DIFFUSIBLE, NONFIBRILLAR LIGANDS DERIVED FROM A-BETA(1-42) ARE POTENTCENTRAL-NERVOUS-SYSTEM NEUROTOXINS

A beta(1-42) is a self-associating peptide whose neurotoxic derivative s are thought to play a role in Alzheimer's pathogenesis. Neurotoxicit y of amyloid beta protein (A beta) has been attributed to its fibrilla r forms, but experiments presented here characterize neurotoxins that assemble when fibril formation is inhibited. These neurotoxins compris e small diffusible A beta oligomers (referred to as ADDLs, for A beta- derived diffusible ligands), which were found to kill mature neurons i n organotypic central nervous system cultures at nanomolar concentrati ons. At cell surfaces, ADDLs bound to trypsin-sensitive sites and surf ace-derived tryptic peptides blocked binding and afforded neuroprotect ion. Germ-line knockout of Fyn, a protein tyrosine kinase linked to ap optosis and elevated in Alzheimer's disease, also was neuroprotective. Remarkably, neurological dysfunction evoked by ADDLs occurred well in advance of cellular degeneration. Without lag, and despite retention of evoked action potentials, ADDLs inhibited hippocampal long-term pot entiation, indicating an immediate impact on signal transduction. We h ypothesize that impaired synaptic plasticity and associated memory dys function during early stage Alzheimer's disease and severe cellular de generation and dementia during end stage could be caused by the biphas ic impact of A beta-derived diffusible ligands acting upon particular neural signal transduction pathways.