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 x 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.