ATP11B-related Mitochondrial Dysfunction Serves as an Early Alert of Alzheimer’s Disease

• Authors: Jiao Wang^#, Shibo Zhang^#, Qian Li^#, Ruiqi Sun^#, Wenxin Qi^#, Naijun Dong^#, Chengshang LYU, Xiaoping Liu, Hao Wu, Jianxin Zhou, Hongwei Shi, Cuiping Liu, Junyi Zhuang, Peiru Wu, Lin Huang, Jintao Gong, Shuaijing Ma, Di Li, Xingyan An, Wanwei Zhao, Xuanting Liu, Qin Han, Rongjia Zhu, Shihua Wang, Hongling Li, Jing Li, Tieqiao Wen, Evelyne Bischof, Luonan Chen^*, Robert Chunhua Zhao^*.

• Abstract: The progressive nature of Alzheimer’s disease (AD) poses significant challenges in reversing cognitive decline and motor impairments once irrecoverable damage has occurred. This underscores the importance of prioritizing the development of strategies for early detection, prevention, and intervention. Here, we confirm mitochondrial dysfunction as a pivotal pre-disease indicator of AD, with 12 of 13 protein-encoding genes contributed by mitochondrial DNA and key nuclear genes required for the assembly and regulation of mitochondrial respiratory supercomplex showing early alterations. ATP11B, encoding a type IV P-type ATPase, was revealed as a tipping point gene at AD pre-disease stage and essential for maintaining mitochondrial integrity and energy homeostasis in major brain cell populations. ATP11B overexpression enhances cognitive performance in adult mice and an AD mouse model, providing substantial support for the proposition that mitochondrial dysfunction precedes AD pathology. This research positions ATP11B-indicated mitochondrial dysfunction as a potential biomarker for timely diagnosis of AD, contributing further insights to the understanding of early AD pathogenesis and offering a promising avenue for future therapeutic strategies.

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