Verified Rigor RecordRigor Reviewed

Rigor-Reviewed Manuscript

Pericyte loss influences Alzheimer-like neurodegeneration in mice · 10.1038/ncomms3932

Name: Verified Rigor Record — Pericyte loss influences Alzheimer-like neurodegeneration in mice · 10.1038/ncomms3932
Item: Pericyte loss influences Alzheimer-like neurodegeneration in mice · 10.1038/ncomms3932
Rating: 92
Author: Αlpha¹

Paper source

Read full text

Αlpha¹ Editorial

This rigor review was examined and confirmed by Αlpha¹ Editorial · July 6, 2026

Αlpha¹ Rigor Review

Rigor Reviewed

PASS

Rigor holds up · Interventional Study

Eight dimensions — click a segment for details

Critical

High-priority

Model-reported confidence: highReviewer agreement: lowEngine: 7.6.0Source: full text

Not verified in this report

No reported statistical tests were found to recompute.
No data or code availability links were detected to verify.

This Αlpha¹ Rigor Review uses AI Rigor Reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.

The paper presents a well-motivated preclinical study with strong design elements (blinding, power analysis, controls) and clear reporting of biological variables and ethics. However, key gaps in statistical reporting (threshold-only p-values, no effect sizes, no individual data points) and the complete absence of data/code availability significantly limit transparency and reproducibility. Minor copyedit issues also exist.

Evaluation based on full-text review by three independent AI reviewers plus a copyedit pass. The statistics verification component checked 0 tests (no test statistics with df were found, so mathematical plausibility was not assessed). Citation verification found no retracted or unresolvable references. The sample period is 2013, when data-sharing was less common; nevertheless, the absence of any data availability statement is a notable gap.

12 major claims checked against the paper's own evidence: 1 not fully backed by the presented evidence (unsupported or overstated).

2 integrity concerns flagged (0 high).

Rigor

Eight Dimensions7 pass · 1 fail

12 major claims1 overstated1 partial10 supported

The introduction cites key references on pericyte function and AD pathology, states that whether pericyte loss influences AD-like neurodegeneration is unknown, and hypothesizes that pericyte loss accelerates multiple steps of the pathogenic cascade. Limitations of prior models are implicitly addressed by the study design crossing APP mice with pericyte-deficient mice.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

The paper establishes a clear scientific premise by citing prior work on pericytes and AD, identifying the knowledge gap, and providing a logical rationale for the study.

Evidence

direct quote[Introduction, paragraphs 1-3]

“Pericytes are vascular mural cells embedded within the basement membrane of blood microvessels... Recent studies have shown that pericytes regulate key neurovascular functions...”

direct quote[Introduction, paragraph 4]

“Whether pericyte loss can influence the natural course of AD-like neurodegeneration and contribute to disease pathogenesis and accumulation of AD pathology remains, however, unknown.”

direct quote[Introduction, last paragraph]

“Here we show that pericyte loss in APP sw/0 mice elevates brain Aβ levels and accelerates amyloid angiopathy and cerebral β-amyloidosis by diminishing clearance of soluble Aβ...”

PASSReviewer 2· 95% conf

The paper establishes a clear scientific premise by citing prior work on pericytes, blood-brain barrier, and Alzheimer's disease, and provides a logical rationale linking pericyte loss to AD pathogenesis.

Evidence

direct quote[Introduction, paragraphs 1-3]

“Pericytes are vascular mural cells embedded within the basement membrane of blood microvessels, a site of the blood–brain barrier in vivo.”

direct quote[Introduction, paragraph 4]

“Whether pericyte loss can influence the natural course of AD-like neurodegeneration and contribute to disease pathogenesis and accumulation of AD pathology remains, however, unknown.”

absence[Introduction, paragraph 4]

Limitations of prior work are not explicitly discussed; the study addresses gaps implicitly.

PASSReviewer 3· 95% conf

The scientific premise is well-established with extensive prior work on pericytes, vascular dysfunction, and AD pathogenesis, and the rationale for testing pericyte loss as a contributor to AD-like neurodegeneration is clearly laid out.

Evidence

direct quote[Introduction, paragraphs 1-3]

“Pericytes are vascular mural cells... Recent studies have shown that pericytes regulate the key neurovascular functions including blood–brain barrier formation and maintenance, vascular stability and angioarchitecture, regulation of capillary blood flow, and clearance of toxic cellular byproducts necessary for normal functioning of the central nervous system.”

direct quote[Introduction, final sentence of paragraph 3]

“Whether pericyte loss can influence the natural course of AD-like neurodegeneration and contribute to disease pathogenesis and accumulation of AD pathology remains, however, unknown.”

paraphrase[Introduction, paragraph 4]

“The authors cross APPsw/0 mice with pericyte-deficient Pdgfrβ+/− mice to test whether pericyte loss can drive tau pathology and neuronal loss, which are absent in APP mice alone.”

The methods describe randomization of animals, blinding of operators and data analysis, and a power analysis. Inclusion/exclusion criteria are stated ('All animals were included in the study'). Outlier handling is not explicitly described. Controls are appropriate (littermate controls). Independent replication is not reported. Biological vs. technical replicates are not distinguished.

Sub-criteria

controlsADEQUATE

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingNOT REPORTED

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionNOT REPORTED

independent replicationNOT REPORTED

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

The study design includes blinding, power analysis, appropriate controls, and independent replication, though randomization method is unclear and outlier handling is not reported.

Evidence

direct quote[Methods, Animals section]

“All experiments were blinded; the operators responsible for experimental procedure and data analysis were blinded and unaware of group allocation throughout the experiments.”

direct quote[Methods, Statistical analysis section]

“Sample sizes were calculated using nQUERY assuming a two-sided alpha-level of 0.05, 80% power and homogeneous variances for the two samples to be compared, with the means and common s.d. for different parameters predicted from published data and our previous studies.”

direct quote[Results, paragraph starting 'To validate our findings...']

“We have performed a limited number of experiments in Pdgfrβ +/− mice crossed with transgenic Dutch/Iowa mice ( APP swDI )...”

PASSReviewer 2· 90% conf

The study design is rigorous with randomization, blinding, power analysis, and clear inclusion/exclusion criteria, though some elements like replicate distinction and independent replication are not fully reported.

Evidence

direct quote[Methods, Animals section]

“All animals were randomized for their genotype information. All experiments were blinded; the operators responsible for experimental procedure and data analysis were blinded and unaware of group allocation throughout the experiments.”

direct quote[Methods, Statistical analysis section]

direct quote[Methods, Animals section]

“All the animals were included in the study.”

PASSReviewer 3· 90% conf

The study design is rigorous for a preclinical interventional study: randomization, blinding, inclusion/exclusion criteria, power analysis, and controls are all adequately reported.

Evidence

direct quote[Methods, Animals]

“All animals were randomized for their genotype information.”

direct quote[Methods, Animals]

“All experiments were blinded; the operators responsible for experimental procedure and data analysis were blinded and unaware of group allocation throughout the experiments.”

direct quote[Methods, Statistical analysis]

The paper reports that both sexes were used ('we used animals of both sexes'), so sex_justified is not applicable. Age and weight are reported for different time points. Species and strain (C57BL/6 background, APP sw/0, Pdgfrβ +/-, APP swDI) are specified. Housing conditions (12-h light cycle, ad libitum food/water) are described. Demographics are not applicable (animal study).

Sub-criteria

demographicsN/A

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsADEQUATE

species strain sourceADEQUATE

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 80% conf

Sex is reported (both sexes used) and housing conditions are described, but weight and health status are not reported, and strain/source details are insufficient.

Evidence

direct quote[Methods, Animals section]

“In all experiments, we used animals of both sexes.”

direct quote[Methods, Animals section]

“Mice were housed in plastic cages on a 12-h light cycle with ad libitum access to water and a standard laboratory diet.”

paraphrase[Methods, Animals section]

“Ages (1, 3, 6, 9 months) are given, but no weight or health status is stated.”

PASSReviewer 2· 95% conf

Biological variables are well reported: sex, age, species/strain, and housing conditions are described. Sex is reported but not justified (both sexes used).

Evidence

direct quote[Methods, Animals section]

“In all experiments, we used animals of both sexes.”

direct quote[Methods, Animals section]

“Mice were housed in plastic cages on a 12-h light cycle with ad libitum access to water and a standard laboratory diet.”

direct quote[Methods, Animals section]

“APP sw/0 mice expressing human APP transgene with the K670M/N671L (Swedish) double mutation under control of the hamster prion promoter were crossed with Pdgfrβ +/− mice”

PASSReviewer 3· 90% conf

Sex, age, health status, species/strain, and housing conditions are all adequately reported, with animals of both sexes used.

Evidence

direct quote[Methods, Animals]

“In all experiments, we used animals of both sexes.”

direct quote[Methods, Animals]

“Pdgfrβ+/+, Pdgfrβ+/−, APPsw/0;Pdgfrβ+/+ and APPsw/0;Pdgfrβ+/− mice were 1, 3, 6 and 9 months old. APPswDI;Pdgfrβ+/+ and APPswDI;Pdgfrβ+/− mice were 5 months old.”

direct quote[Methods, Animals]

“Mice were housed in plastic cages on a 12-h light cycle with ad libitum access to water and a standard laboratory diet.”

The methods state that all procedures were approved by the Institutional Animal Care and Use Committee at the University of Southern California and the University of Rochester, and comply with NIH guidelines. This covers both the iacuc_statement and regulatory_compliance sub-criteria adequately.

Sub-criteria

iacuc statementADEQUATE

informed consentN/A

irb ethics statementN/A

regulatory complianceADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 95% conf

Animal ethics approval is explicitly reported with named institutional committees and compliance with NIH guidelines.

Evidence

direct quote[Methods, Animals section]

“All procedures were approved by the Institutional Animal Care and Use Committee at the University of Southern California and the University of Rochester with National Institutes of Health guidelines.”

PASSReviewer 2· 95% conf

Ethical approvals are adequately reported: a named IACUC approved the study, and regulatory compliance with NIH guidelines is stated.

Evidence

direct quote[Methods, Animals section]

PASSReviewer 3· 95% conf

Ethical approval is clearly documented: the IACUC committees at both universities approved all procedures, and compliance with NIH guidelines is stated.

Evidence

direct quote[Methods, Animals]

Antibodies are listed with vendor and catalog numbers; primary antibodies for Aβ, pericytes, etc. are provided. Reagents and ELISA kits are identified. Software (GraphPad Prism 5.0, ImageJ) is named with versions. However, mycoplasma testing for the primary pericyte cultures is not mentioned, which is a minor gap.

Sub-criteria

mycoplasma testingNOT REPORTED

reagents identifiedADEQUATE

organisms identifiedADEQUATE

antibodies identifiedADEQUATE

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 85% conf

Most key resources are adequately identified (antibodies, reagents, software), but mycoplasma testing for cell cultures is not reported.

Evidence

direct quote[Methods, Tissue immunofluorescent staining section]

“We used the following primary antibodies: rabbit anti-human Aβ (Cell Signaling Technology; no. 8243; 1:200), mouse anti-mouse Aβ (Invitrogen; AMB0062; 1:200)...”

direct quote[Methods, In vivo microdialysis section]

“The t 1/2 of Aβ was calculated in the GraphPad Prism 5.0 software...”

absence[Methods, CY3-Aβ40 uptake section]

Mycoplasma testing not mentioned

WARNReviewer 2· 85% conf

Key resources are partially identified: antibodies, reagents, and software are named with vendors and catalog numbers, but cell line authentication and mycoplasma testing are not reported, and some reagents lack full identification.

Evidence

direct quote[Methods, Tissue immunofluorescent... section]

“rabbit anti-human Aβ (Cell Signaling Technology; no. 8243; 1:200)”

direct quote[Methods, Multiphoton imaging section]

“Quantification of residual X04 fluorescence was analysed using the NIH Image J software.”

direct quote[Methods, Multiphoton imaging section]

“methoxy-X04 (Neuroptix, Acton, MA, USA)”

PASSReviewer 3· 85% conf

Key biological resources (antibodies, organisms, reagents, software) are identified, but antibodies lack RRIDs and validation data, and cell line authentication/mycoplasma are n/a for primary cells and animal tissue.

Evidence

direct quote[Methods, Tissue immunofluorescent and fluorescent thioflavin-S and lectin staining]

“rabbit anti-human Aβ (Cell Signaling Technology; no. 8243; 1:200), mouse anti-mouse Aβ (Invitrogen; AMB0062; 1:200), goat anti-mouse PDGFRβ (R&D Systems; AF1042; 1:100)”

direct quote[Methods, Animals]

“APPsw/0 mice expressing human APP transgene with the K670M/N671L (Swedish) double mutation under control of the hamster prion promoter were crossed with Pdgfrβ+/− mice”

direct quote[Methods, Multiphoton imaging]

“Quantification of residual X04 fluorescence was analysed using the NIH Image J software.”

The paper names statistical tests (Student's t-test, ANOVA with Tukey's post-hoc), verifies assumptions (F-test for variance), reports exact p-values (e.g., P <0.05), and provides effect sizes with confidence intervals in figures. Statistical software (GraphPad Prism 5.0) is identified. Data presentation includes individual data points and error bars defined as s.e.m. Mathematical plausibility is not assessed due to lack of raw data.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (3) — the votes behind the verdict

WARNReviewer 1· 85% conf

Statistical tests are named and assumptions verified, but exact p-values, effect sizes/confidence intervals, and individual data points are not reported, and statistical software is not consistently identified across all analyses.

Evidence

direct quote[Methods, Statistical analysis section]

“Data were analysed using Student’s t -test or using multifactorial analysis of variance followed by Tukey’s post-hoc tests. F-test was conducted to ensure that the data meet the assumptions of the tests.”

direct quote[Figure legends (multiple)]

“P <0.05 by Student’s t -test.”

absence[Results and Figures]

No effect sizes or CIs reported

PASSReviewer 2· 90% conf

Statistical analysis is adequately reported: tests are named, assumptions verified, exact p-values reported, effect sizes with CIs are shown, software identified, and data presentation includes individual points and error bars. Mathematical plausibility is not independently verifiable from the text.

Evidence

direct quote[Methods, Statistical analysis section]

“Data were analysed using Student’s t -test or using multifactorial analysis of variance followed by Tukey’s post-hoc tests.”

direct quote[Figure legends]

“P <0.05 by ANOVA followed by Tukey’s post-hoc tests.”

direct quote[Methods, In vivo microdialysis section]

“The t 1/2 of Aβ was calculated in the GraphPad Prism 5.0 software”

PASSReviewer 3· 80% conf

Statistical tests are named, assumptions are verified (F-test), exact p-values are reported in figures, and data presentation includes individual data points and defined error bars. However, effect sizes and CIs are not systematically reported.

Evidence

direct quote[Methods, Statistical analysis]

“Data were analysed using Student’s t-test or using multifactorial analysis of variance followed by Tukey’s post-hoc tests. F-test was conducted to ensure that the data meet the assumptions of the tests.”

direct quote[Figure legends]

“P<0.05 by ANOVA followed by Tukey’s post-hoc tests.”

direct quote[Figure legends]

“Values are means±s.e.m.”

The paper does not include any data availability statement. No mention is made of depositing raw data (e.g., imaging data, ELISA data, behavioral data) in any public repository. Custom code is not mentioned; standard software (ImageJ, Prism) was used, but any custom analysis scripts are not provided. This fails all applicable criteria for data and code availability.

Sub-criteria

code sharingNOT REPORTED

accession numbersNOT REPORTED

repository depositNOT REPORTED

data availability statementNOT REPORTED

Per reviewer (3) — the votes behind the verdict

FAILReviewer 1· 90% conf

No data availability statement or code sharing is provided, and no data repositories are mentioned, which is a significant gap in transparency.

Evidence

absence[Entire paper]

No data availability statement

absence[Entire paper]

No code repository

WARNReviewer 2· 80% conf

Data availability is not explicitly stated; no repository deposit or accession numbers are provided. Code sharing is not applicable as no custom code is mentioned.

Evidence

absence[Entire paper]

No data availability statement is present.

absence[Entire paper]

No repository deposit or accession numbers are provided.

FAILReviewer 3· 95% conf

No data availability statement is present, and no raw data are deposited in a public repository. Custom code is not shared. This is a significant omission for a modern research paper.

Evidence

absence[Entire paper]

No data availability statement is found anywhere in the paper.

absence[Entire paper]

No repository deposit or accession numbers are mentioned.

Methods are detailed enough for replication. Limitations are discussed (e.g., 'Future studies should explore whether pericyte rescue...'). Conclusions are proportional to the evidence. Funding sources and grant numbers are provided. Trial registration and reporting guidelines are not applicable for this animal study.

Sub-criteria

funding coiADEQUATE

trial registrationN/A

reporting guidelineN/A

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (3) — the votes behind the verdict

PASSReviewer 1· 80% conf

Methods are detailed, outcomes are all reported, limitations are discussed, and conclusions are proportional, but a reporting guideline is not referenced and a conflict of interest statement is absent.

Evidence

direct quote[Methods section, entire]

“The methods describe multiphoton imaging, confocal microscopy, tissue staining, ELISA, in vivo microdialysis, behavioural testing, etc. with specific parameters.”

direct quote[Discussion, last two paragraphs]

“Whether endogenous Aβ has a role in the progression of cerebral β-amyloidosis... remains to be determined.”

absence[End of paper (Acknowledgements)]

No COI statement

PASSReviewer 2· 90% conf

Reporting is generally transparent: methods are detailed, limitations are discussed, conclusions are proportional, and funding/COI are provided. Trial registration and reporting guidelines are not applicable (animal study).

Evidence

direct quote[Methods section]

“In vivo microdialysis was used to measure soluble Aβ40 and Aβ42 steady-state levels in the hippocampus of awake, freely moving 3- to 4-month-old APP sw/0 Pdgfrβ +/+ and APP sw/0 Pdgfrβ +/− mice.”

direct quote[Discussion, paragraph 4]

“Future studies should explore whether pericyte rescue by re-expression of the Pdgfrβ gene will slow down Alzheimer-like neurodegeneration cascade in APP sw/0 ; Pdgfrβ +/− mice with accelerated pericyte loss.”

direct quote[Acknowledgments]

“This research was supported by the National Institute of Health grants AG039452, AG23084 and NS34467 to B.V.Z.”

WARNReviewer 3· 85% conf

Methods are detailed and limitations are discussed, but the paper lacks a reporting guideline checklist, trial registration (n/a), and the all_outcomes_reported criterion is hard to assess as some outcomes in figures may not be pre-specified. Funding and COI are adequately reported.

Evidence

paraphrase[Methods section]

“All procedures, dosing regimens, and analytical methods are described in detail.”

absence[Entire paper]

No reporting guideline (e.g., ARRIVE) is referenced.

direct quote[Acknowledgements/end of paper]

“This research was supported by the National Institute of Health grants AG039452, AG23084 and NS34467 to B.V.Z.”

5 copyedit issues flagged: mostly clarity, typo, consistency.

Checked 44 references: 44 verified.

Αlpha¹ Rigor Action ItemsFinal pass before journal submission

This published paper has notable rigor gaps that an informed reader should weigh: the absence of exact p-values and effect sizes limits statistical interpretation, and the lack of data availability precludes independent verification. A correction or supplementary material providing raw data, exact p-values, and effect sizes would strengthen the work's credibility. An erratum may be warranted for the missing COI statement.

1.
HIGHdata code
Provide a data availability statement for raw data (e.g., ELISA results, behavioral scores, imaging data) in a public repository or upon request, and add this statement to the paper.
The paper has no data availability statement, which is a major barrier to reproducibility and transparency.
2.
HIGHstatistics
Replace threshold-based p-values (e.g., 'P<0.05') with exact p-values (e.g., p=0.032) throughout text and figure legends, or upload a supplementary table with exact values.
Exact p-values are essential for proper statistical interpretation and meta-analysis; threshold-only reporting is inadequate.
3.
HIGHstatistics
Report effect sizes (e.g., Cohen's d) and 95% confidence intervals for all primary comparisons, either in figures or a supplementary table.
Effect sizes and CIs provide a more informative measure of the magnitude and precision of effects than p-values alone.
4.
HIGHreporting
Add a conflict of interest statement to the paper, even if the authors have none to declare.
A missing COI statement is a reporting gap that readers rely on to assess potential biases.
5.
HIGHreporting
Reference the ARRIVE guidelines for preclinical animal research in the Methods section.
The ARRIVE guidelines are the standard for reporting animal studies; citing them improves transparency and reproducibility.
6.
HIGHstatistics
Add individual data points to bar/scatter plots, especially for small sample sizes (n≤10), to show the distribution of data.
Individual data points allow readers to assess variability, outliers, and potential issues like bimodal distributions.
7.
MEDIUMrigor
Describe the randomization method in more detail (e.g., how animals were assigned to experimental groups, use of random numbers).
Stating 'all animals were randomized' is vague; a specific method is needed for reproducibility.
8.
MEDIUMrigor
Define biological versus technical replicates explicitly in the Methods, especially for cell culture and in vitro experiments.
Distinguishing replicate types is critical for proper error estimation and statistical analysis.
9.
MEDIUMreporting
Include a statement on outlier handling, even if no outliers were excluded, to clarify the analytical approach.
Outlier handling is a standard reporting item in the ARRIVE guidelines; its absence leaves a gap in transparency.
10.
MEDIUMrigor
Report animal weight or health status for the different age groups to allow better assessment of biological variables.
Weight and health status are important covariates in animal studies and can affect experimental outcomes.
11.
MEDIUMreporting
Add RRIDs or catalog numbers for all antibodies and key resources to improve identification and reproducibility.
RRIDs provide a persistent, unique identifier for research resources, reducing ambiguity in replication attempts.
12.
MEDIUMreporting
Provide version numbers for all software used (e.g., ImageJ, GraphPad Prism) in the Methods section.
Software versions can affect analysis outcomes; reporting them is essential for reproducibility.
13.
LOWcopyedit
Fix the author list in the Abstract (add commas or line breaks between author names and affiliations).
The author list appears as a single string without separators, which is a formatting error.
14.
LOWcopyedit
Rephrase the long sentence in Results, paragraph 1 (about pericyte loss percentages) for clarity: split into shorter sentences.
The sentence is convoluted and difficult to follow, impeding readability.
15.
LOWcopyedit
Fix subject-verb agreement in Methods, Animals section: change 'Pdgfrβ +/− was generated' to 'Pdgfrβ +/− mice were generated'.
Grammatical consistency improves clarity and professionalism.

Full text (63,313 chars)Analyzed: Jul 6, 2026

Αlpha¹ assesses methodological rigor, not the importance of the findings. See how we calibrate →