Beta-amyloid causes depletion of synaptic vesicles leading to neurotransmission failure.
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 beta-peptide (A beta), a principal agent in Alzheimer disease, affects synapses in brain neurons. In this study, we found that similar to other pore-forming neurotoxins, A beta 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 beta-induced pore prevented the delayed failure, indicating that A beta blocks neurotransmission by causing vesicular depletion. This new mechanism for A beta synaptic toxicity should provide an alternative pathway to search for small molecules that can antagonize these effects of A beta.
Parodi
Jorge
J
Laboratory of Neurophysiology, Department of Physiology, University of Concepción, Edmundo Larenas S/N, P.O. Box 160-C, Concepción, Chile.
Sepúlveda
Fernando J
FJ
Roa
Jorge
J
Opazo
Carlos
C
Inestrosa
Nibaldo C
NC
Aguayo
Luis G
LG
D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D051379:Mice; D009474:Neurons / Q000473:pathology / Q000502:physiology*; D009498:Neurotoxins / Q000378:metabolism / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013572:Synaptic Vesicles / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D002118:Calcium