Physiological roles of amyloid-β and implications for its removal in Alzheimer's disease
Physiological roles of amyloid-β and implications for its removal in Alzheimer's disease
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DOI：
10.2165/00002512-200421100-00001
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发表时间：
2004-01-01
期刊：
影响因子：
2.8
通讯作者：
Robinson, SR
中科院分区：
文献类型：
--
作者：
Bishop, GM;Robinson, SR
阿尔茨海默病的潜在病理学原因被认为是过量的淀粉样蛋白-β（Abeta），其聚集成脑细胞外空间内的毒性纤维状沉积物，从而破坏神经元和突触功能并最终导致神经元变性和痴呆。因此，已经开发了旨在从大脑中去除Abeta的治疗策略。需要谨慎对待这些策略，因为除了存在于神经炎斑块中之外，Abeta还广泛分布于大脑和身体中，即使在认知正常的个体中也是如此。证据表明，可溶性Abeta不是一种有毒肽，而是具有多种生理功能，包括调节突触功能、促进神经元生长和存活、保护免受氧化应激以及监测神经活性化合物、毒素和病原体。这些生理功能必须考虑到策略时，开发，以减少阿尔茨海默病的Abeta负荷。理想情况下，这些策略应该靶向非生物可利用的Abeta形式，如纤维状Abeta，或被认为在阿尔茨海默病中过表达的形式（如寡聚体），同时保持正常的可溶性Abeta（1-40）和Abeta（1-42）完整。目前可用的治疗策略似乎没有这样的选择性。在这些技术限制和关于从大脑中消耗Abeta的影响的不确定性得到解决之前，开始进一步的临床试验是不明智的。
The underlying pathological cause of Alzheimer's disease has been postulated to be an excess of amyloid-beta (Abeta) which aggregates into toxic fibrillar deposits within the extracellular space of the brain, thereby disrupting neuronal and synaptic function and eventually leading to neuronal degeneration and dementia. As a result, therapeutic strategies have been developed that are designed to remove Abeta from the brain. Caution needs to be exercised concerning such strategies because, in addition to its presence in neuritic plaques, Abeta has a widespread distribution through the brain and body, even in cognitively normal individuals. Evidence indicates that instead of being a toxic peptide, soluble Abeta serves a variety of physiological functions, including modulation of synaptic function, facilitation of neuronal growth and survival, protection against oxidative stress, and surveillance against neuroactive compounds, toxins and pathogens. These physiological functions must be taken into account when strategies are developed to reduce Abeta load in Alzheimer's disease. Ideally, such strategies should target forms of Abeta that are not bioavailable, such as fibrillar Abeta, or forms that are regarded to be overexpressed in Alzheimer's disease (such as oligomers) while leaving normal soluble Abeta(1-40) and Abeta(1-42) intact. At present none of the available therapeutic strategies appears to have such selectivity. Until these technical limitations and the uncertainties regarding the effect of depletion of Abeta from the brain are resolved, it would not be prudent to begin further clinical trials.