Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins

摘要: Aβ1–42 is a self-associating peptide whose neurotoxic derivatives are thought to play role in Alzheimer’s pathogenesis. Neurotoxicity of amyloid β protein (Aβ) has been attributed its fibrillar forms, but experiments presented here characterize neurotoxins that assemble when fibril formation inhibited. These comprise small diffusible Aβ oligomers (referred as ADDLs, for Aβ-derived ligands), which were found kill mature neurons organotypic central nervous system cultures at nanomolar concentrations. At cell surfaces, ADDLs bound trypsin-sensitive sites and surface-derived tryptic peptides blocked binding afforded neuroprotection. Germ-line knockout Fyn, tyrosine kinase linked apoptosis elevated disease, also was neuroprotective. Remarkably, neurological dysfunction evoked by occurred well advance cellular degeneration. Without lag, despite retention action potentials, inhibited hippocampal long-term potentiation, indicating an immediate impact on signal transduction. We hypothesize impaired synaptic plasticity associated memory during early stage disease severe degeneration dementia end could be caused the biphasic ligands acting upon particular neural transduction pathways.