科研之友
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摘要
Alzheimer's disease (AD) is the most common progressive neurodegenerative disorder causing dementia. Massive deposition of amyloid beta peptide (A beta) as senile plaques in the brain is the pathological hallmark of AD, but oligomeric, soluble forms of A beta have been implicated as the synaptotoxic component. The apolipoprotein E epsilon 4 (apoE epsilon 4) allele is known to be a genetic risk factor for developing AD. However, it is still unknown how apoE impacts the process of A beta oligomerization. Here, we found that the level of A beta oligomers in APOE epsilon 4/epsilon 4AD patient brains is 2.7 times higher than those in APOE epsilon 3/epsilon 3 AD patient brains, matched for total plaque burden, suggesting that apoE4 impacts the metabolism of A beta oligomers. To test this hypothesis, we examined the effect of apoE on A beta oligomer formation. Using both synthetic A beta and a split-luciferase method for monitoring A beta oligomers, we observed that apoE increased the level of A beta oligomers in an isoform-dependent manner (E2 < E3 < E4). This effect appears to be dependent on the ApoE C-terminal domain. Moreover, these results were confirmed using endogenous apoE isolated from the TBS-soluble fraction of human brain, which increased the formation of A beta oligomers. Together, these data show that lipidated apoE, especially apoE4, increases A beta oligomers in the brain. Higher levels of A beta oligomers in the brains of APOE epsilon 4/epsilon 4 carriers compared with APOE epsilon 3/epsilon 3 carriers may increase the loss of dendritic spines and accelerate memory impairments, leading to earlier cognitive decline in AD.
- 出版日期2012-10-24
