ATAD3A oligomerization promotes neuropathology and cognitive deficits in Alzheimer’s disease models

Yuanyuan Zhao, Di Hu, Rihua Wang, Xiaoyan Sun, Philip Ropelewski, Zita Hubler, Kathleen Lundberg, Quanqiu Wang, Drew J. Adams, Rong Xu and Xin Qi ()
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Yuanyuan Zhao: Case Western Reserve University School of Medicine
Di Hu: Case Western Reserve University School of Medicine
Rihua Wang: Case Western Reserve University School of Medicine
Xiaoyan Sun: Case Western Reserve University School of Medicine
Philip Ropelewski: Case Western Reserve University School of Medicine
Zita Hubler: Case Western Reserve University School of Medicine
Kathleen Lundberg: Case Western Reserve University School of Medicine
Quanqiu Wang: Case Western Reserve University School of Medicine
Drew J. Adams: Case Western Reserve University School of Medicine
Rong Xu: Case Western Reserve University School of Medicine
Xin Qi: Case Western Reserve University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract Predisposition to Alzheimer’s disease (AD) may arise from lipid metabolism perturbation, however, the underlying mechanism remains elusive. Here, we identify ATPase family AAA-domain containing protein 3A (ATAD3A), a mitochondrial AAA-ATPase, as a molecular switch that links cholesterol metabolism impairment to AD phenotypes. In neuronal models of AD, the 5XFAD mouse model and post-mortem AD brains, ATAD3A is oligomerized and accumulated at the mitochondria-associated ER membranes (MAMs), where it induces cholesterol accumulation by inhibiting gene expression of CYP46A1, an enzyme governing brain cholesterol clearance. ATAD3A and CYP46A1 cooperate to promote APP processing and synaptic loss. Suppressing ATAD3A oligomerization by heterozygous ATAD3A knockout or pharmacological inhibition with DA1 restores neuronal CYP46A1 levels, normalizes brain cholesterol turnover and MAM integrity, suppresses APP processing and synaptic loss, and consequently reduces AD neuropathology and cognitive deficits in AD transgenic mice. These findings reveal a role for ATAD3A oligomerization in AD pathogenesis and suggest ATAD3A as a potential therapeutic target for AD.

Date: 2022
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DOI: 10.1038/s41467-022-28769-9

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