Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
Department of Surgery and Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA, USA.
J Alzheimers Dis. 2018;63(3):927-934. doi: 10.3233/JAD-180161.
Alzheimer's disease (AD) is a major contemporary and escalating malady in which amyloid-β (Aβ) peptides are the most likely causative agent. Aβ peptides spontaneously tend to aggregate in extracellular fluids following a progression from a monomeric state, through intermediate forms, ending in amyloid fibers and plaques. It is generally accepted now that the neurotoxic agents leading to cellular death, memory loss, and other AD characteristics are the Aβ intermediate aggregated states. However, Aβ peptides are continuously produced, released into the extracellular space, and rapidly cleared from healthy brains. Coincidentally, members of the heat shock proteins (hsp) family are present in the extracellular medium of healthy cells and body fluids, opening the possibility that hsps and Aβ could meet and interact in the extracellular milieu of the brain. In this perspective and reflection article, we place our investigation showing that the presence of Hsp70s mitigate the formation of low molecular weight Aβ peptide oligomers resulting in a reduction of cellular toxicity, in context of the current understanding of the disease. We propose that it may be an inverse relationship between the presence of Hsp70, the stage of Aβ oligomers, neurotoxicity, and the incidence of AD, particularly since the expression and circulating levels of hsp decrease with aging. Combining these observations, we propose that changes in the dynamics of Hsp70s and Aβ concentrations in the circulating brain fluids during aging defines the control of the formation of Aβ toxic aggregates, thus determining the conditions for neuron degeneration and the incidence of AD.
阿尔茨海默病（AD）是一种主要的现代疾病，其发病率正在不断上升，淀粉样蛋白-β（Aβ）肽是最有可能的致病因子。Aβ肽在从单体状态到中间状态，最后形成淀粉样纤维和斑块的过程中，会自发地在细胞外液中聚集。现在人们普遍认为，导致细胞死亡、记忆丧失和其他 AD 特征的神经毒性剂是 Aβ中间聚集状态。然而，Aβ肽在不断产生、释放到细胞外空间，并迅速从健康的大脑中清除。巧合的是，热休克蛋白（hsp）家族的成员存在于健康细胞和体液的细胞外介质中，这使得 hsp 和 Aβ 有可能在大脑的细胞外环境中相遇和相互作用。在这篇观点和反思文章中，我们将展示我们的研究结果，即 Hsp70 的存在减轻了低分子量 Aβ 肽寡聚物的形成，从而降低了细胞毒性，这与目前对该疾病的认识相一致。我们提出，Hsp70 的存在、Aβ 寡聚物的阶段、神经毒性和 AD 的发病率之间可能存在反比关系，特别是由于 hsp 的表达和循环水平随着年龄的增长而下降。结合这些观察结果，我们提出，在衰老过程中，Hsp70s 和 Aβ 在循环脑液中的浓度变化决定了 Aβ 毒性聚集形成的控制，从而决定了神经元退化和 AD 发病率的条件。
