Authors
Yang, N. V., Wang, S., Li, B., Simms, J., Dinh, L., Huang, A., Oei, J. H., Yassine, H. N., Krauss, R. M.
Abstract
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 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. DISCUSSION: TOMM40 is a novel mediator of AD pathology through dual effects on MERCs that regulate cholesterol homeostasis and mitochondrial function.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 02 Nov 2025.
Advertisement
Stats
- Recommendations n/a n/a positive of 0 vote(s)
- Views 44
- Comments 0