ATAD3A oligomerization promotes neuropathology and cognitive deficits in Alzheimer\u2019s disease models

Yuanyuan Zhao,Kathleen Lundberg,Zita Hubler,Xiaoyan Sun,Rihua Wang,Quanqiu Wang,Philip Ropelewski,Xin Qi,Drew J Adams,Rong Xu,Di Hu

doi:10.1038/s41467-022-28769-9

Yuanyuan Zhao, Kathleen Lundberg + Show 9 more

Open Access

https://doi.org/10.1038/s41467-022-28769-9

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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.

Highlights

Predisposition to Alzheimer’s disease (AD) may arise from lipid metabolism perturbation, the underlying mechanism remains elusive
The data mining showed that ATPase family AAAdomain containing protein 3A (ATAD3A) was closely associated with ADspecific phenotypes and AD-associated genes, ranking in the top 20.82% and 14.49%, respectively, which were significantly higher than random ranking (p < 0.0001; Supplementary Fig. 1a–c)
We recently reported that ATAD3A forms oligomers under pathological conditions, showing a gain-offunction that promotes neuropathology in Huntington’s disease (HD) models[27]

Summary

Introduction

Predisposition to Alzheimer’s disease (AD) may arise from lipid metabolism perturbation, the underlying mechanism remains elusive. 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 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. The amyloid precursor protein (APP) processing γ-secretases, presenilin-1 and presenilin-2, are highly enriched in the MAMs relative to other cell compartments, such as the plasma membrane, mitochondria, and ER10 These findings highlight the role of MAMs in amyloidogenesis.

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