β-Amyloid1–42Induces Neuronal Death through the p75 Neurotrophin Receptor

Authors:
  • ASAlex M. Sykes
    Alex M. Sykes
  • BFBriony Fox
    Briony Fox
  • CUClare K. Underwood
    Clare K. Underwood
  • WTWipawan Thangnipon
    Wipawan Thangnipon
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Abstract
Alzheimer's disease is characterized by the accumulation of neurotoxic amyloidogenic peptide Aβ, degeneration of the cholinergic innervation to the hippocampus (the septohippocampal pathway), and progressive impairment of cognitive function, particularly memory. Aβ is a ligand for the p75 neurotrophin receptor (p75NTR), which is best known for mediating neuronal death and has been consistently linked to the pathology of Alzheimer's disease. Here we examined whether p75NTRis required for Aβ-mediated effects. Treatment of wild-type but not p75NTR-deficient embryonic mouse hippocampal neurons with human Aβ1–42peptide induced significant cell death. Furthermore, injection of Aβ1–42into the hippocampus of adult mice resulted in significant degeneration of wild-type but not p75NTR-deficient cholinergic basal forebrain neurons, indicating that the latter are resistant to Aβ-induced toxicity. We also found that neuronal death correlated with Aβ1–42peptide-stimulated accumulation of the death-inducing p75NTRC-terminal fragment generated by extracellular metalloprotease cleavage of full-length p75NTR. Although neuronal death was prevented in the presence of the metalloprotease inhibitor TAPI-2 (tumor necrosis factor-α protease inhibitor-2), Aβ1–42-induced accumulation of the C-terminal fragment resulted from inhibition of γ-secretase activity. These results provide a novel mechanism to explain the early and characteristic loss of cholinergic neurons in the septohippocampal pathway that occurs in Alzheimer's disease.

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