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bioRxiv · 10.1101/2025.10.31.685963

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

Yang, N. V.·Wang, S.·Li, B.·Simms, J.·Dinh, L.·Huang, A.·Oei, J. H.·Yassine, H. N.·Krauss, R. M.
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Abstract

INTRODUCTIONWhile the APOE4 allele is a major risk factor for Alzheimers disease (AD), the role of TOMM40--an adjacent gene involved in mitochondrial protein import--is not known. METHODSMice, human iPSC-derived neurons (iNeurons), and human brain tissue were used for study of animal cognition, cholesterol metabolism, mitochondrial function, and gene expression. RESULTSTOMM40 knockdown (KD) impaired memory in mice and increased cholesterol and A{beta} 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 A{beta} 42 independent of APOE4. Human brain transcriptomics showed reduced TOMM40 expression that correlated with cholesterol regulatory gene expression, amyloid burden, and clinical AD diagnosis. DISCUSSIONTOMM40 is a novel mediator of AD pathology through dual effects on MERCs that regulate cholesterol homeostasis and mitochondrial function. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=163 SRC="FIGDIR/small/685963v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@e3e3e2org.highwire.dtl.DTLVardef@1861f67org.highwire.dtl.DTLVardef@77a813org.highwire.dtl.DTLVardef@1bb9a83_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Yang, N. V., Wang, S., Li, B., Simms, J., Dinh, L., Huang, A., Oei, J. H., Yassine, H. N., Krauss, R. M.. 2025-11-01. TOMM40 suppression promotes neuronal cholesterol imbalance and molecular and behavioral phenotypes of Alzheimer's disease. https://doi.org/10.1101/2025.10.31.685963

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