Genetic ablation of neuronal mitochondrial calcium uptake impedes Alzheimer's disease progression.
Overview
- Aging + Cardiovascular Discovery Center, Department of Cardiovascular Sciences, Lewis Katz School of Medicine at Temple University,Philadelphia, PA USA
- Department of Internal Medicine, Wake Forest University School of Medicine,Winston-Salem, NC USA
Abstract
Loss of mCa2+ efflux capacity contributes to the pathogenesis and progression of Alzheimer’s disease (AD) by promoting mitochondrial Ca2+ (mCa2+) overload. Here, we utilized loss-of-function genetic mouse models to causally evaluate the role of mCa2+ uptake by conditionally deleting the mitochondrial calcium uniporter channel (mtCU) in a robust mouse model of AD. Loss of neuronal mCa2+ uptake reduced Aβ and tau-pathology, synaptic dysfunction, and cognitive decline in 3xTg-AD mice. Knockdown of Mcu in an in vitro model of AD significantly reduced matrix Ca2+ content, redox imbalance, and mitochondrial dysfunction. The preservation of mitochondrial function rescued the AD-dependent decline in autophagic capacity and protected neurons against amyloidosis and cell death. This was corroborated by in vivo data showing improved mitochondrial structure and apposition in AD mice with loss of neuronal Mcu. These results suggest that inhibition of neuronal mCa2+ uptake represents a powerful therapeutic target to impede AD progression.
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
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Data
Data links
- ebi.ac.uk/
biostudies/ , EMBL-EBI; found in the notessourcedata
Data availability
All data supporting the findings of this study, including all raw data and complete statistical analysis files, are available as downloadable ZIP archives via the EMBO Journal submission system. Our study includes no large datasets deposited in public repositories.
The source data of this paper are collected in the following database record: biostudies:S-SCDT-10_103
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 1, 28 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 14 authors, 3 keywords, 12 MeSH terms, 8 funders, 96 references.
Cite
This paper
Jadiya, P., Berezhnaya, E., Kolmetzky, D. W., Tomar, D., Cohen, H. M., Shukla, S., Thomas, M., Khaledi, S., Garbincius, J. F., Kennedy, L., Salik, O., Raghav, D., Hildebrand, A. N., & Elrod, J. W. (2026). Genetic ablation of neuronal mitochondrial calcium uptake impedes Alzheimer's disease progression. The EMBO journal, 45(13), 4469-4491. https://
BibTeX
@article{jadiya2026genet
author = {Jadiya, Pooja and Berezhnaya, Elena and Kolmetzky, Devin W and Tomar, Dhanendra and Cohen, Henry M and Shukla, Shatakshi and Thomas, Manfred and Khaledi, Salman and Garbincius, Joanne F and Kennedy, Liam and Salik, Oniel and Raghav, Darpan and Hildebrand, Alycia N and Elrod, John W},
title = {{Genetic ablation of neuronal mitochondrial calcium uptake impedes Alzheimer's disease progression}},
journal = {The EMBO journal},
year = {2026},
month = may,
volume = {45},
number = {13},
pages = {4469--4491},
publisher = {Nature Publishing Group},
issn = {0261-4189},
doi = {10.1038/
url = {https://
pmid = {42174122},
pmcid = {PMC13324160}
}
RIS
TY - JOUR
AU - Jadiya, Pooja
AU - Berezhnaya, Elena
AU - Kolmetzky, Devin W
AU - Tomar, Dhanendra
AU - Cohen, Henry M
AU - Shukla, Shatakshi
AU - Thomas, Manfred
AU - Khaledi, Salman
AU - Garbincius, Joanne F
AU - Kennedy, Liam
AU - Salik, Oniel
AU - Raghav, Darpan
AU - Hildebrand, Alycia N
AU - Elrod, John W
TI - Genetic ablation of neuronal mitochondrial calcium uptake impedes Alzheimer's disease progression
T2 - The EMBO journal
J2 - EMBO J
PY - 2026
DA - 2026/
VL - 45
IS - 13
SP - 4469
EP - 4491
SN - 0261-4189
PB - Nature Publishing Group
DO - 10.1038/
UR - https://
LA - en
ER -
CSL-JSON
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