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Mitochondrial Calcium Uniporter Beta in Alzheimer's Disease

Kaye, Sarah D.
; 
Raghav, Darpan
; 
Kadam, Ashlesha
; 
Elrod, John W.
; 
Tomar, Dhanendra
; 
Jadiya, Pooja
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Journal article
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2025-01-03
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Cardiovascular Sciences
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https://scholarshare.temple.edu/handle/20.500.12613/11642
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https://doi.org/10.1002/alz.086190
Abstract
Background Alzheimer’s disease (AD) is a complex neurodegenerative disorder marked by progressive memory loss and cognitive decline. The precise molecular mechanisms underlying AD pathogenesis remain uncertain, underscoring the need for further investigation to identify novel therapeutic targets. We recently demonstrated that mitochondrial calcium (mCa2+) overload significantly contributes to the development of AD, capable of independently driving AD-like pathology. Modulating mCa2+ dynamics, such as blocking mCa2+ uptake, holds promise in reducing neuronal cell death in AD. However, these approaches challenge bioenergetic processes due to the role mCa2+ plays in metabolic regulation. Therefore, it is essential to identify a regulator that can maintain mCa2+ homeostasis while preserving bioenergetic functions. Methods To identify a new molecular regulatory mechanism for reducing mCa2+ overload and preserving bioenergetics in AD, we focused on Mitochondrial Calcium Uniporter Beta (MCUB), a negative regulator of mCa2+ uptake. Initially, we examined MCUB expression in AD patient samples, AD model mice, and AD cell lines. Observing reduced MCUB expression in AD, we used 5xFAD mutant mice with neuronal-specific MCUB overexpression to assess age-associated changes in cognitive function, neuropathology, and mitochondrial bioenergetics. A neuroblastoma cell line expressing human amyloid precursor protein with the Swedish mutation (N2a/APPswe) and adenovirus encoded MCUB was examined for alterations in mitochondrial Ca2+ dynamics and functions. Results Our findings revealed that expression of MCUB is lost in non-familial AD samples, AD mouse models, and AD cell lines. MCUB overexpression in 5xFAD mice rescued spatial and fear-associated memory impairments and alleviated amyloid beta pathology at 9 months of age. Furthermore, MCUB overexpression mitigated mCa2+ overload, preserved crucial mitochondrial bioenergetic functions including oxidative phosphorylation (OXPHOS) and ATP production, and prevented neuronal cell loss. Conclusions This study demonstrates for the first time that modulating MCUB holds therapeutic promise in preserving bioenergetics and mitigating neuronal damage and AD progression. These findings have the potential to significantly advance our understanding of AD pathogenesis and pave the way for effective treatments for AD.
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Kaye, S.D., Raghav, D., Kadam, A., Elrod, J.W., Tomar, D. and Jadiya, P. (2024), Mitochondrial Calcium Uniporter Beta in Alzheimer’s Disease. Alzheimer's Dement., 20: e086190. https://doi.org/10.1002/alz.086190
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Wiley
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Alzheimer's & Dementia, Vol. 20, Iss. S1
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