Abstract
Resveratrol, a natural polyphenol found in red wine, has wide spectrum of pharmacological properties including antioxidative and antiaging activities. Beta amyloid peptides (Aβ) are known to involve cognitive impairment, neuroinflammatory and apoptotic processes in Alzheimer's disease (AD). Activation of cAMP and/or cGMP activities can improve memory performance and decrease the neuroinflammation and apoptosis. However, it remains unknown whether the memory enhancing effect of resveratrol on AD associated cognitive disorders is related to the inhibition of phosphodiesterase 4 (PDE4) subtypes and subsequent increases in intracellular cAMP and/or cGMP activities. This study investigated the effect of resveratrol on Aβ1-42-induced cognitive impairment and the participation of PDE4 subtypes related cAMP or cGMP signaling. Mice microinfused with Aβ1-42 into bilateral CA1 subregions displayed learning and memory impairment, as evidenced by reduced memory acquisition and retrieval in the water maze and retention in the passive avoidance tasks; it was also significant that neuroinflammatory and pro-apoptotic factors were increased in Aβ1-42-treated mice. Aβ1-42-treated mice also increased in PDE4A, 4B and 4D expression, and decreased in PKA level. However, PKA inhibitor H89, but not PKG inhibitor KT5823, prevented resveratrol's effects on these parameters. Resveratrol also reversed Aβ1-42-induced decreases in phosphorylated cAMP response-element binding protein (pCREB), brain derived neurotrophic factor (BDNF) and anti-apoptotic factor BCl-2 expression, which were reversed by H89. These findings suggest that resveratrol reversing Aβ-induced learning and memory disorder may involve the regulation of neuronal inflammation and apoptosis via PDE4 subtypes related cAMP-CREB-BDNF signaling.
Highlights
Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by accumulation of beta amyloid peptides (Aβ) and neurofibrillary tangles (NFTs) in the brain, widespread cortical neuronal loss and the progressive memory impairment [1]
To determine whether resveratrol reversed memory impairment caused by Aβ 42, we examined memory performance in the Morris water maze test in mice treated with Aβ 42 in the presence or absence of resveratrol
The results showed that vehicle-treated Aβ group mice took longer to reach the platform in block 6 compared with vehicletreated sham group mice (p < 0.01), these were reversed by resveratrol at 40 mg/kg (RES40) for 21 days, the latencies to reach the platform for RES40-treated Aβ mice were significantly shorter than that of the vehicle-treated Aβ group in the 6th block (p < 0.05; Figure 1A)
Summary
Alzheimer’s Disease (AD) is a neurodegenerative disorder characterized by accumulation of beta amyloid peptides (Aβ) and neurofibrillary tangles (NFTs) in the brain, widespread cortical neuronal loss and the progressive memory impairment [1]. The accumulation of Aβ, Aβ 1-40 (Aβ 40) and Aβ1-42 (Aβ 42), and their deposition in insoluble plaques are the major neuropathological hallmarks of AD. Injection of plaques of Aβ 42 isolated from AD brains into different brain regions of rats including hippocampus and cortex results in neurodegenerative response, such as neuroinflammation and cell apoptosis [3]. The contradictory results argue the role of Aβ in the onset of AD [4], inhibition of cerebral Aβ 42 seems necessary and sufficient for preventing memory impairment in the early stage of AD. It is urgent to identify new targets and develop novel anti-aging agents against AD
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