Role of A beta in Alzheimer's-related synaptic dysfunction

Synaptic dysfunction is closely related to Alzheimer's disease (AD) which is also recognized as synaptic disorder. beta-amyloid (A beta) is one of the main pathogenic factors in AD, which disrupts synaptic plasticity and mediates the synaptic toxicity through different mechanisms. A beta disrupts glutamate receptors, such as NMDA and AMPA receptors, which mediates calcium dyshomeostasis and damages synapse plasticity characterized by long-term potentiation (LTP) suppression and long-term depression (LTD) enhancement. As A beta stimulates and Ca2+ influx, microglial cells and astrocyte can be activated and release cytokines, which reduces glutamate uptake and further impair synapse function. Besides, extracellular glutamate accumulation induced by A beta mediates synapse toxicity resulting from reduced glutamate receptors and glutamate spillovers. A beta also mediates synaptic dysfunction by acting on various signaling pathways and molecular targets, disrupting mitochondria and energy metabolism. In addition, A beta overdeposition aggravates the toxic damage of hyperphosphorylated tau to synapses. Synaptic dysfunction plays a critical role in cognitive impairment of AD. The review addresses the possible mechanisms by which A beta mediates AD-related synaptic impairment from distant perspectives.