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Epidemiological studies suggest that cerebral ischemia may contribute to the onset and progression of Alzheimer's disease (AD). However, the mechanism by which ischemic events trigger the onset and progression of AD is poorly understood. Acetylcholine (ACh) is one of the key factors in memory, and cholinergic disturbance is a primary feature of AD. To clarify whether cholinergic disturbance is implicated in the exacerbation of AD symptoms by cerebral ischemia, memory impairment and hippocampal ACh release were examined in young (4-6 month-old) Tg2576 (Tg) mice, an AD transgenic mouse model, and in age-matched control mice with or without transient cerebral ischemia (bilateral common carotid artery occlusion: 2VO). 2VO induced memory impairment and decreased high-K(+)-evoked ACh release in Tg mice, but not in control mice. There were no differences in memory and ACh release between sham-operated control and Tg mice. Increases in β-amyloid (Aβ) 40 and Aβ42 were also observed in 2VO-operated Tg mice compared with sham-operated Tg mice, but no evident amyloid plaques or neuronal loss were found in the hippocampus of these mice. These results suggest that the memory of Tg mice is affected by 2VO, and the memory impairment may be due to cholinergic dysfunction induced by Aβ. Our findings support the idea that cerebral hypoperfusion could be a risk factor for AD.

Acetylcholine (ACh) release is one of the key factors in memory mechanisms. To clarify whether beta-amyloid (Aβ) induces a disturbance of the cholinergic system leading to memory impairment, we examined memory impairment and measured hippocampal ACh release in Tg2576 (Tg) mice that over-express the Swedish mutant amyloid precursor protein (APPsw). Furthermore, we examined Aβ burden with aging. Tg mice aged 9–11 months, but not aged 4–6 months, showed memory impairment in the 8-arm radial maze behavior test. Spontaneous ACh release was not altered in Tg mice compared with age-matched control mice at 4–6 or 9–11 months of age. On the other hand, high-K + -evoked ACh release was decreased in Tg mice aged 9–11 months, but not in Tg mice aged 4–6 months. Hippocampal Aβ increased in an age-dependent manner, but evident amyloid plaques were not found in the hippocampus of Tg mice aged 11 months. These results suggest that memory impairment in Tg mice could be attributed to cholinergic synapse dysfunction that could not be caused predominantly by amyloid plaques. Measuring ACh release in this model might be a useful index for the screening of new drugs to treat the early-phase of Alzheimer's disease.

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.