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bioRxiv · 10.1101/2025.10.01.679889

Association of cytochrome c oxidase dysfunction with amyloidosis in Alzheimer's disease and patient-derived cerebral organoids

Chen, Y.·Wang, T.·Tian, J.·Ashraf, K.·Guo, L.·Ma, T.·Du, H.
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Abstract

Patients with Alzheimers disease (AD) demonstrate brain mitochondrial dysfunction and energy deficiency that are closely associated with cognitive impairment. Cytochrome c oxidase (CCO), also known as mitochondrial complex IV, is the terminal enzyme in mitochondrial electron transport chain (ETC). Consistent with the pivotal role of CCO in mitochondrial bioenergetics and high demand for energy to sustain neuronal function, CCO dysfunction has been linked to neurological disorders including AD. However, it remains unclear whether mitochondrial CCO dysfunction represents an adaptive response to AD-associated toxic molecules versus a bona fide pathology to promote AD development. In this study, by meta-analysis of publicly available proteomics analysis of post-mortem frontal lobe tissues from four large cohorts of patients with AD we identified loss of key CCO subunits including mitochondrial DNA (mtDNA)-encoded COX1 and COX3 as well as nuclear DNA (nDNA)-encoded COX5A, COX6B1, COX7C, COX8A, and NDUFA4 in patients with AD. Further biochemical analysis using post-mortem frontal lobe tissues showed lowered CCO activity of neuronal mitochondria from patients with AD, suggesting CCO vulnerability and its potential association with amyloidosis in AD. Lastly, in addition to the inverse relationship between neuronal CCO activity and brain amyloidosis in the tested AD cohort, pharmacological inhibition of CCO promoted amyloid production and elevated beta-secretase 1 (BACE1) activity in cerebral organoids derived from human induced pluripotent stem cells (hiPSCs) from one nonAD and one AD subject. The simplest interpretation of the results is that CCO dysfunction in the frontal lobe is a phenotypic mitochondrial change accompanying AD, which may contribute to the development of brain amyloidosis.

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Chen, Y., Wang, T., Tian, J., Ashraf, K., Guo, L., Ma, T., Du, H.. 2025-10-02. Association of cytochrome c oxidase dysfunction with amyloidosis in Alzheimer's disease and patient-derived cerebral organoids. https://doi.org/10.1101/2025.10.01.679889

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