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Amyloid β oligomers constrict human capillaries in Alzheimer's disease via signaling to pericytes
Open accessPublished version of a preprint
Abstract
Pericytes put the squeeze on cognition: Like a computer, the brain needs a reliable source of power, which is provided as oxygen and glucose in the blood. However, in many neurological disorders this energy supply is disrupted. Brain blood flow is controlled by adjustment of the diameters of the vessels supplying the blood. Nortley et al. found that, both in humans developing Alzheimer's disease (AD) and in a mouse model of AD, brain capillaries become squeezed by pericytes (see the Perspective by Liesz). By defining the underlying mechanism, they suggest potential targets for therapy in early AD. Science , this issue p. eaav9518 ; see also p. 223
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TL;DR
Amyloid β oligomers constrict human and rodent brain capillaries at pericyte locations via reactive oxygen species, endothelin-1, and pericyte ETA receptors. In human cognitive-decline biopsies and an AD mouse model, this pericyte-mediated capillary constriction is predicted to substantially reduce cerebral blood flow and can be reversed by C-type natriuretic peptide.
Key findings
- Soluble Aβ1–42 constricted all 4 human capillaries tested by ~25% after 40 min (p=0.01); in rat slices, 16/20 capillaries (80%) constricted >5%, reaching ~15% after 1 h (p=0.006), with an apparent EC50 of 4.7 nM.
- The Aβ-evoked constriction was blocked by ETA receptor blocker BQ-123 (p=0.008), SOD1 (p=3.7×10⁻⁶), NADPH oxidase inhibitor DPI (p=0.032), and NOX4 blocker GKT137831 (p=0.0011); NOX2 blocker ebselen reduced it by only 45%. Aβ increased ROS in pericytes 7.28-fold (p=0.001) versus 1.76-fold in Iba1-expressing immune cells (p=0.05), giving 6.4-fold more total ROS generation by pericytes.
- In rapidly fixed biopsies from 13 living patients with cognitive decline, 7 had Aβ deposition and 6 did not. Mean capillary diameter was 8.1% smaller with Aβ deposition (p=0.0007); near pericyte somata, diameter was ~25% larger in no-Aβ patients (p=3.7×10⁻⁷) but ~30% smaller in Aβ-deposition patients (p=1.6×10⁻²⁰), predicted to reduce flow by ~50% (Discussion; Methods calculation gives 58%).
- In APPNL-G-F AD mice in vivo, capillary diameter was smaller (p=1.7×10⁻⁹) and more strongly reduced at pericyte somata (p=1.6×10⁻¹⁷), while arterioles and venules were not constricted; cerebellar capillaries showed no constriction. CNP (100 nM) reversed Aβ-evoked capillary constriction (p=0.029), whereas combined NOX4 + ETA blockade prevented further constriction (p=0.027) but did not reverse diameter to baseline within 1 h.
Methods
- Live human cortical slices from neurosurgical tumour-access tissue, rapidly fixed human cortical biopsies from patients with cognitive decline, rat cortical slices, and APPNL-G-F × NG2-DsRed mice were used; methods included immunohistochemistry, two-photon imaging, pericyte Ca²⁺ imaging, ROS/GSH imaging, propidium iodide death assays, and pimonidazole hypoxia labelling.
- Capillary diameters were measured blinded to Aβ status, often as a function of distance from PDGFRβ-labelled pericyte somata; analyses used t-tests, Mann-Whitney tests, linear regression slopes, and Holm-Bonferroni correction.
- Flow effects were estimated from Poiseuille’s law, assuming pericytes spaced at 2L and capillary constriction near somata.
Limitations
- Stated: limited live human tissue precluded detailed mechanistic analysis; the authors cannot rule out that ETA receptors are on a different cell type; the Aβ deposition measure may largely reflect plaques; GSH changes cannot be converted to ROS synthesis rates; future work is needed on ageing humans who accumulate Aβ without AD and on ET receptor affinity in AD mice.
- Evident from the text: human biopsy data come from a small cohort (13 patients; subgroups of 6 no Aβ, 3 moderate, 4 severe), live human slice data are very limited (94 pericytes from 2 patients; 4 capillaries for Aβ), most mechanistic work is in rat slices, and the in vivo AD mouse data are from ~4-month-old mice.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the processes of 36% of pericytes labeled for α smooth muscle actin (Fig. 1D)”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Amyloid β constricts human capillaries at pericytes
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In the paper
“Applying soluble Aβ1−42 (oligomeric + monomeric, 72 nM calculated from the monomeric MW) to human brain slices evoked a slowly developing constriction of all 4 capillaries tested, which reduced their diameter by ~25% after 40 mins (Fig. 1H, significantly reduced, p=0.01).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Amyloid β constricts human capillaries at pericytes
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In the paper
“Aβ1−42 evoked a constriction of rat capillaries near pericyte locations”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Amyloid β constricts human capillaries at pericytes
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In the paper
“hypoxic tissue labeling by pimonidazole (hypoxyprobe) was increased significantly in vivo in the AD mice (Fig. S7).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Hypoxia is increased in the AD cortex
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In the paper
“and the diameter at pericyte somata was more strongly reduced (Fig. 5E, p=1.6x10-17).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Pericytes constrict capillaries in vivo in AD mice
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In the paper
“The Aβ1−42-evoked capillary constriction in rat cortical slices was blocked by the endothelin-1 (ET) type A receptor blocker BQ-123 (1 μM, p=0.008, Fig. 2E, G)”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Reactive oxygen species and endothelin-1 generate the capillary constriction
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In the paper
“whereas the NOX2 blocker ebselen (2 μM) reduced the constriction by only 45% (n=8, p=0.027”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Reactive oxygen species and endothelin-1 generate the capillary constriction
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In the paper
“In patients with no detectable Aβ deposition the capillary diameter increased at locations near pericyte somata compared to at locations far from the somata (~25% larger, slope of line is significantly less than zero, p=3.7x10-7 for 813 data points from 6 such patients, Fig. 4D).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Pericytes constrict capillaries in human cognitive decline patients with Aβ deposition
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In the paper
“we found no significant change in capillary density (12% larger in subjects depositing Aβ, p=0.56, see Materials and Methods).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Pericytes constrict capillaries in human cognitive decline patients with Aβ deposition
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In the paper
“ET still evoked a constriction in the presence of SOD1 (p=1.3x10-8, Fig. 2I)”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Reactive oxygen species and endothelin-1 generate the capillary constriction
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In the paper
“The mean distance between human pericytes was 65.3±0.4 μm (for 94 pericytes imaged in tissue from 2 patients), 30% larger than in rodents (19).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Amyloid β constricts human capillaries at pericytes
What the sources say
- Not checked yetcites [19] Hall CN Reynell C Gesslein B Hamilton NB Mishra A Sutherland BA O’Farrell FM Buchan AM Lauritzen M Attwell D Capillary pericytes regulate cerebral blood flow in health and disease Nature 2014 508 55 60 24670647 PMC3976267 source
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In the paper
“superfused noradrenaline constricted and glutamate dilated the capillaries at pericyte locations (Fig. 1E, F).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Amyloid β constricts human capillaries at pericytes
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In the paper
“Capillaries monitored for an hour without applying Aβ, or those to which a version of Aβ1−42 with a scrambled sequence was applied (prepared as for the Aβ oligomers), showed no significant diameter change (Fig. 2C, G).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Amyloid β constricts human capillaries at pericytes
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In the paper
“Aβ1−42 (72 nM, applied for 40 mins) evoked an increase in ROS level that was suppressed by the presence of SOD1 (Fig. 3A, B).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Reactive oxygen species and endothelin-1 generate the capillary constriction
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In the paper
“Aβ increased ROS production in pericytes by a factor of 7.28 (p=0.001) and in immune (Iba1-expressing) cells by a factor of 1.76 (p=0.05).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Reactive oxygen species and endothelin-1 generate the capillary constriction
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In the paper
“This prevented further constriction evoked by Aβ(p=0.027), but did not reverse the capillary diameter to its baseline value on a 1 hour time scale (Fig. 6A).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Reversal of Aβ-evoked capillary constriction
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In the paper
“which was blocked by the ETA blocker BQ-123 (1 μM, p=2.6x10-11), but not by the ETB blocker BQ-788 (1 μM, p=0.91, Fig. 2H).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Reactive oxygen species and endothelin-1 generate the capillary constriction
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In the paper
“Aβ (72 nM for 40 mins) reduced the GSH level in pericytes by 20% and in microglia by 55% (Fig. S4, p=0.014 and p=2x10-29 respectively).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Reactive oxygen species and endothelin-1 generate the capillary constriction
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In the paper
“In cerebellum, both WT and AD mice (n=3 each) showed a larger capillary diameter near pericyte somata (Fig. 5G, p=0.002), with no evidence for a constriction in the AD mice.”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Pericytes constrict capillaries in vivo in AD mice
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In the paper
“applying ET (10 nM) evoked a rise in [Ca2+]i while aCSF had no effect (Fig. 2K-L).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Reactive oxygen species and endothelin-1 generate the capillary constriction
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In the paper
“In contrast, applying these agents alone did not affect capillary diameter (changes after 1 hour were: BQ-123, -0.7±5.2%, n=13, p=0.9; SOD1, 3.4±5.8%, n=9, p=0.57; DPI, -7.4±3.2%, n=5, p=0.082).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Reactive oxygen species and endothelin-1 generate the capillary constriction
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In the paper
“It was not possible to make pure monomeric preparations of Aβ1-42 or Aβ1-40.”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Oligomerising Aβ and assessing the form and concentration of Aβ applied
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In the paper
“Healthy capillaries (<10 μm in diameter, mean diameter 5.61±0.03 μm (n=299) in rat, and 5.08±0.33 μm (n=12) in human, with no rings of arteriolar smooth muscle around them) were selected as previously described (41)”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Imaging capillaries in brain slices
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In the paper
“Aβ1-42 and Aβ1-40 formed monomers and oligomers, while scrambled Aβ1-42 formed mainly monomers (Fig. 1G).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Oligomerising Aβ and assessing the form and concentration of Aβ applied
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In the paper
“Healthy capillaries (<10 μm in diameter, mean diameter 5.61±0.03 μm (n=299) in rat, and 5.08±0.33 μm (n=12) in human, with no rings of arteriolar smooth muscle around them) were selected as previously described (41)”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Imaging capillaries in brain slices
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The mean age of patients without Aβ deposition was 50.5±5.5 (n=6, 4 women and 2 men), and of those with Aβ deposition was 62.1±4.2 (n=7, 4 women and 3 men, not significantly different, p=0.11).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Human biopsy data
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“Mice aged ~4 months (P119-P143, not significantly different for WT and AD, p=0.13) were anesthetised using urethane (1.55 g/kg given in two doses 15 minutes apart).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Experiments in vivo on AD mice
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In the paper
“Regressing mean capillary diameter against age from all patients, or from the patients lacking Aβ deposition, showed that there was no significant dependence on age (p=0.5 and p=0.82 respectively).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Human biopsy data
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In the paper
“Cerebral blood flow in the grey matter can be reduced by over 40% (3)”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Abstract
What the sources say
- Not checked yetcites [3] Asllani I Habeck C Scarmeas N Borogovac A Brown TR Stern Y Multivariate and univariate analysis of continuous arterial spin labeling perfusion MRI in Alzheimer's disease J Cereb Blood Flow Metab 2008 28 725 736 17960142 PMC2711077 source
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In the paper
“reduced blood flow increases Aβ production (13, 14).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Abstract
What the sources say
- Not checked yetcites [13] Sun X He G Qing H Zhou W Dobie F Cai F Staufenbiel M Huang LE Song W Hypoxia facilitates Alzheimer’s disease pathogenesis by up-regulating BACE1 gene expression Proc Natl Acad Sci USA 2006 103 18727 18732 17121991 PMC1693730 source
- Not checked yetcites [14] Zhang X Zhou K Wang R Cui J Lipton SA Liao FF Xu H Zhang YW Hypoxia-inducible factor 1α(HIF-1α)-mediated hypoxia increases BACE1 expression and β-amyloid generation J Biol Chem 2007 282 10873 10880 17303576 source
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In the paper
“A subset of pericytes on capillary walls is contractile (these are the only contractile cells on capillaries (18))”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Abstract
What the sources say
- Not checked yetcites [18] Peppiatt CM Howarth C Mobbs PG Attwell D Bidirectional control of CNS capillary diameter by pericytes Nature 2006 443 700 704 17036005 PMC1761848 source
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In the paper
“Aβ1−42 oligomers, the molecular species believed to be responsible for Aβ’s toxic effects in AD (22, 23).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Abstract
What the sources say
- Not checked yetcites [22] Klein WL Krafft GA Finch CE Targeting small Aβ oligomers: the solution to an Alzheimer’s disease conundrum? Trends Neurosci 2001 24 219 224 11250006
- Not checked yetcites [23] Attems J Lintner F Jellinger KA Amyloid β peptide 1-42 highly correlates with capillary cerebral amyloid angiopathy and Alzheimer disease pathology Acta Neuropathol 2004 107 283 291 14986026
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In the paper
“Exogenous amyloid β can reduce cerebral blood flow (10–12)”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Abstract
What the sources say
- Not checked yetcites [10] Suo Z Humphrey J Kundtz A Sethi F Placzek A Crawford F Mullan M Soluble Alzheimer’s β-amyloid constricts the cerebral vasculature in vivo Neurosci Lett 1998 257 77 80 9865931
- Not checked yetcites [11] Deane R Du Yan S Submamaryan RK LaRue B Jovanovic S Hogg E Welch D Manness L Lin C Yu J Zhu H RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain Nat Med 2003 9 907 913 12808450 source
- Not checked yetcites [12] Dietrich HH Xiang C Han BH Zipfel GJ Holtzman DM Soluble amyloid-beta, effect on cerebral arteriolar regulation and vascular cells Molec Neurodegen 2010 5 15 PMC2873254 20388225
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In the paper
“the cells showing the brightest oxidised dihydroethidium fluorescence were located on capillaries, had the morphology of pericytes, and labeled for NG2 but not Iba1 (Fig. 3C), implying that they are pericytes.”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Reactive oxygen species and endothelin-1 generate the capillary constriction
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In the paper
“For each z-stack, a mean intensity per pericyte or Iba-1-labeled cell, and the total intensity per population of pericytes or Iba1-labeled cells, were calculated, and analysis was performed using the z-stack as the statistical unit.”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Imaging ROS production
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In the paper
“The work on fresh living human brain tissue received ethical approval from the National Health Service (REC number 15/NW/0568) and all patients gave informed consent.”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Human brain slices
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In the paper
“Cellular production of reactive oxygen species (ROS) in brain slices was visualised through the O2.-specific oxidation of dihydroethidium to ethidium, which binds to the DNA and RNA of O2.-producing cells (46).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Imaging ROS production
What the sources say
- Not checked yetcites [46] Wu L-J Wu G Akhavan Sharif MR Baker A Jia Y Fahey FH Luo HR Feener EP Clapham DE The voltage-gated proton channel, Hv1, enhances brain damage from ischemic stroke Nat Neurosci 2012 15 565 573 22388960 PMC3314139 source
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In the paper
“C-type natriuretic peptide (CNP), which can reverse ET-mediated effects (36) by blocking Ca2+ release from internal stores and activating myosin light chain phosphatase (Fig. S8).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Reversal of Aβ-evoked capillary constriction
What the sources say
- Not checked yetcites [36] Špiranec K Chen W Werner F Nikolaev VO Naruke T Koch F Werner A Eder-Negrin P Diéguez-Hurtado R Adams RH Baba HA Endothelial C-type natriuretic peptide acts on pericytes to regulate microcirculatory flow and blood pressure Circulation 2018 138 494 508 29626067 source
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In the paper
“In some experiments pericytes were identified prior to imaging by incubating slices for 30 min in 10 μg/ml isolectin B4 conjugated to Alexa 488 or 568 (ThermoFisher I21411 or 121412), which binds to α-D-galactose residues in the basement membrane generated by pericytes and endothelial cells, and outlines pericytes (41).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Imaging capillaries in brain slices
What the sources say
- Not checked yetcites [41] Mishra A O’Farrell FM Reynall C Hamilton NB Hall CN Attwell D Imaging pericytes and capillary diameter in brain slices and isolated retinae Nat Protoc 2014 9 323 336 24434801
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Throughout this work pericytes were identified by their morphology (spatially isolated cells located outside capillaries) as confirmed by isolectin B4 labelling, or by antibody labelling for their characteristic marker PDGFRβ, or by expression of dsRed under the NG2 promoter.”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Discussion
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“with the experimenter blinded to the occurrence of Aβ deposition (viewing only the PDGFRβ image channel)”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Pericytes constrict capillaries in human cognitive decline patients with Aβ deposition
Strength:plain· not yet calibratedn = 13Tests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Oligodendrocyte precursor cells (OPCs), identified based on a star-like morphology and weaker baseline fluorescence, and arteriolar smooth muscle cells, were excluded from the analysis.”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Imaging pericyte [Ca2+]i
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“No preincubation with DHE was used, to limit the intracellular accumulation of oxidised product.”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Imaging ROS production
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Capillary diameter was measured from the resulting movies, by an analyst blinded to the time and identity of drug application, by placing a line across the lumen on magnified images using Metamorph software.”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Imaging capillaries in brain slices
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Pericyte responses to noradrenaline and glutamate as documented in Fig. 1 were observed whether or not there was tumour infiltration.”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Human brain slices
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“To avoid counting cells killed by the slicing procedure, quantification of the percentage of pericytes that were dead excluded cells within 20 μm of the slice surface.”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Assessing pericyte death
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Aβ was only applied to slices that showed no tumour infiltration.”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Human brain slices
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“Capillary constriction by pericytes may explain why some capillaries become occluded by neutrophils in AD (37)”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Discussion
What the sources say
- Not checked yetcites [37] Roberts BR Lind M Wagen AZ Rembach A Frugier T Li QX Ryan TM McLean CA Doecke JD Rowe CC Villemagne VL Biochemically-defined pools of amyloid-β in sporadic Alzheimer’s disease: correlation with amyloid PET Brain 2017 140 1486 1498 28383676
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Adequate anesthesia was ensured by confirming the absence of a withdrawal response to a paw pinch.”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Experiments in vivo on AD mice
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Data normality was assessed with Shapiro-Wilk or D'Agostino-Pearson omnibus tests.”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Statistics
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“P values were corrected for multiple comparisons using a procedure equivalent to the Holm-Bonferroni method (for N comparisons, the most significant p value is multiplied by N, the 2nd most significant by N-1, the 3rd most significant by N-2, etc.; corrected p values are significant if they are less than 0.05).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Statistics
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“The dura was left intact, to reduce perturbation of the brain.”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Experiments in vivo on AD mice
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“AD mice, in which APP with a humanised Aβ region containing 3 AD-related mutations (APPNL-G-F) is knocked in (49), to avoid artefacts associated with over-expressing APP, were crossed with NG2-DsRed mice in which pericytes express DsRed (19).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Experiments in vivo on AD mice
What the sources say
- Not checked yetcites [49] Saito T Matsuba Y Mihira N Takano J Nilsson P Itohara S Iwata N Saido TC Single App knock-in mouse models of Alzheimer's disease Nat Neurosci 2014 1 661 663 24728269 source
- Not checked yetcites [19] Hall CN Reynell C Gesslein B Hamilton NB Mishra A Sutherland BA O’Farrell FM Buchan AM Lauritzen M Attwell D Capillary pericytes regulate cerebral blood flow in health and disease Nature 2014 508 55 60 24670647 PMC3976267 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“The sections were additionally immunolabeled with a GSH-NEM antibody (Millipore MAB3194, 1:500) which is specific to this adduct, allowing quantification of reduced glutathione after reaction with NEM (47).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Imaging ROS production
What the sources say
- Not checked yetcites [47] Won SJ Kim JE Cittolin-Santos GF Swanson RA Assessment at the single-cell level identifies neuronal glutathione depletion as both a cause and effect of ischemia-reperfusion oxidative stress J Neurosci 2015 35 7143 7152 25948264 PMC4420782
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Although this measure of Aβ may largely reflect the presence of plaques, it is likely that the soluble Aβ concentration correlates with plaque load (48).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Human biopsy data
What the sources say
- Not checked yetcites [48] Murphy MP Levine H III Alzheimer’s disease and the β-amyloid peptide J Alzheimer’s Dis 2010 19 311 323 20061647 PMC2813509
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Images were analysed to assess capillary diameter with the experimenter blinded to the level of Aβ deposits (i.e. viewing only the PDGFRβ channel: the condition of the tissue was sometimes worse for patients with Aβ deposition, but it was not possible to unambiguously decide whether the patient had Aβ deposition without viewing the Aβ channel).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Human biopsy data
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“An estimate of the sample size needed for a typical experiment is as follows: For a control response of 100%, a response standard deviation of 10%, a response in a drug of 70% (30% inhibition), a power of 80% and p<0.05, less than 6 vessels are needed in each of the control and drug groups (www.biomath.info/power/ttest.htm).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Statistics
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“the contractility of capillary pericytes decreases for higher branching orders of capillary (19)”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Calculation of effect of vessel constriction on flow
What the sources say
- Not checked yetcites [19] Hall CN Reynell C Gesslein B Hamilton NB Mishra A Sutherland BA O’Farrell FM Buchan AM Lauritzen M Attwell D Capillary pericytes regulate cerebral blood flow in health and disease Nature 2014 508 55 60 24670647 PMC3976267 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In reality the flow reduction could be greater than this because Poiseuille’s law does not apply for small capillary diameters for which the effective blood viscosity increases as the diameter decreases below 10 μm (50).”
§ Amyloid β oligomers constrict human capillaries in Alzheimer’s disease via signaling to pericytes > Materials and Methods > Calculation of effect of vessel constriction on flow
What the sources say
- Not checked yetcites [50] Pries AR Secomb TW Gaehtgens P Gross JF Blood flow in microvascular networks. Experiments and simulation Circ Res 1990 67 826 834 2208609
Strength:hedged· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The authors state this as an assumption.
The ETA receptors involved in ET-evoked pericyte constriction are located on the pericytes themselves.
“We assume that the ETA receptors involved are located on the pericytes themselves, since ET raised the [Ca2+]i in pericytes, but we cannot rule out the possibility that they are on a different cell type.”
The paper relies on this without support.
The soluble Aβ concentration correlates with plaque load.
“although this measure of Aβ may largely reflect the presence of plaques, it is likely that the soluble Aβ concentration correlates with plaque load”
The paper relies on this without support.
In humans, the cerebellum is relatively spared of amyloid plaque pathology.
“an area that is relatively spared of amyloid plaque pathology in humans”
The authors state this as an assumption.
Pericytes are regularly spaced on capillaries at an interval of 2L.
“We assume that pericytes are regularly spaced on capillaries at an interval of 2L.”
The authors state this as an assumption.
Flow in capillaries is governed by Poiseuille's law.
“For flow governed by Poiseuille’s law, the resistance of a segment of capillary of length L (from a pericyte soma to midway between two pericytes) and radius r1 is given by k.L/r14 where k is a constant.”
The authors state this as an assumption.
The reduction in capillary diameter from the midpoint between pericytes to the pericyte soma is linear with distance.
“then if this reduction is linear with distance the resistance of the capillary segment from the soma to the midpoint is given by k.L.(r12+r1.r2+r22)/(3.r13r23)”
The authors state this as an assumption.
The pressure is fixed at the pial end of penetrating arterioles and venules.
“if the pressure is fixed at the pial end of penetrating arterioles and venules”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Such recovery of neuron and NVU morphology is associated with the improvement of neurovascular coupling as indicated by a whisker pad electrical stimulation and laser speckle contrast imaging (LSCI) experiment (Figure 6f).[ 37 ]”
From Multifunctional Nanostructure RAP‐RL Rescues Alzheimer's Cognitive Deficits through Remodeling the Neurovascular Unit (2021) · cites this paper as [37]
Experimental — accuracy not yet measuredIn the citing paper
“A recent study shows that the presence of Aβ also causes capillary constriction in human cortical slices by acting on pericytes to generate reactive oxygen species (ROS) leading to endothelin-1 release”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Nortley et al., 2019
In the citing paper
“Similarly, a recent study has suggested that NOX4 in pericytes is the major source of ROS which is involved in the constriction of capillaries early in the response to Aβ [48].”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
EC50 result is assigned to two different figures
MinorThe results section places the 4.7 nM EC50 in Fig. 2D, but the methods section says the same measurement is in Fig. 1D. Elsewhere, Fig. 1D is identified as showing α-smooth-muscle-actin labeling of pericytes.
“Thus, the measured EC50 of 4.7 nM for the effect of Aβ1-42 on constriction in Fig. 1D”
“The pericyte-mediated constriction evoked by Aβ1−42 showed a Michaelis-Menten dependence on Aβ concentration, with an apparent EC50 (Km) of 4.7 nM (Fig. 2D).”
Citations
Cites
Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.1860-14.2014 · Cited by 4,875 · cited 2×
“These data suggest that NOX4 in pericytes or endothelial cells (27–29), rather thanNOX2 in immune cells (28, 29), is the NADPH oxidase mainly responsible for generating the ROS that evoke capillary constriction.”
BackgroundThe precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor
Kang, J., Lemaire, H.-G., Unterbeck, A., Salbaum, J. M., Masters, C. L., Grzeschik, K.-H., Multhaup, G., Beyreuther, K., & Müller-Hill, B. (1987) · Nature · doi:10.1038/325733a0 · Cited by 4,619
The molecular pathology of Alzheimer's disease
Selkoe, D. J. (1991) · Neuron · doi:10.1016/0896-6273(91)90052-2 · Cited by 2,708
Molecular Architecture of the Mouse Nervous System
Zeisel, A., Hochgerner, H., Lönnerberg, P., Johnsson, A., Memic, F., van der Zwan, J., Häring, M., Braun, E., Borm, L. E., La Manno, G., et al. (2018) · Cell · doi:10.1016/j.cell.2018.06.021 · Cited by 2,552
Amyloid deposition as the central event in the aetiology of Alzheimer’s disease
Hardy, J., & Allsop, D. (1991) · Trends in Pharmacological Sciences · doi:10.1016/0165-6147(91)90609-v · Cited by 2,538
Capillary pericytes regulate cerebral blood flow in health and disease
Hall, C. N., Reynell, C., Gesslein, B., Hamilton, N. B., Mishra, A., Sutherland, B. A., O’Farrell, F. M., Buchan, A. M., Lauritzen, M., & Attwell, D. (2014) · Nature · doi:10.1038/nature13165 · Cited by 1,870
Self-citationThe Pathobiology of Vascular Dementia
Iadecola, C. (2013) · Neuron · doi:10.1016/j.neuron.2013.10.008 · Cited by 1,857
Alzheimer's Disease and the Amyloid-β Peptide
Murphy, M. P., & LeVine, H. (2010) · Journal of Alzheimer's Disease · doi:10.3233/jad-2010-1221 · Cited by 1,750
RAGE mediates amyloid-β peptide transport across the blood-brain barrier and accumulation in brain
Deane, R., Du Yan, S., Submamaryan, R. K., LaRue, B., Jovanovic, S., Hogg, E., Welch, D., Manness, L., Lin, C., Yu, J., et al. (2003) · Nature Medicine · doi:10.1038/nm890 · Cited by 1,426
Single App knock-in mouse models of Alzheimer’s disease
Saito, T., Matsuba, Y., Mihira, N., Takano, J., Nilsson, P., Itohara, S., Iwata, N., & Saido, T. C. (2014) · Nature Neuroscience · doi:10.1038/nn.3697 · Cited by 1,366 · cited 1×
“AD mice, in which APP with a humanized Ab region containing three AD-related mutations (App) is knocked in (49) to avoid artifacts associated with overexpressing APP, were crossed with NG2-DsRed mice in which pericytes express DsRed (19).”
BackgroundSelf-citation
Flagged first, then by citations
Cited by
Sorted by citations
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204
“A recent study shows that the presence of Aβ also causes capillary constriction in human cortical slices by acting on pericytes to generate reactive oxygen species (ROS) leading to endothelin-1 release (Nortley et al., 2019).”
Synergy between amyloid-β and tau in Alzheimer’s disease
Busche, M. A., & Hyman, B. T. (2020) · Nature Neuroscience · doi:10.1038/s41593-020-0687-6 · Cited by 1,242
APOE and Alzheimer’s disease: Advances in genetics, pathophysiology, and therapeutic approaches
Serrano-Pozo, A., Das, S., & Hyman, B. T. (2021) · The Lancet Neurology · doi:10.1016/s1474-4422(20)30412-9 · Cited by 1,037
Comparative cellular analysis of motor cortex in human, marmoset and mouse
Bakken, T. E., Jorstad, N. L., Hu, Q., Lake, B. B., Tian, W., Kalmbach, B. E., Crow, M., Hodge, R. D., Krienen, F. M., Sorensen, S. A., et al. (2021) · Nature · doi:10.1038/s41586-021-03465-8 · Cited by 812
Park, M. W., Cha, H. W., Kim, J., Kim, J. H., Yang, H., Yoon, S., Boonpraman, N., Yi, S. S., Yoo, I. D., & Moon, J.-S. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101947 · Cited by 683
“Similarly, a recent study has suggested that NOX4 in pericytes is the major source of ROS which is involved in the constriction of capillaries early in the response to Aβ [48].”
Background
Metadata
- Authors
- Nortley, R., Korte, N., Izquierdo, P., Hirunpattarasilp, C., Mishra, A., Jaunmuktane, Z., Kyrargyri, V., Pfeiffer, T., Khennouf, L., Madry, C., Gong, H., Richard-Loendt, A., Huang, W., Saito, T., Saido, T. C., Brandner, S., Sethi, H., & Attwell, D.
- Affiliations
- University College London (GB)
- Oregon Health & Science University (US)
- National Hospital for Neurology and Neurosurgery (GB)
- Saarland University (DE)
- RIKEN Center for Brain Science (JP)
- UCL Queen Square Institute of Neurology (GB)
- Corresponding author
- Korte, Nils
- Izquierdo, Pablo
- Hirunpattarasilp, Chanawee
- Mishra, Anusha
- Jaunmuktane, Zane
- Kyrargyri, Vasiliki
- Attwell, David
- ORCID
- Venue
- Science
- Published
- 2019-07-19
- Volume
- 365
- Issue
- 6450
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC6658218
- OpenAlex
- W2951514146
- Semantic Scholar
- cc2df1df8221a1fa3d428338a5ead55bc1a47948
- Cited by
- 682
- References
- 53
- Citations by year
- 2026: 64 · 2025: 90 · 2024: 105 · 2023: 108 · 2022: 93 · 2021: 102 · 2020: 102 · 2019: 16
- FWCI
- 34.70
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Science (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Wellcome Trust (099222, PhD studentship)
- European Research Council (BrainPower & BrainEnergy)
- Deutsche Forschungsgemeinschaft (KI 503/14-1 and SFB894)
- EMBO (Fellowship)
- Lundbeckfonden (Fellowship)
- national institute of health research (Biomedical Research Centre)
- Leonard Wolfson Experimental Neurology Centre (PhD studentship)
- BBSRC (PhD studentship)
- Chulabhorn Royal Academy (PhD studentship)
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid-beta oligomers, Alzheimer's disease, pericytes, brain capillaries, cerebral blood flow, vasoconstriction, mouse models of Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Animals, Hypoxia, Biopsy, Capillaries, Cerebral Cortex, Cerebrovascular Circulation, Constriction, Pathologic, Humans, Vascular Resistance, Signal Transduction, Amyloid beta-Peptides, Rats, Sprague-Dawley, Reactive Oxygen Species, Endothelin-1, Pericytes, Receptor, Endothelin A, Mice, Rats, Protein Multimerization
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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