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

[This corrects the article DOI: 10.1371/journal.pone.0170345.].

There are several errors throughout the paper. The publisher apologizes for these errors. The figure legend for Fig 1 is incorrect. Please see the Fig 1 and the correct figure legend below.

Fig 1

Characterization of hypoxia treatment protocols used in this study.

(A) Schematic of acute (top) and chronic sustained (bottom) hypoxia treatment protocol used in this study. White arrowheads represent reoxygenation (21% O2) for 24 h. (B) Top, WB for HIF1α in brain extracts from 2–3 month-old wild-type mice subjected to AH (9% O2) for either 4 h or 16 h. Bottom, quantification of HIF1α WB. p < 0.05; Kruskal-Wallis ANOVA with Dunn’s multiple comparison test, n = 3 per group. (C) Vegfa mRNA levels measured by qRT-PCR in 2–3 month-old wild-type mice in normoxia and after AH (9% O2) for 16 h. Note the ~5-fold up-regulation of Vegfa expression caused by AH, which was reverted by 24 h reoxygenation. * p < 0.05; Kruskal-Wallis ANOVA with Dunn’s multiple comparison test, n = 4 per group. (D) Vegfa mRNA levels measured by qRT-PCR in 2–3 month-old wild-type mice in normoxia and after CSH (21 days, 9% O2), with and without reoxygenation (24 h, 21% O2). Note the ~2-fold up-regulation caused by CSH, which was not reverted by 24 h reoxygenation.* p < 0.05; Kruskal-Wallis ANOVA with Dunn’s multiple comparison test, n = 4 per group. (E) Vegf protein levels were measured by ELISA in 2–3 month-old wild-type mice subjected to either CSH (30 days, 9% O2) or normoxia (30 days, 21% O2 within the same chamber). A non-significant ~3-fold increase was observed in CSH compared to normoxia. Mann-Whitney U test, n = 4 per group. (F) Hematocrit of 14-month-old APP/PS1 mice subjected to CSH (21 days, 9% O2) or normoxia (21 days, 21% O2 within the same chamber). CSH was associated with a ~2-fold increase. p = 0.003; Mann-Whitney U test, n = 4 per group. Bars ± error bars represent mean ± s.e.m. HIF1α = hypoxia inducible factor 1 alpha; α-tub = alpha-tubulin; Vegf = vascular endothelial growth factor.

The Table 2 legend is incorrectly incorporated into the body of the manuscript. Additionally, the order of rows for Table 2 is incorrect. The correct order of columns from left to right should be: Author / year, Model, Hypoxia method, Hypoxia level, Hypoxia duration, CO2 level, Results (APP, BACE, γ-secretase, Aβ, Neprilysin, Tau, Synapses, Behavior). Please see the correct Table 2 and Table 2 legend below.

Table 2

Literature review on regulation of Aβ Metabolism by hypoxia.

Results of a search in the US National Library of Medicine of the National Institutes of Health (http://www.ncbi.nlm.nih.gov/pubmed/) using the combination of keywords “hypoxia AND Alzheimer”. Both in vitro and in vivo studies were included. In vitro studies used either exposure to a low O2 level within the cell incubator or treatment with hypoxia mimics (i.e. NiCl2 or DMOG), and either cell lines stably expressing an AβPP construct, (i.e. the 695 amino acid wild-type form or the Swedish mutation) or primary rat cortical cultures, both neuronal and astrocytic. Note: Articles were excluded if: 1) they exclusively described the effects of hypoxia on tau phosphorylation/pathology or some other aspect of AD pathophysiology (i.e. mitochondrial dysfunction) without addressing its effects on Aβ; 2) they used a paradigm other than pure hypoxia (i.e. ischemia, hypocapnia, oxygen and glucose deprivation, oxidative stress), and 3) they were written in a language different from English.

Abbreviations: ↓: significant decrease; ↑: significant increase; =: no significant change; d: days; EM: electron microscopy; F: female; FA: formic acid; h: hours; hu: human; M: male; Mme = neprilysin mRNA; mo: month; mu: murine; MWM: Morris water maze (↓ indicates worse performance); NA: not available; NFT: neurofibrillary tangle; OF: open field; syn: synaptophysin; TST: tail suspension test (↓ indicates worse performance). Note: mRNAs are expressed in Italics, whereas proteins are Capitalized.

Author / year	Model	Hypoxia method	Hypoxia level	Hypoxia duration	CO2 level	RESULTS
						APP	BACE	Y-secretase	Aβ	Neprilysin	Tau	Synapses	Behavior
Chen et al. 2003	Rat cortical neuron primary culture	Sealed but “not 100% leak-proof” chamber	NA	4 & 8 h followed by 20%O2 for 24 or 48 h	5%	↑ AβPP	NA	NA	↑ Aβ	NA	↑ tau	NA	NA
Smith et al. 2004	Rat cortical astrocyte primary culture	Incubator	2.5% O2	24 h	5%	NA	NA	↑ Presenilin-1	↑ Aβ	NA	NA	NA	NA
Sun et al. 2006	SH-SYS5-APPswe cells	Incubator	2% O2	12 & 24 h	5%	↑ C99	↑ Bace1 & Bace1	NA	↑ Aβ40↑ Aβ42	NA	NA	NA	NA
	HEK-APP695wt	Incubator	2% O2	12 h	5%	↑ C99	NA	NA	↑ Aβ40↑ Aβ42	NA	NA	NA	NA
	APP23 mice (8 mo, M:F 1:1)	Semisealable hypoxia chamber	8% O2	16 h/day for 1 mo	NA	↑ C99	↑ Bace1 (in wt)	NA	↑ Aβ40↑ Aβ42↑ plaque number	NA	NA	NA	↓ MWM
Wang et al. 2006	HeLa-APPswe cells	1 mM NiCl2	NA	2, 4, 8, 12 & 20 h	5%	↑ sAβPPα= AβPP↓ AβPP-CTFs	NA	↑ Aph1a & Aph1a= Presenilin-1= Nicastrin= Pen2	NA	NA	NA	NA	NA
Zhang et al. 2007	N2a-APP695wt cells	Incubator	1% O2	2, 4 & 8 h	NA	↑ C99= AβPP	↑ Bace1 & Bace1	= Presenilin 1	↑ Aβ40↑ Aβ42	NA	NA	NA	NA
Li et al. 2009	SH-SYS5-C99 cells	1 mM NiCl2	NA	4 h	5%	↓ HA-C99	NA	↑ Aph-1a	↑ Aβ42	NA	NA	NA	NA
	APPswe/PS1A246E mice (9 mo, F)	Sealed 125 mL jar with fresh air	NA, until “first gasping breath”	Once daily for 60 d	NA	↑ C99/C83 ratio	NA	↑ Aph-1a	↑ soluble & FA-Aβ42↑ plaque area & number	NA	NA	NA	NA
Guglielmotto et al 2009	SK-N-BE neuroblastoma cells	Incubator	3% O2	1, 3, 6, 12, 24, 48 & 72 h	5%	NA	↑ Bace1 & Bace1	NA	NA	NA	NA	NA	NA
Moussavi Nik et al. 2012	Zebra fish embryos & adults	Bubbling N2 to the medium	Embryos: ≈10% of controlsAdults: ≈17% of controls	Embryos: from 6 hpf to 24 or 48 hpf stageAdults: 3 h	NA	↑ Appa↑ Appb	↑ Bace1	↑ Psen1↑ Psen2	NA	NA	NA	NA	NA
Shiota et al. 2013	SH-SYS5-APPwt cells	Incubator	1% O2	1% 10 min vs 21% 20 min for 8 cycles	5%	NA	NA	NA	↑ Aβ42= Aβ40	NA	NA	NA	NA
	3xTg mice (6 mo, M)	Hypoxia chamber	5% O2	5% vs 21% every 10 min for 8 h per day during 8 weeks	<0.03%	= AβPP	= Bace1	NA	↑ Aβ42↑ intraneuronal Aβ= Aβ40	NA	NA	NA	= MWM
Gao et al. 2013	APPswe/PS1dE9 mice (6 mo)	Sealed 125 mL jar with fresh air	NA, until “first gasping breath”	Once daily for 60 d	NA	NA	NA	NA	↑ Aβ42↑ plaque area & number	NA	↑ p-tau= tau	NA	↓ MWM↓ TST= OF
Zhang et al 2013	APPswe/PS1A246E pregnant mice	Hypobaric chamber	11.1% O2	6 h/day for days 7 to 20 of gestation followed by normoxia up to age 3, 6 & 9 mo	NA	↑ AβPP	= Bace1	NA	↑ soluble & FA hu Aβ42 & Aβ40↑ soluble mu Aβ42 & Aβ40↑ plaque area & number	↓ Neprilysin	↑ p-tau	↓ syn↓ EM	↓ MWM
Kerridge et al 2015	NB7 (SJ-N-CG) neuroblastoma cells	Incubator	1% O2	24 h	NA	NA	NA	NA	NA	↓ Mme↓ Neprilysin level & activity	NA	NA	NA
Liu et al. 2016	APPswe/PS1dE9 mice (3 mo)	Hypobaric chamber	11.1% O2	6 h/day for 30 d followed by up to 5 mo normoxia prior to sacrifice	NA	↑ AβPP= C99/C83 ratio	↑ Bace1 (in wt)	↑ Aph1a↑ Nicastrin↑ Pen2= Presenilin-1	↑ soluble & FA Aβ42/Aβ40 ratio↑ plaque area & number	↓ Neprilysin	= NFT number↑ p-tau/tau ratio (at 4 mo)	↓ syn↓ EM	↓ MWM