Cholinergic impairment in the dorsal motor nucleus of the vagus during experimental Alzheimer's disease
- 1The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
Abstract
Cholinergic neurons in the dorsal motor nucleus of the vagus (DMN) in the brainstem are a key source of efferent vagus nerve fibers that regulate vital functions, including heart rate and inflammation. Whether the integrity of DMN cholinergic neurons is affected during Alzheimer's disease (AD) remains unknown. Here, in female and male mice with experimental AD (5xFAD), which exhibit age-dependent memory impairment, basal forebrain cholinergic neurodegeneration, and microglial alterations, we observe a reduction in cholinergic neuron density in the DMN at 6 and 10 months of age. Furthermore, while an important physiological function of DMN cholinergic signaling, such as suppression of heart rate, is preserved in control mice upon electrical DMN stimulation, the extent of suppression diminishes with age in both female and male 5xFAD mice. In addition, while electrical DMN stimulation lowers pro-inflammatory cytokine levels in control mice subjected to endotoxemia, this anti-inflammatory effect is diminished with age in 5xFAD mice, with females showing earlier dysfunction at 6 months. These results reveal previously unrecognized age-dependent cholinergic deficits in the DMN and disrupted brain - to - periphery vagus nerve circuits in experimental AD. These findings advance our understanding of AD mechanisms and are of interest for the development of conceptually novel therapies.
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BibTeX
@misc{falvey2026cholinergic,
title = {{Cholinergic impairment in the dorsal motor nucleus of the vagus during experimental Alzheimer's disease}},
author = {A. Falvey and S. P. Palandira and S. Chaudhry and J. J. Strohl and P. T. Huerta and T. Tsaava and A. Tynan and C. d'Abramo and L. Giliberto and J. Koppel and Y. Al-Abed and M. Brines and P. Marambaud and S. S. Chavan and E. H. Chang and K. J. Tracey and V. A. Pavlov},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.19.752906},
url = {https://www.biorxiv.org/content/10.64898/2026.09.19.752906v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Cholinergic impairment in the dorsal motor nucleus of the vagus during experimental Alzheimer's disease
AU - A. Falvey
AU - S. P. Palandira
AU - S. Chaudhry
AU - J. J. Strohl
AU - P. T. Huerta
AU - T. Tsaava
AU - A. Tynan
AU - C. d'Abramo
AU - L. Giliberto
AU - J. Koppel
AU - Y. Al-Abed
AU - M. Brines
AU - P. Marambaud
AU - S. S. Chavan
AU - E. H. Chang
AU - K. J. Tracey
AU - V. A. Pavlov
PY - 2026
DA - 2026/09/19
PB - bioRxiv
DO - 10.64898/2026.09.19.752906
UR - https://www.biorxiv.org/content/10.64898/2026.09.19.752906v1
AB - Cholinergic neurons in the dorsal motor nucleus of the vagus (DMN) in the brainstem are a key source of efferent vagus nerve fibers that regulate vital functions, including heart rate and inflammation. Whether the integrity of DMN cholinergic neurons is affected during Alzheimer's disease (AD) remains unknown. Here, in female and male mice with experimental AD (5xFAD), which exhibit age-dependent memory impairment, basal forebrain cholinergic neurodegeneration, and microglial alterations, we observe a reduction in cholinergic neuron density in the DMN at 6 and 10 months of age. Furthermore, while an important physiological function of DMN cholinergic signaling, such as suppression of heart rate, is preserved in control mice upon electrical DMN stimulation, the extent of suppression diminishes with age in both female and male 5xFAD mice. In addition, while electrical DMN stimulation lowers pro-inflammatory cytokine levels in control mice subjected to endotoxemia, this anti-inflammatory effect is diminished with age in 5xFAD mice, with females showing earlier dysfunction at 6 months. These results reveal previously unrecognized age-dependent cholinergic deficits in the DMN and disrupted brain - to - periphery vagus nerve circuits in experimental AD. These findings advance our understanding of AD mechanisms and are of interest for the development of conceptually novel therapies.
ER -