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

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.

A CHCHD6–APP axis connects amyloid and mitochondrial pathology in Alzheimer’s disease

“…Moreover, neuron-specific compensation of CHCHD6 may avoid the side effect of cholesterol synthesis inhibitors, like statins, in regulating cholesterol levels in plasma and peripheral tissue. Our recent study proposed a model in which CYP46A1 expression is suppressed by ATAD3A oligomerization under AD-associated conditions [ 76 ]. Given that both CHCHD6 and ATAD3A localize on the mitochondrial contact site [ 14 , 76 , 77 ], this could potentially explain the observed phenotypes.…”

“…Our recent study proposed a model in which CYP46A1 expression is suppressed by ATAD3A oligomerization under AD-associated conditions [ 76 ]. Given that both CHCHD6 and ATAD3A localize on the mitochondrial contact site [ 14 , 76 , 77 ], this could potentially explain the observed phenotypes. Future study of CHCHD6-ATAD3A interaction will help to test this possibility and further address the impact of CHCHD6 on cholesterol turnover.…”

“…PLA was performed using the Duolink ® In Situ Red Starter Kit (mouse/rabbit, DUO92101, Sigma), and Duolink In Situ Detection Reagents Green (DUO92014, Sigma) as described previously [ 76 ]. Briefly, fixed cells or brain sections were permeabilized and blocked with PLA blocking buffer for 1 h at 37 °C and incubated with the indicated primary antibodies overnight at 4 °C.…”

“…APP is also highly enriched in mitochondria of the hippocampus and other brain regions that are particularly vulnerable in AD [ 7 , 13 ], and APP-deficient mice exhibit extensively compromised mitochondrial bioenergetics [ 41 ]. APP overexpression in mice also causes mitochondrial fragmentation, respiratory failure, and neuronal apoptosis [ 10 , 52 , 58 ], and neurons with impaired mitochondrial function display aberrant APP processing [ 51 , 72 , 76 ]. Thus, a proper balance of APP is essential for healthy mitochondrial function.…”

PERK-ATAD3A interaction protects mitochondrial proteins synthesis during ER stress

“…The mechanism proposed here would result in maintenance of translation rates local to mitochondria during ER stress and a potential continuous supply of newly synthesised protein essential for proper function. Sequestration of ATAD3A in disease, as occurs in AD and HD models (13,20) and FUS (21), could provide a basis for dysregulated PERK signalling seen in many neurodegenerative diseases (22)(23)(24). This mode of modulation is specific to the PERK signalling arm of the ISR due to the unique cytoplasmic insert loop present in PERK's kinase domain.…”