Acute and Chronic Sustained Hypoxia Do Not Substantially Regulate Amyloid-β Peptide Generation In Vivo.

Alberto Serrano-Pozo,Marisa Vizuete,José López-Barneo,Manuel A Sánchez-García,Antonio Heras-Garvín,Victoria Navarro,Javier Vitorica,Alberto Pascual,Rosana March-Díaz

doi:10.1371/journal.pone.0170345

Abstract

BackgroundRecent epidemiological evidence has linked hypoxia with the development of Alzheimer disease (AD). A number of in vitro and in vivo studies have reported that hypoxia can induce amyloid-β peptide accumulation through various molecular mechanisms including the up-regulation of the amyloid-β precursor protein, the β-secretase Bace1, or the γγ-secretase complex components, as well as the down-regulation of Aβ-degrading enzymes.ObjectivesTo investigate the effects of acute and chronic sustained hypoxia in Aβ generation in vivo.Methods2–3 month-old C57/Bl6J wild-type mice were exposed to either normoxia (21% O2) or hypoxia (9% O2) for either 4 to 72 h (acute) or 21–30 days (chronic sustained) in a hermetic chamber. Brain mRNA levels of Aβ-related genes were measured by quantitative real-time PCR, whereas levels of Bace1 protein, full length AβPP, and its C-terminal fragments (C99/C88 ratio) were measured by Western blot. In addition, 8 and 14-month-old APP/PS1 transgenic mice were subjected to 9% O2 for 21 days and levels of Aβ40, Aβ42, full length AβPP, and soluble AβPPα (sAβPPα) were measured by ELISA or WB.ResultsHypoxia (either acute or chronic sustained) did not impact the transcription of any of the Aβ-related genes in young wild-type mice. A significant reduction of Bace1 protein level was noted with acute hypoxia for 16 h but did not correlate with an increased level of full length AβPP or a decreased C99/C83 ratio. Chronic sustained hypoxia did not significantly alter the levels of Bace1, full length AβPP or the C99/C83 ratio. Last, chronic sustained hypoxia did not significantly change the levels of Aβ40, Aβ42, full length AβPP, or sAβPPα in either young or aged APP/PS1 mice.DiscussionOur results argue against a hypoxia-induced shift of AβPP proteolysis from the non-amyloidogenic to the amyloidogenic pathways. We discuss the possible methodological caveats of previous in vivo studies.

Highlights

Alzheimer disease (AD) is the most common neurodegenerative disease and the most prevalent dementia
A number of in vitro and in vivo studies have reported that hypoxia can induce amyloid-β peptide accumulation through various molecular mechanisms including the upregulation of the amyloid-β precursor protein, the β-secretase by the β-site AβPP cleaving enzyme 1 (Bace1), or the γγ-secretase complex components, as well as the down-regulation of Aβ-degrading enzymes
A significant reduction of Bace1 protein level was noted with acute hypoxia for 16 h but did not correlate with an increased level of full length amyloid-β precursor protein (AβPP) or a decreased C99/C83 ratio

Summary

Introduction

Alzheimer disease (AD) is the most common neurodegenerative disease and the most prevalent dementia. The cleavage of AβPP by the β-site AβPP cleaving enzyme 1 (Bace1) produces two fragments: soluble AβPPβ (sAβPPβ) and a 99 amino acid C-terminal fragment (βCTF or C99). The latter is cleaved by γ-secretase to produce Aβ peptides of different lengths from 37 to 43 amino acids depending on the cleaving site. A number of in vitro and in vivo studies have reported that hypoxia can induce amyloid-β peptide accumulation through various molecular mechanisms including the upregulation of the amyloid-β precursor protein, the β-secretase Bace, or the γγ-secretase complex components, as well as the down-regulation of Aβ-degrading enzymes.

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