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Posted on Jan 08, 2009, 7 a.m.
By Rich Hurd
Research into the pathology of Alzheimer's disease has led scientists from the US and Europe to discover that impaired energy metabolism may play a key role in the development of the disease. It is hoped that the discovery may lead to new treatments for the devastating neurodegenerative condition.
Research into the pathology of Alzheimer's disease has led scientists from the US and Europe to discover that impaired energy metabolism may play a key role in the development of the disease. It is hoped that the discovery may lead to new treatments for the devastating neurodegenerative condition.
Previous research has suggested that the amyloid precursor protein (APP) cleaving enzyme (BACE1), the enzyme responsible for the generation of amyloid β (Aβ) the constituent of the amyloid plaques characteristic of Alzheimer's disease, may play a key role in the development of the disease. More recently, it was found that impaired energy metabolism in the brain caused BACE1 levels, and, in turn, Aβ levels, to rise.
Dr. Robert Vassar from Northwestern University Feinberg School of Medicine led a study to determine the molecular mechanisms behind the rise in BACE1 in response to impaired energy metabolism. Results showed that glucose deprivation triggered an increase in BACE1 levels and led to the phosphorylation of the stress-inducible translation initiation factor, eIF2α-P. They also found that direct phosphorylation of increased both BACE1 levels and Aβ production, whilst inhibition of eIF2α-P phosphorylation prevented energy-deprivation induced increases in BACE1. Further investigation revealed that elevated levels of both phosphorylated and BACE1 were found in an aggressive Aβ plaque-forming mouse model and in humans with Alzheimer's disease.
"Our findings implicate phosphorylated eIF2α-P in both the initiation and progression of sporadic Alzheimer's disease. Future experiments will determine whether inhibition of eIF2α-P phosphorylation could be an efficacious therapeutic approach for the prevention and treatment of Alzheimer's disease."
O'Connor T, Sadleir KR, Maus E, et al. Phosphorylation of the Translation Initiation Factor eIF2 Increases BACE1 Levels and Promotes Amyloidogenesis. Neuron 2008;60:988-1009. doi:10.1016/j.neuron.2008.10.047
News release: Impaired energy metabolism linked with initiation of plaques in Alzheimer's brain. Cell Press December 24th 2008.
