Sulatsky Maksim I, Stepanenko Olga V, Stepanenko Olesya V, Povarova Olga I, Kuznetsova Irina M, Turoverov Konstantin K, Sulatskaya Anna I
Laboratory of Cell Morphology, Institute of Cytology of the Russian Academy of Sciences, 4 Tikhoretsky ave., 194064 St. Petersburg, Russia.
Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology of the Russian Academy of Sciences, 4 Tikhoretsky ave., 194064 St. Petersburg, Russia.
J Adv Res. 2025 Apr;70:45-62. doi: 10.1016/j.jare.2024.04.018. Epub 2024 Apr 19.
The accumulation of ordered protein aggregates, amyloid fibrils, accompanies various neurodegenerative diseases (such as Parkinson's, Huntington's, Alzheimer's, etc.) and causes a wide range of systemic and local amyloidoses (such as insulin, hemodialysis amyloidosis, etc.). Such pathologies are usually diagnosed when the disease is already irreversible and a large amount of amyloid plaques have accumulated. In recent years, new drugs aimed at reducing amyloid levels have been actively developed. However, although clinical trials have demonstrated a reduction in amyloid plaque size with these drugs, their effect on disease progression has been controversial and associated with significant side effects, the reasons of which are not fully understood.
The purpose of this review is to summarize extensive array of data on the effect of exogenous and endogenous factors (physico-mechanical effects, chemical effects of low molecular weight compounds, macromolecules and their complexes) on the structure and pathogenicity of mature amyloids for proposing future directions of the development of effective and safe anti-amyloid therapeutics.
Our analysis show that destruction of amyloids is in most cases incomplete and degradation products often retain the properties of amyloids (including high and sometimes higher than fibrils, cytotoxicity), accelerate amyloidogenesis and promote the propagation of amyloids between cells. Probably, the appearance of protein aggregates, polymorphic in structure and properties (such as amorphous aggregates, fibril fragments, amyloid oligomers, etc.), formed because of uncontrolled degradation of amyloids, may be one of the reasons for the ambiguous effectiveness and serious side effects of the anti-amyloid drugs. This means that all medications that are supposed to be used both for degradation and slow down the fibrillogenesis must first be tested on mature fibrils: the mechanism of drug action and cytotoxic, seeding, and infectious activity of the degradation products must be analyzed.
有序蛋白质聚集体——淀粉样纤维的积累与多种神经退行性疾病（如帕金森病、亨廷顿舞蹈症、阿尔茨海默病等）相关，并导致多种全身性和局部性淀粉样变性（如胰岛素、血液透析淀粉样变性等）。此类病症通常在疾病已不可逆转且大量淀粉样斑块已经积累时才被诊断出来。近年来，旨在降低淀粉样蛋白水平的新药得到了积极研发。然而，尽管临床试验已证明这些药物可使淀粉样斑块尺寸减小，但其对疾病进展的影响仍存在争议，且伴有显著副作用，其原因尚未完全明确。
本综述的目的是总结关于外源性和内源性因素（物理机械效应、低分子量化合物、大分子及其复合物的化学效应）对成熟淀粉样蛋白结构和致病性影响的大量数据，以提出有效且安全的抗淀粉样蛋白疗法的未来发展方向。
我们的分析表明，在大多数情况下，淀粉样蛋白的破坏并不完全，降解产物往往保留淀粉样蛋白的特性（包括高于纤维状淀粉样蛋白、有时甚至更高的细胞毒性），加速淀粉样蛋白生成并促进淀粉样蛋白在细胞间的传播。可能由于淀粉样蛋白的无控制降解而形成的结构和性质多态的蛋白质聚集体（如无定形聚集体、纤维片段、淀粉样寡聚体等）的出现，可能是抗淀粉样蛋白药物疗效不明确和出现严重副作用的原因之一。这意味着所有旨在用于降解和减缓纤维形成的药物都必须首先在成熟纤维上进行测试：必须分析药物作用机制以及降解产物的细胞毒性、种子形成和感染活性。
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