Neurotrophic and Neurotoxic Effects of Amyloid β Protein: Reversal by Tachykinin Neuropeptides

TLDR

Amyloid β protein accumulates in Alzheimer’s disease brains, but its pathogenic role remains unclear. In vitro, amyloid β is neurotrophic to undifferentiated hippocampal neurons at low doses but becomes neurotoxic to mature neurons at higher doses, inducing dendritic/axonal retraction and death; these effects are mediated by residues 25–35, are mimicked by tachykinin antagonists, and are fully reversed by tachykinin agonists, suggesting a dual role that may contribute to neuronal degeneration in Alzheimer’s disease.

Abstract

The amyloid β protein is deposited in the brains of patients with Alzheimer's disease but its pathogenic role is unknown. In culture, the amyloid β protein was neurotrophic to undifferentiated hippocampal neurons at low concentrations and neurotoxic to mature neurons at higher concentrations. In differentiated neurons, amyloid β protein caused dendritic and axonal retraction followed by neuronal death. A portion of the amyloid β protein (amino acids 25 to 35) mediated both the trophic and toxic effects and was homologous to the tachykinin neuropeptide family. The effects of the amyloid β protein were mimicked by tachykinin antagonists and completely reversed by specific tachykinin agonists. Thus, the amyloid β protein could function as a neurotrophic factor for differentiating neurons, but at high concentrations in mature neurons, as in Alzheimer's disease, could cause neuronal degeneration.