Genetic ablation of neuronal mitochondrial calcium uptake impedes Alzheimer’s disease progression
Abstract Loss of m Ca 2+ efflux capacity contributes to the pathogenesis and progression of Alzheimer’s disease (AD) by promoting mitochondrial Ca 2+ ( m Ca 2+ ) overload. Here, we utilized loss-of-function genetic mouse models to causally evaluate the role of m Ca 2+ uptake by conditionally deleting the mitochondrial calcium uniporter channel (mtCU) in a robust mouse model of AD. Loss of neuronal m Ca 2+ 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 Ca 2+ 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 m Ca 2+ uptake represents a powerful therapeutic target to impede AD progression.
Authors
- Dhanendra Tomar (ORCID: https://orcid.org/0000-0002-3144-7257)
- John W. Elrod (ORCID: https://orcid.org/0000-0003-3925-2224)
- Joanne F. Garbincius (ORCID: https://orcid.org/0000-0002-4334-6445)
- Oniel Salik (ORCID: https://orcid.org/0000-0001-9785-4173)
- Darpan Raghav (ORCID: https://orcid.org/0000-0002-2067-1384)
- Salman Khaledi
- Alycia N. Hildebrand
- Devin W. Kolmetzky (ORCID: https://orcid.org/0000-0001-8905-0079)
- H Cohen (ORCID: https://orcid.org/0000-0002-2172-2008)
- Pooja Jadiya (ORCID: https://orcid.org/0000-0003-4807-9304)
- Manfred Thomas
- E.V. Berezhnaya
- Shatakshi Shukla
- Liam Kennedy (ORCID: https://orcid.org/0009-0003-2372-3447)
Institutions
- Wake Forest University (US)
- Temple University (US)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2026-05-22
- DOI
- https://doi.org/10.1038/s44318-026-00809-w
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Alzheimer's Association
- American Heart Association
- Pennsylvania Department of Health
- National Institute on Aging
- National Heart, Lung, and Blood Institute
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Neurological Disorders and Stroke
- Alzheimer's Disease Research Center, Wake Forest School of Medicine