Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
Handb Clin Neurol. 2022;184:417-438. doi: 10.1016/B978-0-12-819410-2.00022-9.
The synapse is the locus of plasticity where short-term alterations in synaptic strength are converted to long-lasting memories. In addition to the presynaptic terminal and the postsynaptic compartment, a more holistic view of the synapse includes the astrocytes and the extracellular matrix to form a tetrapartite synapse. All these four elements contribute to synapse health and are crucial for synaptic plasticity events and, thereby, for learning and memory processes. Synaptic dysfunction is a common pathogenic trait of several brain disorders. In Alzheimer's Disease, the degeneration of synapses can be detected at the early stages of pathology progression before neuronal degeneration, supporting the hypothesis that synaptic failure is a major determinant of the disease. The synapse is the place where amyloid-β peptides are generated and is the target of the toxic amyloid-β oligomers. All the elements constituting the tetrapartite synapse are altered in Alzheimer's Disease and can synergistically contribute to synaptic dysfunction. Moreover, the two main hallmarks of Alzheimer's Disease, i.e., amyloid-β and tau, act in concert to cause synaptic deficits. Deciphering the mechanisms underlying synaptic dysfunction is relevant for the development of the next-generation therapeutic strategies aimed at modifying the disease progression.
突触是可塑性的发生部位，在这里短期的突触强度变化可以转化为长期记忆。除了突触前末梢和突触后区，对突触的更全面的认识还包括星形胶质细胞和细胞外基质，它们共同构成了四联体突触。所有这四个元素都有助于突触的健康，对于突触可塑性事件以及学习和记忆过程至关重要。突触功能障碍是几种脑部疾病的常见致病特征。在阿尔茨海默病中，突触的退化可以在神经元退化之前的病理进展的早期阶段被检测到，这支持了突触衰竭是疾病的主要决定因素的假说。突触是淀粉样β肽生成的地方，也是有毒淀粉样β寡聚体的靶标。构成四联体突触的所有元素在阿尔茨海默病中都发生了改变，并可能协同导致突触功能障碍。此外，阿尔茨海默病的两个主要标志，即淀粉样β和 tau，协同作用导致突触缺陷。解析突触功能障碍的机制对于开发旨在改变疾病进展的下一代治疗策略具有重要意义。
