Dynamin 1 depletion and memory deficits in rats treated with Abeta and cerebral ischemia.
Alzheimer's disease (AD) is progressive dementia with senile plaques composed of beta-amyloid (Abeta). Recent studies suggest that synaptic dysfunction is one of the earliest events in the pathogenesis of AD. Here we provide the first experimental evidence that a change in the level of dynamin 1 induced by Abeta correlates with memory impairment in vivo. We treated rats with transient cerebral ischemia with oligomeric forms of Abeta (Abeta oligomers), including dimers, trimers, and tetramers, intracerebroventricularly. The combination of Abeta oligomers and cerebral ischemia, but not cerebral ischemia alone, significantly impaired memory and decreased the level of dynamin 1, which plays a critical role in synaptic vesicle recycling, but did not affect the levels of other synaptic proteins, such as synaptophysin and synaptobrevin, in the hippocampus. Furthermore, the N-methyl-D-aspartate (NMDA) receptor antagonist memantine prevented memory impairment and dynamin 1 degradation, suggesting that these changes might be mediated by NMDA receptors. These results suggest that Abeta oligomers induce memory impairment via dynamin 1 degradation, which may imply that dynamin 1 degradation is one of the causes of synaptic dysfunction in AD.
Watanabe
Takuya
T
Department of Neuropharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan.
Iwasaki
Katsunori
K
Takasaki
Kotaro
K
Yamagata
Norito
N
Fujino
Mutsumi
M
Nogami
Ai
A
Ii
Miyuki
M
Katsurabayashi
Shutaro
S
Mishima
Kenichi
K
Fujiwara
Michihiro
M
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D034284:Dynamin I / Q000172:deficiency / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008559:Memantine / Q000494:pharmacology; D008569:Memory Disorders / Q000188:drug therapy / Q000378:metabolism*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000378:metabolism*; D055503:Protein Multimerization; D050683:R-SNARE Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism
D016229:Amyloid beta-Peptides; D018691:Excitatory Amino Acid Antagonists; D010446:Peptide Fragments; D050683:R-SNARE Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D016708:Synaptophysin; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D034284:Dynamin I; D008559:Memantine