Characterization of histamine H3 receptors in Alzheimer's Disease brain and amyloid over-expressing TASTPM mice |
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Authors: | AD Medhurst JC Roberts J Lee CPL-H Chen SH Brown S Roman MKP Lai |
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Institution: | 1.Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Third Avenue, Harlow, Essex, UK;2.Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore;3.Dementia Research Laboratory, Department of Clinical Research, Singapore General Hospital, Singapore |
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Abstract: | Background and purpose:Histamine H3 receptor antagonists are currently being evaluated for their potential use in a number of central nervous system disorders including Alzheimer''s Disease (AD). To date, little is known about the state of H3 receptors in AD.Experimental approach:In the present study we used the radiolabelled H3 receptor antagonist 3H]GSK189254 to investigate H3 receptor binding in the amyloid over-expressing double mutant APPswe × PSI.MI46V (TASTPM) transgenic mouse model of AD and in post-mortem human AD brain samples.Key results:No significant differences in specific H3 receptor binding were observed between wild type and TASTPM mice in the cortex, hippocampus or hypothalamus. Specific 3H]GSK189254 binding was detected in sections of human medial frontal cortex from AD brains of varying disease severity (Braak stages I–VI). With more quantitative analysis in a larger cohort, we observed that H3 receptor densities were not significantly different between AD and age-matched control brains in both frontal and temporal cortical regions. However, within the AD group, 3H]GSK189254 binding density in frontal cortex was higher in individuals with more severe dementia prior to death.Conclusions and implications:The maintenance of H3 receptor integrity observed in the various stages of AD in this study is important, given the potential use of H3 antagonists as a novel therapeutic approach for the symptomatic treatment of AD. |
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Keywords: | H3 receptor Alzheimer''s Disease [3H]GSK189254 TASTPM mouse neocortex |
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