| Abstract: |
INTRODUCTION: While the apolipoprotein E (APOE) ε4 allele is a major risk factor for Alzheimer's disease (AD), the role of translocase of outer mitochondrial membrane 40 (TOMM40)—an adjacent gene involved in mitochondrial protein import—is not known. METHODS: Human brain tissue, human induced pluripotent stem cell–derived neurons (iNeurons), and mice were used for study of gene expression, cholesterol metabolism, mitochondrial function, and animal cognition. RESULTS: Human brain transcriptomics showed reduced TOMM40 expression that correlated with cholesterol regulatory gene expression, amyloid burden, and clinical AD diagnosis. In human iNeurons, TOMM40 knockdown (KD) disrupted mitochondria–endoplasmic reticulum contact sites (MERCs), causing mitochondrial dysfunction and promoting reactive oxygen species that led to activation of liver X receptor beta (NR1H2), upregulation of APOE and low‐density lipoprotein receptor (LDLR), and increased cellular cholesterol and amyloid beta (Aβ)42 independent of APOE ε4. Consistently, Tomm40 KD in mice induced increased brain cholesterol, Aβ42 content, and impaired memory. DISCUSSION: TOMM40 is a novel mediator of AD pathology through dual effects on MERCs that regulate cholesterol homeostasis and mitochondrial function. Highlights: RNA sequencing shows that TOMM40 expression is reduced in post mortem human brain samples from AD patients versus controls, and correlates with phenotypes of cholesterol metabolism and AD phenotypes.Increases in cholesterol and Aβ42 content of iPSC‐derived neurons with TOMM40 KD are independent of the effects of the APOE ε4 allele.In human induced pluripotent stem cell (iPSC)–derived neurons TOMM40 KD causes disruption of mitochondria–endoplasmic reticulum contact sites, resulting in increased cholesterol uptake due to liver X receptor beta activation and upregulation of apolipoprotein E (apoE) and low‐density lipoprotein receptor.Translocase of outer mitochondrial membrane 40 (TOMM40) knockdown (KD) in mice results in cognitive impairment, including declarative memory deficits, together with increased brain content of cholesterol and amyloid beta (Aβ)42, measures associated with Alzheimer's disease (AD) risk. [ABSTRACT FROM AUTHOR] |