Crestini Alessio, Santilli Francesca, Martellucci Stefano, Carbone Elena, Sorice Maurizio, Piscopo Paola, Mattei Vincenzo
Department of Neuroscience, Istituto Superiore di Sanità, Rome, Italy.
Biomedicine and Advanced Technologies Rieti Center, "Sabina Universitas", Rieti, Italy.
J Alzheimers Dis. 2022;85(2):503-518. doi: 10.3233/JAD-215171.
Specific protein misfolding and aggregation are mechanisms underlying various neurodegenerative diseases such as prion disease and Alzheimer's disease (AD). The misfolded proteins are involved in prions, amyloid-β (Aβ), tau, and α-synuclein disorders; they share common structural, biological, and biochemical characteristics, as well as similar mechanisms of aggregation and self-propagation. Pathological features of AD include the appearance of plaques consisting of deposition of protein Aβ and neurofibrillary tangles formed by the hyperphosphorylated tau protein. Although it is not clear how protein aggregation leads to AD, we are learning that the cellular prion protein (PrPC) plays an important role in the pathogenesis of AD. Herein, we first examined the pathogenesis of prion and AD with a focus on the contribution of PrPC to the development of AD. We analyzed the mechanisms that lead to the formation of a high affinity bond between Aβ oligomers (AβOs) and PrPC. Also, we studied the role of PrPC as an AβO receptor that initiates an AβO-induced signal cascade involving mGluR5, Fyn, Pyk2, and eEF2K linking Aβ and tau pathologies, resulting in the death of neurons in the central nervous system. Finally, we have described how the PrPC-AβOs interaction can be used as a new potential therapeutic target for the treatment of PrPC-dependent AD.
特定蛋白质的错误折叠和聚集是多种神经退行性疾病（如朊病毒病和阿尔茨海默病（AD））的潜在机制。错误折叠的蛋白质涉及朊病毒、淀粉样β蛋白（Aβ）、tau蛋白和α-突触核蛋白紊乱；它们具有共同的结构、生物学和生化特征，以及相似的聚集和自我传播机制。AD的病理特征包括由Aβ蛋白沉积形成的斑块以及由过度磷酸化的tau蛋白形成的神经原纤维缠结。虽然尚不清楚蛋白质聚集如何导致AD，但我们了解到细胞朊蛋白（PrPC）在AD的发病机制中起重要作用。在此，我们首先研究了朊病毒和AD的发病机制，重点关注PrPC对AD发展的贡献。我们分析了导致Aβ寡聚体（AβOs）与PrPC之间形成高亲和力结合的机制。此外，我们研究了PrPC作为AβOs受体的作用，该受体启动了一个由AβOs诱导的信号级联反应，涉及mGluR5、Fyn、Pyk2和eEF2K，将Aβ和tau病理学联系起来，导致中枢神经系统神经元死亡。最后，我们描述了PrPC-AβOs相互作用如何作为治疗PrPC依赖性AD的新潜在治疗靶点。
