Amyloid-β as a positive endogenous regulator of release probability at hippocampal synapses

Accumulation of cerebral amyloid-beta peptide (A Beta) is essential for developing synaptic and cognitive deficits in Alzheimer's disease. However, the physiological functions of A beta, as well as the primary mechanisms that initiate early A beta-mediated synaptic dysfunctions, remain largely unknown. Here we examine the acute effects of endogenously released A beta peptides on synaptic transfer at single presynaptic terminals and synaptic connections in rodent hippocampal cultures and slices. Increasing extracellular A beta by inhibiting its degradation enhanced release probability, boosting ongoing activity in the hippocampal network. Presynaptic enhancement mediated by A beta was found to depend on the history of synaptic activation, with lower impact at higher firing rates. Notably, both elevation and reduction in A beta levels attenuated short-term synaptic facilitation during bursts in excitatory synaptic connections. These observations suggest that endogenous A beta peptides have a crucial role in activity-dependent regulation of synaptic vesicle release and might point to the primary pathological events that lead to compensatory synapse loss in Alzheimer's disease.