AGE-DEPENDENT EFFECTS OF VALPROIC ACID IN ALZHEIMER'S DISEASE (AD) MICE ARE ASSOCIATED WITH NERVE GROWTH FACTOR (NGF) REGULATION

摘要

Alzheimer's disease (AD) is a progressive neurode-generative disease that causes cognitive impairment. Major pathophysiological AD characteristics include numerous senile plaque, neurofibrillary tangles, and neuronal loss in the specific regions of patients' brains. In this study, we aimed to understand disease stage-dependent regulation of histone modification for the expression of specific markers in plasma and the hippocampus of in vivo AD model. Since the control of histone acetylation/deacetylation has been studied as one of major epigenetic regulatory mechanisms for specific gene expression, we detected the effects of histone deacetylase (HDAC) inhibitor on marker expression and neuroprotection in in vivo AD model mice. We determined the effects of valproic acid (VPA, HDAC inhibitor), on the levels of cytokines, secreted form of APP (sAPP), nerve growth factor (NGF), and cognitive function in Tg6799 AD mice in three different disease stages (1 month: pre-symptomatic; 5 months: early symptomatic; and 10 months: late-symptomatic stages). VPA decreased the mRNA levels of nuclear factor kappaB (NF-kappaB) and IL-1R in the plasma of Tg6799 mice compared to vehicle control at 10 months of age. VPA increased the protein levels of NGF in the hippocampus of Tg6799 mice at 5 and 10 months of age. In addition, VPA decreased escape latencies of Tg6799 mice at 5 and 10 months of age in Morris water maze assessment. Taken together, HDAC inhibition is a promising therapeutic target for AD and it needs to be considered in n age-dependent and/or stage-dependent manner.