Inhibition of Histamine H3 receptor Attenuates Neuroinflammation and Cognitive Impairments in Alzheimer’s Disease via activating CREB Pathway

Abstract

BackgroundAlzheimer's disease (AD) is an age-related neurodegenerative disease, which characterized by deposition of amyloid-β (Aβ) plaques, neurofibrillary tangles, neuronal loss, and accompanied by neuroinflammation. Neuroinflammatory processes are well acknowledged to contribute to the progression of AD pathology. Histamine H3 receptor (H3R) is a presynaptic autoreceptor regulating histamine release via negative feedback way. H3R antagonist has been reported to have anti-inflammatory efficacy. However, whether inhibition of H3R is responsible for the anti-neuroinflammation and neuroprotection on APP/PS1 Tg mice remains unclear. MethodsIn this study, microgliosis, astrogliosis, A1 type astrocytes and A2 type astrocytes in APP/PS1 Tg mice were measured by immunostaining by Iba1, GFAP, C3 and S100A10 with and without treatment of thioperamide, an H3R antagonist. Inflammatory response of APP/PS1 Tg mice and effects of thioperamide were studied by measuring levels of pro-inflammatory cytokines (tumor necrosis factor α [TNFα] and interleukin-1β [IL-1β]) and anti-inflammatory cytokines (interleukin-4 [IL-4]). Protein levels of p-CREB and p-P65 NF-kB was tested by western blot to study the mechanism of thioperamide on AD. H89 was applied to study whether the mechanism offered by thioperamide was dependent on CREB activating. The effect of thioperamide and H89 on Aβ deposition was measured by immunostaining and ELISA. The cognitive function was tested by novel object recognition, Y maze and morris water maze. ResultsInhibition of H3R by thioperamide reduced the gliosis and induced a phenotypical switch from A1 to A2 in astrocytes, and ultimately attenuated neuroinflammation in APP/PS1 Tg mice. Additionally, thioperamide rescued the decrease of cyclic AMP response element-binding protein (CREB) phosphorylation and suppressed the phosphorylated nuclear factor kappa B (NF-κB) in APP/PS1 Tg mice. H89, an inhibitor of CREB signaling, abolished these effects of thioperamide to suppress gliosis and proinflammatory cytokine release. Lastly, thioperamide alleviated the deposition of Aβ and cognitive dysfunction in APP/PS1 mice, which were both reversed by administration of H89. ConclusionsTaken together, these results suggested the H3R antagonist thioperamide improved cognitive impairment in APP/PS1 Tg mice via modulation of the CREB-mediated gliosis and inflammation inhibiting, which contributed to Aβ clearance. This study uncovered a novel mechanism involving inflammatory regulating behind the therapeutic effect of thioperamide in AD.