Cholinergic synaptic plasticity shapes resilience and vulnerability to tau

• Published in: bioRxiv
• Main Authors: Onuska, Kate M., Devito, Lauren A., Shanks, Hayley R.C., Qi, Qi, Crooks, Alycia M., Haast, Roy A.M., Andrews, Tallulah S., Williams, Kayla M., Beraldo, Flávio H., Qiu, Ting, Fajardo-Valdez, Alfonso, Wearn, Alfie, Turner, Gary R., Thiessen, Jonathan D., Fox, Matthew S., Hicks, Justin W., Bussey, Timothy J., Saksida, Lisa M., Tremblay-Mercier, Jennifer, Breitner, John C.S., Soucy, Jean-Paul, Poirier, Judes, Villeneuve, Sylvia, Prado, Vania F., Prado, Marco A.M., Spreng, R. Nathan, Schmitz, Taylor W.
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Laboratory 28.05.2025
• Edition: 1.1
• Subjects: Neuroscience
• ISSN: 2692-8205
• DOI: 10.1101/2025.05.27.656174

Synaptic dysfunction is a hallmark of Alzheimer’s disease (AD). Yet due to their plasticity, synapses may also adapt to early AD pathology. Using within-subject positron emission tomography scans targeting the vesicular acetylcholine transporter (VAChT) protein, tau, and amyloid in healthy older adults at risk for AD, we show that cholinergic neurons increase presynaptic VAChT levels when colocalized to tau, but not amyloid, with higher responses predicting resilience to cognitive decline over ∼10 years. In mice lacking forebrain VAChT, we demonstrate that cholinergic synaptic plasticity plays a causal role in sustaining cognitive flexibility and hippocampal structural integrity. Whole-brain single-nucleus RNA sequencing atlases reveal that cholinergic neurons upregulate a gene-network enriched for synaptic plasticity, with high centrality for the microtubule-associated protein tau (MAPT) gene. Our findings identify cholinergic synaptic plasticity as a critical mediator of resilience and vulnerability to tau in presymptomatic AD.