beta-Secretase expression in normal and functionally deprived rat olfactory bulbs: inverse correlation with oxidative metabolic activity.
Cerebral hypometabolism, mitochondrial dysfunction, and beta-amyloid peptide (Abeta) accumulation are well-characterized manifestations of Alzheimer's disease (AD). beta-Secretase (BACE) is a prerequisite for amyloidogenesis, and it is up-regulated in sporadic AD. To explore a potential in vivo mechanism by which Abeta production is modulated by neuronal activity and/or oxidative metabolism, we compared BACE expression with cytochrome c oxidase (CO) or succinic dehydrogenase (SDH) activity in normal and functionally deprived adult rat olfactory bulb. In normal bulb, BACE was expressed predominantly in the glomerular layer, but labeling intensity within individual glomeruli varied substantially. A strong negative correlation existed between BACE labeling intensity and CO or SDH activity among individual glomeruli. Unilateral naris occlusion resulted in elevated glomerular BACE labeling in the deprived bulbs relative to the nondeprived counterparts, which was correlated with decreased CO activity in the same anatomic location. Enhanced BACE labeling was confirmed by measurements of elevated protein levels, enzymatic activity, and beta-site cleavage products of amyloid precursor protein in bulb extracts. Our findings reveal a negative regulation of BACE expression by physiological neuronal activity and an intrinsic inverse correlation between BACE expression and oxidative metabolism at the first synapse on the olfactory pathway. The results point to a biological role of BACE in synapse function and plasticity as well as a potential mechanism whereby reduced neuronal activity or metabolism could lead to amyloid overproduction in synaptic terminals.
Yan
Xiao-Xin
XX
Department of Anatomy, Southern Illinois University School of Medicine, Carbondale, Illinois 62901, USA. xyan@siumed.edu
Xiong
Kun
K
Luo
Xue-Gang
XG
Struble
Robert G
RG
Clough
Richard W
RW
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D003578:Cytochrome-c Peroxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D006031:Glycosylation; D007150:Immunohistochemistry; D008297:Male; D015508:Nasal Obstruction / Q000201:enzymology* / Q000378:metabolism; D009830:Olfactory Bulb / Q000201:enzymology* / Q000378:metabolism; D010084:Oxidation-Reduction; D053763:Presenilins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013385:Succinate Dehydrogenase / Q000378:metabolism; D014018:Tissue Distribution; D015854:Up-Regulation
D016564:Amyloid beta-Protein Precursor; D053763:Presenilins; D003578:Cytochrome-c Peroxidase; D013385:Succinate Dehydrogenase; D053829:Amyloid Precursor Protein Secretases