Physiological Concentrations of Amyloid Beta Regulate Recycling of Synaptic Vesicles via Alpha7 Acetylcholine Receptor and CDK5/Calcineurin Signaling

Despite the central role of amyloid beta (A beta) peptide in the etiopathogenesis of Alzheimer's disease (AD), its physiological function in healthy brain is still debated. It is well established that elevated levels of A beta induce synaptic depression and dismantling, connected with neurotoxicity and neuronal loss. Growing evidence suggests a positive regulatory effect of A beta on synaptic function and cognition; however the exact cellular and molecular correlates are still unclear. In this work, we tested the effect of physiological concentrations of A beta species of endogenous origin on neurotransmitter release in rat cortical and hippocampal neurons grown in dissociated cultures. Modulation of production and degradation of the endogenous A beta species as well as applications of the synthetic rodent A beta(40) and A beta(42) affected efficacy of neurotransmitter release from individual presynapses. Low picomolar A beta(40) and A beta(42) increased, while A beta depletion or application of low micromolar concentration decreased synaptic vesicle recycling, showing a hormetic effect of A beta on neurotransmitter release. These A beta-mediated modulations required functional alpha7 acetylcholine receptors as well as extracellular and intracellular calcium, involved regulation of CDK5 and calcineurin signaling and increased recycling of synaptic vesicles. These data indicate that A beta regulates neurotransmitter release from presynapse and suggest that failure of the normal physiological function of A beta in the fine-tuning of SV cycling could disrupt synaptic function and homeostasis, which would, eventually, lead to cognitive decline and neurodegeneration.