TOMM40 suppression promotes neuronal cholesterol imbalance and molecular and behavioral phenotypes of Alzheimer's disease

INTRODUCTION: While the APOE4 allele is a major risk factor for Alzheimer′s disease (AD), the role of TOMM40—an adjacent gene involved in mitochondrial protein import—is not known. METHODS: Mice, human iPSC-derived neurons (iNeurons), and human brain tissue were used for study of animal cognition, cholesterol metabolism, mitochondrial function, and gene expression. RESULTS: TOMM40 knockdown (KD) impaired memory in mice and increased cholesterol and Aβ 42 in mouse brains and human iNeurons. KD disrupted mitochondria-endoplasmic reticulum contact sites (MERCs), causing mitochondrial dysfunction and promoting reactive oxygen species that led to activation of LXRB (NR1H2), upregulation of APOE and LDLR. and increased cellular cholesterol and Aβ 42 independent of APOE4. Human brain transcriptomics showed reduced TOMM40 expression that correlated with cholesterol regulatory gene expression, amyloid burden, and clinical AD diagnosis. DISCUSSION: TOMM40 is a novel mediator of AD pathology through dual effects on MERCs that regulate cholesterol homeostasis and mitochondrial function.