Decoding the mechanisms of amyloid-β in synaptic toxicity

Amyloid-β (Aβ) aggregation is considered a central hallmark in the pathophysiology of Alzheimer's disease (AD). Aβ protein aggregates disrupt synaptic architecture, calcium homeostasis, and mitochondrial function, leading to excitotoxicity and synaptic plasticity deficits. Animal models and human studies reveal that Aβ-induced alterations in synaptic activity and neuronal circuit function appear before irreversible damage and the onset of cognitive impairment. This review examines the multifaceted effects of Aβ on synaptic and neuronal circuits across its distinct aggregation states, including monomeric, oligomeric, protofibrillar, and fibrillar forms. Its novelty lies in providing a comprehensive map of Aβ-induced mechanisms that disrupt neuronal electrical function, based on electrophysiological evidence from neuronal cultures, animal models, and patient studies, with a particular focus on preclinical stages of cognitive decline. We suggest that the Aβ-induced synaptic toxicity could serve, first, as a complementary biomarker of brain deterioration and second, as a readout of current AD therapies. This could potentially lead to better outcomes in AD treatments.