Alzheimer disease is a progressive neurodegenerative brain disorder that leads to major debilitating cognitive deficits. It is believed that the alterations capable of causing brain circuitry dysfunctions have a slow onset and that the full blown disease may take several years to develop. Therefore, it is important to understand the early, asymptomatic, and possible reversible states of the disease with the aim of proposing preventive and disease-modifying therapeutic strategies. It is largely unknown how amyloid ␤-peptide (A␤), a principal agent in Alzheimer disease, affects synapses in brain neurons. In this study, we found that similar to other pore-forming neurotoxins, A␤ induced a rapid increase in intracellular calcium and miniature currents, indicating an enhancement in vesicular transmitter release. Significantly, blockade of these effects by low extracellular calcium and a peptide known to act as an inhibitor of the A␤-induced pore prevented the delayed failure, indicating that A␤ blocks neurotransmission by causing vesicular depletion. This new mechanism for A␤ synaptic toxicity should provide an alternative pathway to search for small molecules that can antagonize these effects of A␤.

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Abstract. It is believed that amyloid-␤ peptide (A␤), in its aggregated-oligomeric state, constitutes one of the neurotoxic factors involved in the pathogenesis of Alzheimer's disease. With the objective of studying a potential role of the peptide on synaptic transmission, we studied the effect of soluble A␤ 1-40 on synaptic transmission in rat hippocampal neurons. Neurons incubated with 500 nM of A␤ 1-40 peptide for 3 days presented higher levels of intracellular calcium transients, as evaluated by fluorimetric techniques. These effects of A␤ were time and concentration dependent and were accompanied by increases in glutamatergic (0.8 ± 0.2 Hz to 2.9 ± 0.6 Hz), but not GABAergic, transmission. The analysis of pharmacologically isolated currents in treated neurons showed increases in both AMPA-and NMDA-mediated currents as compared to control. The effects of the peptide on the frequency of synaptic currents correlated well with increases in the number of SV2 puncta and of FM1-43 destaining, suggesting a presynaptic locus for the peptide. The data also shows that application of either A␤ or bicuculline alone for 24 h was without effects on neurotransmission. However, their co-application induced an increase in synaptic transmission which was accompanied by synchronous discharges reminiscent to those produced by pro-convulsive drugs, such as bicuculline. In conclusion, these results suggest that the soluble form of A␤ 1-40 participates in the regulation of synaptic transmission increasing excitability and producing a pre-epileptogenic state in hippocampal neurons.

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HighlightsHeart failure is associated to autonomic dysfunction of cardiovascular system characterized by sympathetic hyperactivity.Exercise intervention promotes mechanisms that restores the autonomic balance.The effects of exercise training on sympathetic nerve activity in heart failure patients have not been summarized.In patients with heart failure, exercise training reduces sympathetic nerve activity compared with non-trained patients.The quality of evidence across the studies was moderate and the heterogeneity across the studies was high.