TOMM40 suppression promotes neuronal cholesterol imbalance and molecular and behavioral phenotypes of Alzheimer's disease - PubMed
6 hours ago
- #Alzheimer's disease
- #cholesterol metabolism
- #mitochondria
- TOMM40 suppression reduces its expression in human brain, correlating with cholesterol gene dysregulation, amyloid burden, and AD diagnosis.
- In human neurons, TOMM40 knockdown disrupts mitochondria-ER contact sites (MERCs), causing mitochondrial dysfunction and oxidative stress, leading to activation of liver X receptor beta and upregulation of APOE and LDLR.
- TOMM40 knockdown increases cellular cholesterol and Aβ42 levels independently of APOE ε4 status, and in mice, it elevates brain cholesterol, Aβ42, and impairs memory.
- TOMM40 is identified as a novel mediator of AD pathology through dual effects on MERCs that regulate both cholesterol homeostasis and mitochondrial function.