Characterization of histamine H3 receptors in Alzheimer's Disease brain and amyloid over-expressing TASTPM mice.
OBJECTIVE
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.


METHODS
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.


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
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.
Medhurst
A D
AD
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, Third Avenue, Harlow, Essex, UK. andy.medhurst@gsk.com
Roberts
J C
JC
Lee
J
J
Chen
C P L-H
CP
Brown
S H
SH
Roman
S
S
Lai
M K P
MK
D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001345:Autoradiography; D001552:Benzazepines / Q000494:pharmacology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D005260:Female; D054828:Histamine H3 Antagonists / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D019579:Neocortex / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D011869:Radioligand Assay; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D012720:Severity of Illness Index
D016564:Amyloid beta-Protein Precursor; D001552:Benzazepines; D054828:Histamine H3 Antagonists; D018100:Receptors, Histamine H3; D009536:Niacinamide; C521312:6-((3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy)-N-methyl-3-pyridinecarboxamide