Previously, we found that amyloid β-protein (Aβ)1-42 exhibits neurotoxicity, while Aβ1-40 serves as an antioxidant molecule by quenching metal ions and inhibiting metal-mediated oxygen radical generation. Here, we show another neuroprotective action of nonamyloidogenic Aβ1-40 against Aβ1-42-induced neurotoxicity in culture and in vivo. Neuronal death was induced by Aβ1-42 at concentrations higher than 2 μm, which was prevented by concurrent treatment with Aβ1-40 in a dose-dependent manner. However, metal chelators did not prevent Aβ1-42-induced neuronal death. Circular dichroism spectroscopy showed that Aβ1-40 inhibited the β-sheet transformation of Aβ1-42. Thioflavin-T. assay and electron microscopy analysis revealed that Aβ1-40 inhibited the fibril formation of Aβ1-42. In contrast, Aβ1-16, Aβ25-35, and Aβ40-1 did not inhibit the fibril formation of Aβ1-42 nor prevent Aβ1-42-induced neuronal death. Aβ1-42 injection into the rat entorhinal cortex (EC) caused the hyperphosphorylation of tau on both sides of EC and hippocampus and increased the number of glial fibrillary acidic protein (GFAP)-positive astrocytes in the ipsilateral EC, which were prevented by the concurrent injection of Aβ1-40. These results indicate that Aβ1-40 protects neurons from Aβ1-42-induced neuronal damage in vitro and in vivo, not by sequestrating metals, but by inhibiting the β-sheet transformation and fibril formation of Aβ1-42. Our data suggest a mechanism by which elevated Aβ1-42/Aβ1-40 ratio accelerates the development of Alzheimer's disease (AD) in familial AD.
- Alzheimer's disease
- Amyloid β-protein
- Tau phosphorylation
ASJC Scopus subject areas
- Cellular and Molecular Neuroscience