APOE is a presynaptic protein that accumulates with age and modulates neurotransmitter release

The synaptic vesicle (SV) cycle is the fastest membrane trafficking and protein sorting process in biology. It underlies neuronal communication and cognition, yet synaptic function declines during normal aging, increasing vulnerability to neurologic disease. How the SV cycle is maintained across the lifespan of a complex organism remains unclear. Here, we used wild-type mice (C57BL/6J) to define the age- and sex-stratified molecular landscape of SVs and identified apolipoprotein E (APOE) as an abundant presynaptic protein further enriched in aged female samples. Super-resolution imaging, cell-type selective expression, and protease protection assays demonstrate that APOE originates from astroglia and associates with the cytosolic face of SVs. Using iGluSnFR and pHluorin optophysiology, we find that both decreased and increased APOE levels impair neurotransmission during stimulus trains. Together, these findings place APOE at the synapse and establish it as a cell-nonautonomous regulator of the SV cycle.

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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-04-21
DOI
https://doi.org/10.64898/2026.04.20.719736
Primary Topic
Cellular transport and secretion
Type
article
Field-Weighted Citation Impact
0.00

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article

APOE is a presynaptic protein that accumulates with age and modulates neurotransmitter release

Sarayut Phasuk, Anthony A. High, Kyla B. Tooley, Sean Deats et al.
bioRxiv (Cold Spring Harbor Laboratory)
Cellular transport and secretion
article

APOE is a presynaptic protein that accumulates with age and modulates neurotransmitter release

Sarayut Phasuk, Anthony A. High, Kyla B. Tooley, Sean Deats, Gaven Garland, Haiyan Tan, Mazdak M. Bradberry, X Wang, Vishwajeeth Pagala, Ron Korstanje, Jason Vevea, Bonn Belingon, Camenzind G. Robinson, Julianna L. Sun, Jenn Cook, Laura Robinson, Wu Long, Gustavo Palacios, Zuo-Fei Yuan, Ankhbayar Lkhagva
article en

Abstract

The synaptic vesicle (SV) cycle is the fastest membrane trafficking and protein sorting process in biology. It underlies neuronal communication and cognition, yet synaptic function declines during normal aging, increasing vulnerability to neurologic disease. How the SV cycle is maintained across the lifespan of a complex organism remains unclear. Here, we used wild-type mice (C57BL/6J) to define the age- and sex-stratified molecular landscape of SVs and identified apolipoprotein E (APOE) as an abundant presynaptic protein further enriched in aged female samples. Super-resolution imaging, cell-type selective expression, and protease protection assays demonstrate that APOE originates from astroglia and associates with the cytosolic face of SVs. Using iGluSnFR and pHluorin optophysiology, we find that both decreased and increased APOE levels impair neurotransmission during stimulus trains. Together, these findings place APOE at the synapse and establish it as a cell-nonautonomous regulator of the SV cycle.

bioRxiv (Cold Spring Harbor Laboratory)
St. Jude Children's Research Hospital (US), University of Tennessee Health Science Center (US), Jackson Laboratory (US), Columbia University (US)
St. Jude Children's Research Hospital, American Lebanese Syrian Associated Charities, National Cancer Institute
Openalex Percentile: Top 16%
Cellular transport and secretion
DOIOpen Access PDFOpenAlex
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