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阿尔茨海默病与“缺失”假说:β-淀粉样蛋白对内皮细胞和神经元毒性的机制

Alzheimer's disease and the 'ABSENT' hypothesis: mechanism for amyloid beta endothelial and neuronal toxicity.

作者信息

Roy Samir, Rauk Arvi

机构信息

Department of Chemistry, University of Calgary, 2500 University Drive, NW Alberta, Canada T2N 1N4.

出版信息

Med Hypotheses. 2005;65(1):123-37. doi: 10.1016/j.mehy.2004.08.031.

Abstract

Alzheimer's disease [AD] is the most common cause of dementia among people age 65 and older. One of the biggest stumbling blocks in developing effective drug therapy for Alzheimer's disease has been the lack of a comprehensive hypothesis that explains the mechanism behind all of the histopathological changes seen in patients suffering from Alzheimer's disease. An overview of the currently popular 'amyloid' and 'vascular' hypotheses for AD demonstrates that neither hypothesis by itself can explain all the known histopathological and biochemical lesions seen in Alzheimer's disease. The paper presents a hypothesis that tries to explain the mechanism behind almost all the histopathological changes, and varying clinical manifestations seen in both diagnosed AD and Vascular Dementia [VaD]. The new hypothesis is based on the known dual toxicity of beta amyloid to both vascular and neuronal tissues, their synergy and the resultant net effect on the onset and progression of AD. The new hypothesis therefore will be known as the Amyloid Beta Synergistic Endothelial and Neuronal Toxicity [ABSENT] hypothesis. The ABSENT hypothesis will try to show the common chemical mechanism behind almost all of the pathological changes seen in AD. According to the ABSENT hypothesis, beta amyloid itself generates all the free radicals that cause both vascular dysfunction and the neuronal damage seen in AD. The chemical mechanism proposed is based on evidence from physical chemistry experiments, calculations as well as in vitro/in vivo experiments. The ABSENT hypothesis does not favor one mode of beta amyloid-induced brain damage over the other, rather it considers the net effects of the neuronal stress/damage caused by both the cerebrovascular dysfunction and direct neurotoxicity caused by beta amyloid. The hypothesis states that each patient has a different balance of predisposing factors that modulate the extent of neurotoxicity and cerebrovascular dysfunction caused by beta amyloid and thereby explains the wide range and mixed nature of damage and dysfunction seen in the studies done on patients diagnosed with AD, VaD or 'mixed dementias'. According to the hypothesis, beta amyloid peptides are necessary if not sufficient to cause AD, VaD and mixed senile dementias. The hypothesis, therefore, proposes the term Beta Amyloid Dementias [BAD] to describe the conditions currently covered by the diagnoses of 'AD', 'VaD' and 'Mixed [senile] Dementias'. Finally, the ABSENT hypothesis tries to put forth a direct chemical mechanism behind the apparent synergy and increased association between old age, pre- and coexisting vascular disease, diabetes and AD.

摘要

阿尔茨海默病[AD]是65岁及以上人群中痴呆症最常见的病因。在为阿尔茨海默病开发有效药物治疗方法的过程中,最大的障碍之一是缺乏一个全面的假说,来解释阿尔茨海默病患者所出现的所有组织病理学变化背后的机制。对目前流行的AD“淀粉样蛋白”和“血管”假说的概述表明,这两种假说单独都无法解释阿尔茨海默病中所有已知的组织病理学和生化损伤。本文提出了一个假说,试图解释几乎所有组织病理学变化以及在确诊的AD和血管性痴呆[VaD]中出现的不同临床表现背后的机制。这个新假说基于β淀粉样蛋白对血管和神经组织已知的双重毒性、它们的协同作用以及对AD发病和进展的最终净效应。因此,这个新假说将被称为淀粉样β蛋白协同内皮和神经毒性[ABSENT]假说。ABSENT假说将试图揭示AD中几乎所有病理变化背后的共同化学机制。根据ABSENT假说,β淀粉样蛋白本身产生了所有导致AD中血管功能障碍和神经损伤的自由基。所提出的化学机制基于物理化学实验、计算以及体外/体内实验的证据。ABSENT假说并不偏袒β淀粉样蛋白诱导脑损伤的一种模式而轻视另一种,相反,它考虑了脑血管功能障碍和β淀粉样蛋白引起的直接神经毒性所导致的神经应激/损伤的净效应。该假说指出,每位患者具有不同的易感因素平衡,这些因素调节β淀粉样蛋白引起的神经毒性和脑血管功能障碍的程度,从而解释了在对被诊断为AD、VaD或“混合性痴呆”的患者所做研究中看到的广泛且混合的损伤和功能障碍性质。根据该假说,β淀粉样肽即使不足以导致AD、VaD和混合性老年痴呆,也是其发病所必需的。因此,该假说提出用“β淀粉样蛋白痴呆症”[BAD]一词来描述目前涵盖在“AD”、“VaD”和“混合性[老年]痴呆症”诊断中的病症。最后,ABSENT假说试图提出一个直接的化学机制,来解释老年、既往和并存的血管疾病、糖尿病与AD之间明显的协同作用和更高的关联性。

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