Department of Bio-Medical Sciences, Section of Physiology, University of Catania, Catania, Italy.
J Alzheimers Dis. 2013;33 Suppl 1(0 1):S111-20. doi: 10.3233/JAD-2012-129033.
Amyloid-β peptide (Aβ) 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. Aβ derives from amyloid-β protein precursor (AβPP), whose proteolytic processing generates several fragments including Aβ peptides of various lengths. The normal function of AβPP and its fragments remains poorly understood. While some fragments have been suggested to have a function in normal physiological cellular processes, Aβ has been widely considered as a "garbage" fragment that becomes toxic when it accumulates in the brain, resulting in impaired synaptic function and memory. Aβ is produced and released physiologically in the healthy brain during neuronal activity. In the last 10 years, we have been investigating whether Aβ plays a physiological role in the brain. We first demonstrated that picomolar concentrations of a human Aβ42 preparation enhanced synaptic plasticity and memory in mice. Next, we investigated the role of endogenous Aβ in healthy murine brains and found that treatment with a specific antirodent Aβ antibody and an siRNA against murine AβPP impaired synaptic plasticity and memory. The concurrent addition of human Aβ42 rescued these deficits, suggesting that in the healthy brain, physiological Aβ concentrations are necessary for normal synaptic plasticity and memory to occur. Furthermore, the effect of both exogenous and endogenous Aβ was seen to be mediated by modulation of neurotransmitter release and α7-nicotinic receptors. These findings need to be taken into consideration when designing novel therapeutic strategies for AD.
β淀粉样肽（Aβ）被认为是阿尔茨海默病（AD）发病机制中的关键蛋白，因为它具有神经毒性，并且能够形成特征性的不溶性沉积物，称为老年斑。Aβ来源于淀粉样前体蛋白（AβPP），其蛋白水解加工生成几种片段，包括不同长度的 Aβ肽。AβPP 及其片段的正常功能仍知之甚少。虽然一些片段被认为在正常的生理细胞过程中具有功能，但 Aβ 被广泛认为是一种“垃圾”片段，当它在大脑中积累时会变得有毒，导致突触功能和记忆受损。Aβ 在健康大脑的神经元活动过程中生理性地产生和释放。在过去的 10 年中，我们一直在研究 Aβ 是否在大脑中发挥生理作用。我们首先证明了皮摩尔浓度的人 Aβ42 制剂增强了小鼠的突触可塑性和记忆。接下来，我们研究了内源性 Aβ 在健康鼠脑中的作用，发现用特异性抗鼠 Aβ 抗体和抗鼠 AβPP 的 siRNA 处理会损害突触可塑性和记忆。同时添加人 Aβ42 可挽救这些缺陷，表明在健康大脑中，正常的突触可塑性和记忆需要生理浓度的 Aβ 才能发生。此外，外源性和内源性 Aβ 的作用都被认为是通过调节神经递质释放和α7-烟碱型乙酰胆碱受体来介导的。在为 AD 设计新的治疗策略时，需要考虑这些发现。
