科研之友
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摘要
Amyloid-beta peptide (A beta) is considered a key protein in the pathogenesis of Alzheimer's disease (AD) because of its neurotoxicity and capacity to form characteristic insoluble deposits known as senile plaques. A beta derives from amyloid-beta protein precursor (A beta PP), whose proteolytic processing generates several fragments including A beta peptides of various lengths. The normal function of A beta PP and its fragments remains poorly understood. While some fragments have been suggested to have a function in normal physiological cellular processes, A beta has been widely considered as a "garbage" fragment that becomes toxic when it accumulates in the brain, resulting in impaired synaptic function and memory. A beta is produced and released physiologically in the healthy brain during neuronal activity. In the last 10 years, we have been investigating whether A beta plays a physiological role in the brain. We first demonstrated that picomolar concentrations of a human A beta(42) preparation enhanced synaptic plasticity and memory in mice. Next, we investigated the role of endogenous A beta in healthy murine brains and found that treatment with a specific antirodent A beta antibody and an siRNA against murine A beta PP impaired synaptic plasticity and memory. The concurrent addition of human A beta(42) rescued these deficits, suggesting that in the healthy brain, physiological All concentrations are necessary for normal synaptic plasticity and memory to occur. Furthermore, the effect of both exogenous and endogenous A beta was seen to be mediated by modulation of neurotransmitter release and alpha 7-nicotinic receptors. These findings need to be taken into consideration when designing novel therapeutic strategies for AD.
- 出版日期2013
