Synapse dysfunction and loss are hallmarks of neurodegenerative diseases that correlate with cognitive decline. However, the mechanisms and therapeutic strategies to prevent or reverse synaptic damage remain elusive. In this Review, we discuss recent advances in understanding the molecular and cellular pathways that impair synapses in neurodegenerative diseases, including the effects of protein aggregation and neuroinflammation. We also highlight emerging therapeutic approaches that aim to restore synaptic function and integrity, such as enhancing synaptic plasticity, preventing synaptotoxicity, modulating neuronal network activity and targeting immune signalling. We discuss the preclinical and clinical evidence for each strategy, as well as the challenges and opportunities for developing effective synapse-targeting therapeutics for neurodegenerative diseases.
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