Study On The Basis And Experimental Therapy Of Alzheimer 's Disease

Aquaporin-4 (AQP4) is mainly located in astrocyte foot processes and ependyma. In addition to its fast-mediated transport of water, AQP4 is also involved in regulating other important physiological functions of astrocyte, such as maintaining balance of ions in extracellular fluids, influencing neuronal activity and synaptic plasticity, and modulating adult neurogenesis. Several studies in the last few years indicate that AQP4 plays an important role in the pathological process of AD. The in vitro experiments have shown that AQP4 mediates astrocyte response to Ap. The in vivo evidence is also indicated that AQP4 could clear Aβ out of brain by the glymphatic system. However, whether AQP4 gene insufficiency can affect cognitive function, Aβ deposition and other AD-like pathological changes and its mechanisms are still unclear.In this study, AQP4 knockout-APP/PS1 transgenic mice were established and raised to 12 months of age by crossing AQP4 knockout mice with APP/PS1 transgenic littermates. Learning and memory, plaque burden, levels of soluble Aβ, gliosis and synapse loss in these mice were observed. We found that AQP4 gene knockout results in more severe spatial learning and memory declines, increases in soluble Aβ and Aβ deposition, and synapse loss, but attenuated astroglial and microglial reactivity in APP/PS1 transgenic mice. This study reveals that AQP4 gene insufficiency excerbrates AD-like pathological changes in APP/PS1 mice, indicating that AQP4 may be a new therapeutic target for AD.Regular physical exercise can reduce or even prevent mild cognitive decline in older people as well as in aged rodents or in AD model mice. However, there are contradictory conclusions about the therapeutic efficacy of aerobic exercise against moderate-to-severe cognitive impairment. The present study evaluated the combined treatment effects of aerobic exercise and antioxidative stress on moderate-stage Alzheimer’s disease (AD). Ten-month-old APP/PS1 mice were given antioxidative treatment with acetylcysteine, along with aerobic exercise for 6 weeks. Spatial learning and memory were tested using the Morris water maze, and β-amyloid (Aβ) plaque deposits in the forebrain were quantified by Thioflavin-S staining. Levels of soluble Aβ1-42, β-secretase enzyme, y-secretase enzyme, oxidative and antioxidant stress markers nitrotyrosine and peroxiredoxin-1, glial markers glial fibrillary acidic protein and ionized calcium-binding adaptor molecule 1, and synaptic protein synaptophysin in the hippocampus were all measured by western blotting and/or immunohistochemistry. Results showed that APP/PS1 mice had severe declines in spatial learning and memory compared with their wild-type littermates, which were not attenuated by aerobic exercise combined with antioxidative treatment. The pathologic analysis revealed that Aβ deposition and production, oxidative stress, glial inflammation, and synaptic loss were not mitigated in the brain of exercised APP/PS1 mice, compared with the sedentary APP/PS1 animals. These results reveal that a combined treatment of aerobic exercise plus antioxidative stress does not counteract pathophysiology in the moderate- or mid-stages of AD.