synaptic structures. Coordinated presynaptic and postsynaptic function is essential for effective synaptic transmission and cognition.
In their experiments, a brief 30-minute exposure of human neurons to toxic tau oligomers, which accumulate in the brain in Alzheimer's disease, was sufficient to block synaptic plasticity. Researchers then began monitoring how that exposure progressed to synapse loss.
"After that exposure we were able to track activity at both sides of the synapse," says Tracy. "What we found was a dynamic cascade of events which surprisingly impacted postsynaptic structures first. We weren't expecting to see that."
Tracy and her team, led by first author and research scientist Kristeen Pareja-Navarro PhD, leveraged immunocytochemistry, electrophysiology and electron microscopy in the work. The team also developed a new tool that maps real-time proteome changes at the synapses. "A major finding of this work was identifying early postsynaptic mechanisms that are disrupted by tau oligomers and how they relate to protracted synapse deterioration. Being able to study these pathways in more detail is an important next step toward preventing tau-driven synaptic dysfunction," says Pareja-Navarro. "That's the ultimate goal and next stage of our research."
Utilizing all of the tools at their disposal the team delineated the impact of the brief tau oligomer exposure on neurons over time for up to 14 days. Utilizing their new postsynaptic-targeted proximity labeling approach, the team saw an immediate postsynaptic downregulation of motor proteins (Myosin-Va and Myosin IIb) which coincided with impaired synaptic plasticity. This was followed 24 hours later by the upregulation of disease-related proteins (including GSK3b), at postsynaptic sites, a result that Tracy describes as "striking, given that the postsynaptic remodeling that occurred at 24 hours was completely different from the initial response to tau oligomers." At 7 days after tau oligomer exposure, the team saw a loss of postsynaptic structures on neurons, while the loss of presynaptic structures was detected at 14 days. "A tau-induced weakening of synaptic strength could be driving the loss of these connections," says Tracy, noting that the remaining synapses had reduced postsynaptic receptors, impaired plasticity, and abnormal clustering of synaptic vesicles at presynaptic terminals.
Most research on synapse loss in neurodegenerative diseases has involved looking at changes at just one point in time. Now that scientists have the ability to look at changes in the synaptic proteome over time, Tracy thinks it's time for the field to take a new look at the role of synapses and their function in neurodegenerative diseases. "Previous studies have focused on the role of glia in synapse elimination, showing that glia can respond to tau toxicity by pruning synapses. I'm sure glia are part of the process of synapse degeneration, but our work uncovers the critical importance of intrinsic mechanisms at synapses in causing synapse loss, which has been largely underexplored" she says. "The tau oligomers weaken synapses, but the fate of synapses diverge. Not all of the synapses are lost. Some are retained even though they're dysfunctional. The fact that both presynaptic and postsynaptic compartments change progressively over time suggests that multiple important mechanisms are at play in determining the fate of a synapse."
CITATION: Tau oligomers modulate synapse fate by eliciting progressive bipartite synapse dysregulation and synapse loss
DOI: 10.1186/s13024-026-00928-2
Other Buck collaborators include Christina D. King, Grant Kauwe, Yani Y. Ngwala, Doyle Lokitiyakul, Ivy Wong, Aaryan Vira, Yaofu Liu, Jackson H. Chen, Mahima Sharma, Olfat Malak, Chuankai Zhou and Birgit Schilling; plus Gabriel Navarro, Datacca, Moraga, CA, USA
Acknowledgments: This work was support by the National Institute of Health (R01AG070193 R21AG077556, R01AG075201, and T32AG00026624) and the Alzheimer's Association (AARG-21-850893)
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