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Mitochondrial respiratory inhibition and oxidative stress elevate β-secretase (BACE1) proteins and activity in vivo in the rat retina

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Abstract

Cerebral hypometabolism, oxidative stress and β-amyloid peptide (Aβ) accumulation are key pathological events in Alzheimer’s disease (AD). Beta-secretase (BACE, i.e., BACE1), a prerequisite for Aβ genesis, is elevated in sporadic AD. Recent studies show BACE upregulation in experimental conditions likely associated with energy insufficiency and/or oxidative stress. We investigated the effect of sublethal doses of mitochondrial respiratory inhibitors and potential endogenous oxidative substances on BACE expression in vivo using the retina as a model. Retinas were analyzed biochemically and anatomically 48 h following intraocular applications of mitochondrial complex I, II and IV inhibitors including rotenone, 3-nitropropionic acid and sodium azide, and plaque-containing oxidants including Fe3+ and Aβ42 fibrils (Aβ42f). All agents caused elevations of BACE proteins and β-site amyloid precursor protein (APP) cleavage product, β-CTF, in retinal lysates in a dose-dependant manner. BACE activity and Aβ40 levels were also increased in agent-treated retinas relative to vehicle controls. BACE immunoreactivity in normal adult rat retina was present mostly in the plexiform layers, indicating a localization of the enzyme to synaptic terminals. No apparent change in laminar or cellular distribution of BACE labeling was detected in the experimental retinas. However, signs of neuronal stress including glial activation were observed in agent-treated retinas especially in high dosage groups. Our data suggest that mitochondrial respiratory inhibition and oxidative stress facilitate BACE expression in vivo. In addition, plaque constituents such as Fe3+ and Aβ42f may participate in a self-enforcing cycle of amyloidogenesis via BACE upregulation.

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Acknowledgments

We thank Philip C. Wong at Johns Hopkins University for providing mouse brains and Rhona Kelley for proofreading the manuscript. This study was supported by Southern Illinois University School of Medicine (X.X.Y.).

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Authors and Affiliations

  1. Department of Anatomy, Southern Illinois University School of Medicine, Carbondale, IL, 62901, USA

    Kun Xiong, Richard W. Clough & Xiao-Xin Yan

  2. Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA

    Huaibin Cai

  3. Department of Anatomy and Neurobiology, Central South University Xiangya Medical School, Changsha, Hunan, 410078, China

    Kun Xiong & Xue-Gang Luo

  4. Department of Neurology and Center for Alzheimer Disease, Southern Illinois University School of Medicine, Springfield, IL, 62794, USA

    Robert G. Struble

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  1. Kun Xiong
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Correspondence to Xiao-Xin Yan.

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Xiong, K., Cai, H., Luo, XG. et al. Mitochondrial respiratory inhibition and oxidative stress elevate β-secretase (BACE1) proteins and activity in vivo in the rat retina. Exp Brain Res 181, 435–446 (2007). https://doi.org/10.1007/s00221-007-0943-y

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  • DOI: https://doi.org/10.1007/s00221-007-0943-y

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