| Summary: | 碩士 === 國立陽明大學 === 物理治療暨輔助科技學系 === 99 === Background and purpose: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. The memory deficits are characteristics in Alzheimer's disease. Previous studies suggested that the accumulation of beta-amyloid (Aβ) protein, forming oligomer shape, lead to oxidative stress and then induce progressive synaptic failure and neuronal death (apoptosis) in hippocampus which is important for memory formation. It is noted that preconditioning intermittent hypoxia (IH) improved memory function in AD rats, as well as post-conditioning IH reversed the memory impairment in rats with brain ischemia. In addition, brain-derived neurotrophic factor (BDNF) has been suggested to play an important role in memory processing, which enhanced the synaptic plasticity. Moreover, it can also protect neurons from cell death. However, post-conditioning effects of IH on memory in rat with AD is not immediately known. The purposes of present study were to investigate the effects of intermittent hypoxia on memory and to explore the possible mechanisms in rat with AD.
Material and Methods：3-4 month old male Sprague-Dawley (SD) rats were used and randomly assigned into one of the three groups. All rats received bilateral intrahippocampal injection (F-12 and DMSO or oligomeric Aβ) into the upper portion of CA1 (two points each side). Rats in GroupⅠ(sham control, n=14, with F-12 and DMSO injection for total 20μl) rested in normoxia air for 9 days. Rats in GroupⅡ (AD-like, n=16) and GroupⅢ (AD-like+IH, n=15) received injection of oligomeric Aβ (100μM, total 20μl) to induce AD symptoms, and then received IH intervention (Group III) or rested in normoxia air (Group II) from the 2nd day to 8th day post-injection. The IH protocol (12% O2 concentration, 4 h/day for 7 days) followed our previous study. The apoptotic cells in the hippocampus were measured by the TUNEL stain. The level of BDNF was quantified by the ELISA method. The Morris water maze test, including hidden-platform test from the 2nd day to 8th day and a probe trial on 9th day during the overall experimental period, were performed for memory function. The one-way ANOVA test and two-way repeated ANOVA were used for statistic analysis. The significant level was set at 0.05.
Results: According to the results of hidden-platform water maze test, we found a significant day-by-group interaction effect for escape latency (p=0.002). The latency to find the platform was longer in rats in Group II than GroupⅠ(group effect: p<0.001) and Group III (group effect: p<0.001). In the probe trial, rats in GroupⅠand Group III spent more time and crossed more often in the target platform quadrant, which were not noted in Group II (p< 0.001). The ratio of apoptotic cells was decreased after the IH intervention (Group III) in hippocampus compared to the Group II (p=0.044). Moreover, the concentration of BDNF in hypoxia group was higher than in sham control group (p=0.020) and AD-like group (p=0.003) when normalized to sham control. However, the level of BDNF was lower but variable in AD-like group relative to the sham control (p=0.772).
Conclusion：Our results reveal that the learning and memory deficit in AD-like rats can be improved by the intermittent hypoxia intervention. Moreover, the memory improvement is possibly resulted from the BDNF induced by the IH treatment. The elevated level of BDNF may protect cells from apoptosis in hippocampus and facilitate the memory processing in rats with AD-like symptoms. The findings of our study provide possible applications of intermittent hypoxia for Alzheimer's disease.
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