Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.
Institut de Chimie, UMR 7177, CNRS, Université de Strasbourg, Strasbourg, France.
J Alzheimers Dis. 2021;83(1):23-41. doi: 10.3233/JAD-201556.
The cause of Alzheimer's disease (AD) is incompletely defined. To date, no mono-causal treatment has so far reached its primary clinical endpoints, probably due to the complexity and diverse neuropathology contributing to the neurodegenerative process. In the present paper, we describe the plausible etiological role of copper (Cu) imbalance in the disease. Cu imbalance is strongly associated with neurodegeneration in dementia, but a complete biochemical etiology consistent with the clinical, chemical, and genetic data is required to support a causative association, rather than just correlation with disease. We hypothesize that a Cu imbalance in the aging human brain evolves as a gradual shift from bound metal ion pools, associated with both loss of energy production and antioxidant function, to pools of loosely bound metal ions, involved in gain-of-function oxidative stress, a shift that may be aggravated by chemical aging. We explain how this may cause mitochondrial deficits, energy depletion of high-energy demanding neurons, and aggravated protein misfolding/oligomerization to produce different clinical consequences shaped by the severity of risk factors, additional comorbidities, and combinations with other types of pathology. Cu imbalance should be viewed and integrated with concomitant genetic risk factors, aging, metabolic abnormalities, energetic deficits, neuroinflammation, and the relation to tau, prion proteins, α-synuclein, TAR DNA binding protein-43 (TDP-43) as well as systemic comorbidity. Specifically, the Amyloid Hypothesis is strongly intertwined with Cu imbalance because amyloid-β protein precursor (AβPP)/Aβ are probable Cu/Zn binding proteins with a potential role as natural Cu/Zn buffering proteins (loss of function), and via the plausible pathogenic role of Cu-Aβ.
阿尔茨海默病（AD）的病因尚未完全明确。迄今为止，尚无单一病因的治疗方法能达到主要的临床终点，这可能是由于导致神经退行性过程的因素复杂且多样。在本文中，我们描述了铜（Cu）失衡在该疾病中可能的病因作用。Cu 失衡与痴呆症中的神经退行性变密切相关，但需要完整的生化病因来支持因果关系，而不仅仅是与疾病的相关性。我们假设，衰老人脑内的 Cu 失衡可能是从与能量产生和抗氧化功能丧失相关的结合金属离子池逐渐转变为与获得性功能氧化应激相关的松散结合金属离子池的结果，这种转变可能因化学衰老而加剧。我们解释了这如何导致线粒体缺陷、高能需求神经元的能量耗竭以及加剧的蛋白质错误折叠/寡聚化，从而产生不同的临床后果，这些后果受危险因素严重程度、其他合并症以及与其他类型病理学的组合的影响。Cu 失衡应与同时存在的遗传风险因素、衰老、代谢异常、能量不足、神经炎症以及与 tau、朊病毒蛋白、α-突触核蛋白、TAR DNA 结合蛋白-43（TDP-43）的关系以及全身合并症一起进行观察和整合。具体而言，淀粉样蛋白假说与 Cu 失衡密切相关，因为淀粉样前体蛋白（AβPP）/Aβ可能是 Cu/Zn 结合蛋白，具有作为天然 Cu/Zn 缓冲蛋白的潜在作用（功能丧失），并且通过可能的 Cu-Aβ 致病作用。
