Disrupted synaptic vacuolar H+-ATPase renders synaptic vulnerability to Alzheimer’s disease
4 affiliations
- 1Department of Neuroscience, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
- 2Department of Pharmacology and Toxicology, University of Kansas, Lawrence, Kansas, USA.
- 3Alzheimer’s Disease Research Center and
- 4Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
Abstract
Defective synaptic transmission is a prominent pathology that underlies cognitive deficits in Alzheimer’s disease (AD), highlighting the need to elucidate molecular mechanisms of synaptic failure. Vacuolar H+-ATPase (V-ATPase), a proton-pumping enzyme, is essential for synaptic vesicle acidification and neurotransmitter loading. However, whether SV-associated V-ATPase is vulnerable to AD remains unclear. Here, using SV-rich fractions from postmortem brain tissues, we identified SV-associated V-ATPase deficits, including decreased enzymatic activity, impaired complex assembly, and altered expression of its key subunits in AD. SV-associated V-ATPase dysfunction was further associated with pathological and clinical characteristics of AD. Genetic downregulation of the V-ATPase V1D subunit, a component reduced in AD brains, disrupted V-ATPase proton transport and impaired SV acidification. Further experiments using 5×FAD mice, which exhibited AD-like SV-associated V-ATPase deficits, demonstrated the deleterious impact of V-ATPase dysfunction on SV acidification and synaptic transmission including presynaptic neurotransmitter release. In addition, ex vivo studies identified amyloid β–induced oxidative stress as a driver of V1D loss and V-ATPase disassembly, linking AD pathology to SV-associated V-ATPase dysfunction. These findings indicate that SV-associated V-ATPase dysfunction contributes to synaptic failure and cognitive deficits in AD. Therapeutic avenues to mitigate V-ATPase dysfunction have the potential to attenuate synaptic failure for the management of AD.
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BibTeX
@article{chen2026disrupted,
title = {{Disrupted synaptic vacuolar H+-ATPase renders synaptic vulnerability to Alzheimer’s disease}},
author = {Yanting Chen and Khloud Ashraf Farouk Emam and Shuwen Yue and Jing Tian and Tienju Wang and Albert Park and Shalini Mishra and Gagan Deep and Zi-Jun Wang and Heng Du and Lan Guo},
journal = {JCI Insight},
year = {2026},
month = oct,
doi = {10.1172/jci.insight.202983},
url = {https://doi.org/10.1172/jci.insight.202983},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Disrupted synaptic vacuolar H+-ATPase renders synaptic vulnerability to Alzheimer’s disease
AU - Yanting Chen
AU - Khloud Ashraf Farouk Emam
AU - Shuwen Yue
AU - Jing Tian
AU - Tienju Wang
AU - Albert Park
AU - Shalini Mishra
AU - Gagan Deep
AU - Zi-Jun Wang
AU - Heng Du
AU - Lan Guo
PY - 2026
DA - 2026/10/08
JO - JCI Insight
DO - 10.1172/jci.insight.202983
UR - https://doi.org/10.1172/jci.insight.202983
AB - Defective synaptic transmission is a prominent pathology that underlies cognitive deficits in Alzheimer’s disease (AD), highlighting the need to elucidate molecular mechanisms of synaptic failure. Vacuolar H+-ATPase (V-ATPase), a proton-pumping enzyme, is essential for synaptic vesicle acidification and neurotransmitter loading. However, whether SV-associated V-ATPase is vulnerable to AD remains unclear. Here, using SV-rich fractions from postmortem brain tissues, we identified SV-associated V-ATPase deficits, including decreased enzymatic activity, impaired complex assembly, and altered expression of its key subunits in AD. SV-associated V-ATPase dysfunction was further associated with pathological and clinical characteristics of AD. Genetic downregulation of the V-ATPase V1D subunit, a component reduced in AD brains, disrupted V-ATPase proton transport and impaired SV acidification. Further experiments using 5×FAD mice, which exhibited AD-like SV-associated V-ATPase deficits, demonstrated the deleterious impact of V-ATPase dysfunction on SV acidification and synaptic transmission including presynaptic neurotransmitter release. In addition, ex vivo studies identified amyloid β–induced oxidative stress as a driver of V1D loss and V-ATPase disassembly, linking AD pathology to SV-associated V-ATPase dysfunction. These findings indicate that SV-associated V-ATPase dysfunction contributes to synaptic failure and cognitive deficits in AD. Therapeutic avenues to mitigate V-ATPase dysfunction have the potential to attenuate synaptic failure for the management of AD.
SN - 2379-3708
ER -