Amyloid beta-protein (Abeta)1-40 protects neurons from damage induced by Abeta1-42 in culture and in rat brain.
Previously, we found that amyloid beta-protein (Abeta)1-42 exhibits neurotoxicity, while Abeta1-40 serves as an antioxidant molecule by quenching metal ions and inhibiting metal-mediated oxygen radical generation. Here, we show another neuroprotective action of nonamyloidogenic Abeta1-40 against Abeta1-42-induced neurotoxicity in culture and in vivo. Neuronal death was induced by Abeta1-42 at concentrations higher than 2 microm, which was prevented by concurrent treatment with Abeta1-40 in a dose-dependent manner. However, metal chelators did not prevent Abeta1-42-induced neuronal death. Circular dichroism spectroscopy showed that Abeta1-40 inhibited the beta-sheet transformation of Abeta1-42. Thioflavin-T assay and electron microscopy analysis revealed that Abeta1-40 inhibited the fibril formation of Abeta1-42. In contrast, Abeta1-16, Abeta25-35, and Abeta40-1 did not inhibit the fibril formation of Abeta1-42 nor prevent Abeta1-42-induced neuronal death. Abeta1-42 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 Abeta1-40. These results indicate that Abeta1-40 protects neurons from Abeta1-42-induced neuronal damage in vitro and in vivo, not by sequestrating metals, but by inhibiting the beta-sheet transformation and fibril formation of Abeta1-42. Our data suggest a mechanism by which elevated Abeta1-42/Abeta1-40 ratio accelerates the development of Alzheimer's disease (AD) in familial AD.
Zou
Kun
K
Department of Dementia Research, National Institute for Longevity Sciences, Aichi, Japan.
Kim
Daesung
D
Kakio
Atsuko
A
Byun
Kyunghee
K
Gong
Jian-Sheng
JS
Kim
Jaewoo
J
Kim
Myeungju
M
Sawamura
Naoya
N
Nishimoto
Sei-ichi
S
Matsuzaki
Katsumi
K
Lee
Bonghee
B
Yanagisawa
Katsuhiko
K
Michikawa
Makoto
M
D016229:Amyloid beta-Peptides / Q000494:pharmacology* / Q000633:toxicity*; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects; D001921:Brain / Q000166:cytology / Q000187:drug effects*; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018728:Entorhinal Cortex / Q000166:cytology / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology* / Q000633:toxicity*; D010766:Phosphorylation / Q000187:drug effects; D017433:Protein Structure, Secondary / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D018696:Neuroprotective Agents; D010446:Peptide Fragments; C433241:amyloid beta-protein (1-16); C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); D016875:tau Proteins