Diffusible, nonfibrillar ligands derived from Aβ _1–42 are potent central nervous system neurotoxins

TLDR

Aβ 1–42 self‑assembles into neurotoxic species implicated in Alzheimer’s disease, and while fibrillar forms have been the focus, this work shows that neurotoxins also form when fibril formation is blocked. The study tests whether Aβ‑derived diffusible ligands cause early synaptic plasticity impairment and later severe neurodegeneration by targeting specific neural signaling pathways. The authors identified small diffusible Aβ oligomers (ADDLs) that kill neurons at nanomolar concentrations, bind trypsin‑sensitive surface sites, and whose neurotoxicity is mitigated by blocking binding or Fyn knockout; ADDLs induce early neurological dysfunction and rapidly inhibit hippocampal long‑term potentiation before overt cell death.

Abstract

Aβ 1–42 is a self-associating peptide whose neurotoxic derivatives are thought to play a role in Alzheimer’s pathogenesis. Neurotoxicity of amyloid β protein (Aβ) has been attributed to its fibrillar forms, but experiments presented here characterize neurotoxins that assemble when fibril formation is inhibited. These neurotoxins comprise small diffusible Aβ oligomers (referred to as ADDLs, for Aβ-derived diffusible ligands), which were found to kill mature neurons in organotypic central nervous system cultures at nanomolar concentrations. At cell surfaces, ADDLs bound to trypsin-sensitive sites and surface-derived tryptic peptides blocked binding and afforded neuroprotection. Germ-line knockout of Fyn, a protein tyrosine kinase linked to apoptosis 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 potentiation, indicating an immediate impact on signal transduction. We hypothesize that impaired synaptic plasticity and associated memory dysfunction during early stage Alzheimer’s disease and severe cellular degeneration and dementia during end stage could be caused by the biphasic impact of Aβ-derived diffusible ligands acting upon particular neural signal transduction pathways.