Yan Xiao-Xin, Xiong Kun, Luo Xue-Gang, Struble Robert G, Clough Richard W
Department of Anatomy, Southern Illinois University School of Medicine, Carbondale, Illinois 62901, USA.
J Comp Neurol. 2007 Mar 1;501(1):52-69. doi: 10.1002/cne.21239.
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.
脑代谢减退、线粒体功能障碍以及β-淀粉样肽（Aβ）蓄积是阿尔茨海默病（AD）的典型特征。β-分泌酶（BACE）是淀粉样蛋白生成的前提条件，且在散发性AD中上调。为了探究Aβ生成受神经元活动和/或氧化代谢调节的潜在体内机制，我们比较了正常和功能缺失的成年大鼠嗅球中BACE的表达与细胞色素c氧化酶（CO）或琥珀酸脱氢酶（SDH）的活性。在正常嗅球中，BACE主要在肾小球层表达，但单个肾小球内的标记强度差异很大。单个肾小球中BACE标记强度与CO或SDH活性之间存在强烈的负相关。单侧鼻孔闭塞导致剥夺侧嗅球的肾小球BACE标记相对于未剥夺侧升高，这与相同解剖位置的CO活性降低相关。通过测量嗅球提取物中淀粉样前体蛋白的蛋白水平升高、酶活性和β位点裂解产物，证实了BACE标记增强。我们的研究结果揭示了生理神经元活动对BACE表达的负调节作用，以及嗅觉通路第一个突触处BACE表达与氧化代谢之间固有的负相关。结果表明BACE在突触功能和可塑性中的生物学作用，以及神经元活动或代谢降低可能导致突触终末淀粉样蛋白过度产生的潜在机制。
