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 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.
Yan
Xiao-Xin
XX
Bristol-Myers Squibb Company, Pharmaceutical Research Institute, Neuroscience Drug Discovery, Wallingford, Connecticut 06492, USA.
Li
Tong
T
Rominger
Cynthia M
CM
Prakash
Shimoga R
SR
Wong
Philip C
PC
Olson
Richard E
RE
Zaczek
Robert
R
Li
Yu-Wen
YW
D000344:Afferent Pathways / Q000187:drug effects / Q000502:physiology; D000367:Age Factors; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D001345:Autoradiography; D001665:Binding Sites / Q000502:physiology; D001667:Binding, Competitive / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D003714:Denervation; D010450:Endopeptidases / Q000187:drug effects* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009830:Olfactory Bulb / Q000187:drug effects / Q000502:physiology; D053764:Presenilin-1; D051381:Rats; D017207:Rats, Sprague-Dawley; D019287:Zinc Sulfate / Q000494:pharmacology
D004791:Enzyme Inhibitors; D008024:Ligands; D008565:Membrane Proteins; D053764:Presenilin-1; D019287:Zinc Sulfate; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse