Abstract
BackgroundAlzheimer’s disease (AD) is pathologically characterized by excessive accumulation of amyloid-beta (Aβ) fibrils within the brain and activation of astrocytes and microglial cells. In this study, we examined anti-inflammatory and anti-amyloidogenic effects of 2,4-bis(p-hydroxyphenyl)-2-butenal (HPB242), an anti-inflammatory compound produced by the tyrosine-fructose Maillard reaction.Methods12-month-old Tg2576 mice were treated with HPB242 (5 mg/kg) for 1 month and then cognitive function was assessed by the Morris water maze test and passive avoidance test. In addition, western blot analysis, Gel electromobility shift assay, immunostaining, immunofluorescence staining, ELISA and enzyme activity assays were used to examine the degree of Aβ deposition in the brains of Tg2576 mice. The Morris water maze task was analyzed using two-way ANOVA with repeated measures. Otherwise were analyzed by one-way ANOVA followed by Dunnett’s post hoc test.ResultsTreatment of HPB242 (5 mg/kg for 1 month) significantly attenuated cognitive impairments in Tg2576 transgenic mice. HPB242 also prevented amyloidogenesis in Tg2576 transgenic mice brains. This can be evidenced by Aβ accumulation, BACE1, APP and C99 expression and β-secretase activity. In addition, HPB242 suppresses the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as well as activation of astrocytes and microglial cells. Furthermore, activation of nuclear factor-kappaB (NF-κB) and signal transducer and activator of transcription 1/3 (STAT1/3) in the brain was potently inhibited by HPB242.ConclusionsThus, these results suggest that HPB242 might be useful to intervene in development or progression of neurodegeneration in AD through its anti-inflammatory and anti-amyloidogenic effects.
Highlights
Alzheimer’s disease (AD) is pathologically characterized by excessive accumulation of amyloid-beta (Aβ) fibrils within the brain and activation of astrocytes and microglial cells
Inhibition of memory impairment in Tg2576 mice by HPB242 To investigate the preventive effect of HPB242 against memory impairment and Aβ1-42 depositions in the AD model mice, we treated 12-month old Tg2576 transgenic mice with HPB242 for 1 month, and compared memory deficiency with the non-treated mice using the water maze test
The results revealed that glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) levels were significantly decreased in both the cortex and hippocampus of HPB242-treated compared with non-treated mice (Figure 4C)
Summary
Alzheimer’s disease (AD) is pathologically characterized by excessive accumulation of amyloid-beta (Aβ) fibrils within the brain and activation of astrocytes and microglial cells. Alzheimer’s disease (AD) is a fatal progressive neurodegenerative illness and the most common form of dementia [1]. Astrocytes and microglia are the major type of glial cells in the central nervous system and activation of these cells are involved in all types of neurodegenerative processes, indicating prominent remodeling in AD [11,12]. Activated astrocytes expressing glial fibrillary acidic protein (GFAP) are closely associated with AD pathology, such as Tau tangles, neuritic plaques and amyloid depositions [13]. Microglial activation is involved in neuroprotection in the early phase, but, subsequently, extensive and continuous activation of microglia results in the neuroinflammation and Aβ accumulation in AD pathology [17]
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