Synaptic dysfunction in early phases of Alzheimer's Disease

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.