Decrease of dynamin 2 levels in late-onset Alzheimer's disease alters Abeta metabolism.
Eiichiro Kamagata1, Takashi Kudo, Ryo Kimura
1Department of Geriatric Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan.
Biochemical and Biophysical Research Communications
|January 8, 2009
Summary
Dynamin 2 (DNM2) gene expression is reduced in late-onset Alzheimer's disease (LOAD), leading to increased amyloid precursor protein (APP) accumulation. This suggests a novel mechanism contributing to amyloid beta protein (Abeta) secretion in LOAD neurons.
Area of Science:
- Neuroscience
- Genetics
Background:
- Late-onset Alzheimer's disease (LOAD) is linked to genetic factors, including dynamin 2 (DNM2) gene variations.
- The apolipoprotein E-epsilon4 allele is a known risk factor, but LOAD also occurs in non-carriers.
Purpose of the Study:
- To investigate the role of DNM2 in LOAD pathogenesis.
- To explore the impact of reduced DNM2 expression on amyloid precursor protein (APP) processing and amyloid beta protein (Abeta) secretion.
Main Methods:
- Real-time PCR to quantify DNM2 mRNA levels in Alzheimer's disease (AD) brain cortex and patient blood.
- Transfection of neuroblastoma cells with a dominant-negative DNM2 to mimic reduced DNM2 function.
- Analysis of APP localization and Abeta secretion in transfected cells.
Main Results:
- DNM2 mRNA levels were significantly decreased in AD brain cortex and dementia patient blood.
- Cells with reduced DNM2 showed increased Abeta secretion.
- APP accumulated in the plasma membrane of these cells, particularly in flotillin-rich lipid rafts.
Conclusions:
- Reduced DNM2 expression is a feature of LOAD.
- DNM2 deficiency may lead to APP accumulation in lipid rafts, promoting Abeta secretion in neurons.
- This pathway represents a potential therapeutic target for LOAD.
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