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

Cerebral hypometabolism, oxidative stress and beta-amyloid peptide (Abeta) accumulation are key pathological events in Alzheimer's disease (AD). Beta-secretase (BACE, i.e., BACE1), a prerequisite for Abeta genesis, is elevated in sporadic AD. Recent studies show BACE upregulation in experimenta...

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Bibliographic Details
Published in:Experimental brain research 2007-08, Vol.181 (3), p.435-446
Main Authors: KUN XIONG, HUAIBIN CAI, LUO, Xue-Gang, STRUBLE, Robert G, CLOUGH, Richard W, YAN, Xiao-Xin
Format: Article
Language:English
Subjects:
Amyloid beta-Peptides - metabolism
Amyloid beta-Peptides - toxicity
Amyloid beta-Protein Precursor - drug effects
Amyloid beta-Protein Precursor - metabolism
Amyloid Precursor Protein Secretases - metabolism
Animals
Aspartic Acid Endopeptidases - metabolism
Biological and medical sciences
Cell Respiration - drug effects
Cell Respiration - physiology
Ciliary Neurotrophic Factor - drug effects
Ciliary Neurotrophic Factor - metabolism
Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases
Dose-Response Relationship, Drug
Enzyme Activation - drug effects
Enzyme Activation - physiology
Eye and associated structures. Visual pathways and centers. Vision
Fundamental and applied biological sciences. Psychology
Iron - toxicity
Male
Medical sciences
Mitochondria - drug effects
Mitochondria - metabolism
Neurology
Neurons - enzymology
Oxidants - toxicity
Oxidative Stress - drug effects
Oxidative Stress - physiology
Peptide Fragments - metabolism
Peptide Fragments - toxicity
Plaque, Amyloid - metabolism
Presynaptic Terminals - enzymology
Rats
Rats, Sprague-Dawley
Retina - enzymology
Stress, Physiological - metabolism
Stress, Physiological - physiopathology
Uncoupling Agents - pharmacology
Up-Regulation - drug effects
Up-Regulation - physiology
Vertebrates: nervous system and sense organs
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Summary:Cerebral hypometabolism, oxidative stress and beta-amyloid peptide (Abeta) accumulation are key pathological events in Alzheimer's disease (AD). Beta-secretase (BACE, i.e., BACE1), a prerequisite for Abeta 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 Fe(3+) and Abeta42 fibrils (Abeta42f). All agents caused elevations of BACE proteins and beta-site amyloid precursor protein (APP) cleavage product, beta-CTF, in retinal lysates in a dose-dependant manner. BACE activity and Abeta40 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 Fe(3+) and Abeta42f may participate in a self-enforcing cycle of amyloidogenesis via BACE upregulation.
ISSN:0014-4819
1432-1106
DOI:10.1007/s00221-007-0943-y