Spatial Memory Impairment Without Apoptosis Induced by the Combination of Beta-Amyloid Oligomers and Cerebral Ischemia Is Related to Decreased Acetylcholine Release in Rats

Abstract

Abstract. The purpose of the present study was to examine the effect of beta-amyloid (Aβ) oligomers, not the fibrils that make up Aβ plaques, on spatial memory and the cholinergic system in rats. Recently, several researchers have suggested that small assemblies of Aβ, Aβ oligomers, caused memory loss during the early stages of Alzheimer's disease without showing cell death. In the present study, the combination of Aβ oligomers and cerebral ischemia, but not cerebral ischemia alone, significantly impaired spatial memory without apoptosis in the CA1 region of the hippocampus. Donepezil, an acetylcholinesterase inhibitor, ameliorated this memory impairment. Therefore we examined acetylcholine (ACh) release from the dorsal hippocampus. A microdialysis study showed that spontaneous release of ACh was not significantly decreased by the combination of Aβ oligomers and cerebral ischemia; however, high K + -evoked ACh release was decreased. These results suggest that a combination of Aβ oligomers and cerebral ischemia induces memory impairment by cholinergic synapse dysfunction without apoptosis. This model may be useful for developing new drugs for the treatment of early-phase Alzheimer's disease.

Neuroprotective Effects of Citidine-5-diphosphocholine on Impaired Spatial Memory in a Rat Model of Cerebrovascular Dementia

“…In comparison with the report of researchers indicating the effects of CDP-choline on ischemic injury, the dose used in this report is not a low dose (9,10,23), and a previous study reported that 3 mg/kg of donepezil significantly improved the spatial memory impairment induced by the combination of β-amyloid and cerebral ischemia (30). The improvement effect of 1000 mg/kg of CDP-choline on the impaired memory by ischemia is not inferior to that that of 3 mg/kg of donepezil, which was therefore thought to be sufficient to exert the ameliorative effect on memory impairment.…”

Ameliorative Effects of Telmisartan on the Inflammatory Response and Impaired Spatial Memory in a Rat Model of Alzheimer’s Disease Incorporating Additional Cerebrovascular Disease Factors

“…Oligomeric Aβ was prepared as previously described. 8) Aβ40 and Aβ42 peptides were dissolved in a N-(2-hydroxyethyl) piperazine-N′-2-ethanesulfonic acid (HEPES)-buffered solution to a final concentration of 10 µM. They were mixed at a molar ratio of 10 : 1 of Aβ40 : Aβ42 and incubated at 37°C for 150 min (Oligomeric Aβ solution).…”

“…8) Briefly, rats were anesthetized with intraperitoneal injection of 50 mg/ kg of sodium pentobarbital (Tokyo Kasei, Tokyo, Japan) and immobilized in a stereotaxic apparatus. The bilateral vertebral arteries were electrocauterized using a bipolar coagulator (MICRO-3D; Mizuho Industrial Co., Tokyo, Japan).…”

“…8) Rats were anesthetized with sodium pentobarbital (50 mg/kg intraperitoneally (i.p.)) and placed in a stereotaxic frame (Narishige Scientific Instruments, Tokyo, Japan).…”

“…7,8) Since theses animal models reveal that administration of aggregated Aβ could induce neuronal cell death and spatial memory impairment, we have used them to evaluate the related-drug efficacy. Our pharmacological study indicates that the hypoxia treatment enhances Aβ-induced apoptosis in cultured hippocampal neurons.…”