Binding sites of gamma-secretase inhibitors in rodent brain: distribution, postnatal development, and effect of deafferentation

gamma-Secretase is a multimeric complex consisted of presenilins (PSs) and three other proteins. PSs appear to be key contributors for the enzymatic center, the potential target of a number of recently developed gamma-secretase inhibitors. Using radiolabeled and unlabeled inhibitors as ligands, this...

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Bibliographic Details
Published in:The Journal of neuroscience 2004-03, Vol.24 (12), p.2942-2952
Main Authors: Yan, Xiao-Xin, Li, Tong, Rominger, Cynthia M, Prakash, Shimoga R, Wong, Philip C, Olson, Richard E, Zaczek, Robert, Li, Yu-Wen
Format: Article
Language:English
Subjects:
Afferent Pathways - drug effects
Afferent Pathways - physiology
Age Factors
Amyloid Precursor Protein Secretases
Animals
Aspartic Acid Endopeptidases
Autoradiography
Binding Sites - physiology
Binding, Competitive - drug effects
Binding, Competitive - physiology
Brain - embryology
Brain - growth & development
Brain - metabolism
Cellular/Molecular
Denervation
Endopeptidases - drug effects
Endopeptidases - metabolism
Enzyme Inhibitors - metabolism
Enzyme Inhibitors - pharmacokinetics
Ligands
Male
Membrane Proteins - genetics
Membrane Proteins - metabolism
Mice
Mice, Knockout
Olfactory Bulb - drug effects
Olfactory Bulb - physiology
Presenilin-1
Rats
Rats, Sprague-Dawley
Zinc Sulfate - pharmacology
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Summary:gamma-Secretase is a multimeric complex consisted of presenilins (PSs) and three other proteins. PSs appear to be key contributors for the enzymatic center, the potential target of a number of recently developed gamma-secretase inhibitors. Using radiolabeled and unlabeled inhibitors as ligands, this study was aimed to determine the in situ distribution of gamma-secretase in the brain. Characterization using PS-1 knock-out mouse embryos revealed 50 and 80% reductions of gamma-secretase inhibitor binding density in the heterozygous (PS-1(+/-)) and homozygous (PS-1-/-) embryos, respectively, relative to the wild type (PS-1(+/+)). The pharmacological profile from competition binding assays suggests that the ligands may target at the N- and C-terminal fragments of PS essential for gamma-secretase activity. In the adult rat brain, the binding sites existed mostly in the forebrain, the cerebellum, and discrete brainstem areas and were particularly abundant in areas rich in neuronal terminals, e.g., olfactory glomeruli, CA3-hilus area, cerebellar molecular layer, and pars reticulata of the substantia nigra. In the developing rat brain, diffuse and elevated expression of binding sites occurred at the early postnatal stage relative to the adult. The possible association of binding sites with neuronal terminals in the adult brain was further investigated after olfactory deafferentation. A significant decrease with subsequent recovery of binding sites was noted in the olfactory glomeruli after chemical damage of the olfactory epithelium. The findings in this study support a physiological role of PS or gamma-secretase complex in neuronal and synaptic development and plasticity.
ISSN:0270-6474
1529-2401
DOI:10.1523/JNEUROSCI.0092-04.2004