Loss of Inpp5d has disease‐relevant and sex‐specific effects on glial transcriptomes
Open accessAbstract
INTRODUCTION: Inpp5d is genetically associated with Alzheimer's disease risk. Loss of Inpp5d alters amyloid pathology in models of amyloidosis. Inpp5d is expressed predominantly in microglia but its function in brain is poorly understood. METHODS: We performed single‐cell RNA sequencing to study the effect of Inpp5d loss on wild‐type mouse brain transcriptomes. RESULTS: Loss of Inpp5d has sex‐specific effects on the brain transcriptome. Affected genes are enriched for multiple neurodegeneration terms. Network analyses reveal a gene co‐expression module centered around Inpp5d in female mice. Inpp5d loss alters Pleotrophin (PTN), Prosaposin (PSAP), and Vascular Endothelial Growth Factor A (VEGFA) signaling probability between cell types. DISCUSSION: Our data suggest that the normal function of Inpp5d is entangled with mechanisms involved in neurodegeneration. We report the effect of Inpp5d loss without pathology and show that this has dramatic effects on gene expression. Our study provides a critical reference for researchers of neurodegeneration, allowing separation of disease‐specific changes mediated by Inpp5d in disease from baseline effects of Inpp5d loss. Highlights: Loss of Inpp5d has different effects in male and female mice. Genes dysregulated by Inpp5d loss relate to neurodegeneration. Total loss of Inpp5d in female mice collapses a conserved gene co‐expression module. Loss of microglial Inpp5d affects the transcriptome of other cell types.
AI snapshot
Written from the paper’s full text.
TL;DR
In wild-type mice, loss of *Inpp5d* causes sex-specific and cell-type-specific transcriptomic changes, with female *Inpp5d*−/− mice showing far more differentially expressed genes and collapse of an *Inpp5d*-centered microglial co-expression module. The authors provide a baseline single-cell resource for separating *Inpp5d* effects from amyloid pathology.
Key findings
- Female *Inpp5d*−/− mice had 2,874 DEGs, almost three times more than any other comparison; 137 DEGs overlapped across all comparisons, and all overlapping DEG lists were enriched for KEGG neurodegeneration terms including Parkinson disease, amyotrophic lateral sclerosis, Alzheimer's disease, prion disease, pathways of neurodegeneration, and Huntington disease.
- hdWGCNA identified a female microglial module (Female-1) of 5,056 genes with *Inpp5d* as the most central gene; its eigenvalue was dramatically reduced in *Inpp5d*−/− microglia. A male microglial module existed but *Inpp5d* was less central (256/5,798) and showed no notable eigenvalue change by genotype.
- CellChat inferred decreased total interactions in female mice from wild-type (203) to heterozygous (195) to homozygous knockout (70), with interaction strength falling from 8.279/8.384 to 2.154. In male mice, interactions increased from 246/207 to 359 and strength from 6.331/6.482 to 10.628. PTN signaling decreased and PSAP/VEGFA signaling increased in both sexes, while NCAM1 astrocyte communication changed in opposite directions by sex.
- Cluster proportions differed by sex for M1 (p = 4.4 × 10−3), M2 (p = 0.0348), and M3 (p = 8.4 × 10−3); male *Inpp5d*−/− mice showed decreased M1 (p = 0.0129), male *Inpp5d*+/− mice showed increased M3 (p = 0.0323), and homozygous loss increased microglial cluster 4 (p = 0.039).
Methods
- Single-cell RNA sequencing was performed on 6-week-old C57BL/6J wild-type, *Inpp5d*+/−, and *Inpp5d*−/− mice, with two males and two females per genotype (total n = 12), using a custom neuron-depleting dissociation protocol, myelin removal, and 10x Genomics Chromium Next GEM Single Cell 3′ v3.1; 57,742 cells passed quality control.
- Data were processed with CellRanger v4.0.0, SoupX, DoubletFinder, and Seurat/SCTransform; clustering used 26 principal components overall, 22 for female and 25 for male datasets, with annotation by scMCA.
- Differential expression used Wilcoxon rank-sum tests with Bonferroni adjustment; hdWGCNA and CellChat were run on merged astrocyte, endothelial, microglia, and oligodendrocyte clusters.
Limitations
- The paper states that sample size was reduced to n = 2 per genotype and sex, and that high variance in cluster proportions for M1 and M3 made the authors hesitant to draw firm conclusions from those distributions; it also notes that cross-study comparisons are difficult because prior *Inpp5d* studies used differing methodologies.
- Evident from the text: mice were analyzed only at 6 weeks because homozygous knockouts are not viable after 7–12 weeks, and no amyloid/pathology model was used, so findings represent baseline effects before disease onset.
- Evident from the text: CellChat signaling changes are inferred from ligand–receptor expression rather than experimentally validated, and hdWGCNA modules are co-expression associations rather than causal relationships.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
26 of 34 cited sources checked · 13 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Inpp5d is expressed predominantly in microglia in the brain.
“Inpp5d is expressed predominantly in microglia but its function in brain is poorly understood.”
- Also stated in: § INTRODUCTION · hedged
“In the brain, Inpp5d is thought to be expressed mainly in microglia”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [16] Karch CM, Goate AM. Alzheimer's disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry. 2015; 77: 43‐ 51. 24951455 PMC4234692 source
The Immune Response > CD33 section discusses microglial expression of CD33, not INPP5D. Searches of our full-text copy for INPP5D and SHIP1 found no passage addressing whether INPP5D is expressed predominantly in brain microglia; page numbers were unavailable. (LLM, conf=0.75)
Experimental — accuracy not yet measured
- Also stated in: § INTRODUCTION · hedged
- Premisecitation
Loss of Inpp5d alters amyloid pathology in models of amyloidosis.
“Loss of Inpp5d alters amyloid pathology in models of amyloidosis.”
- Also stated in: § INTRODUCTION · plain
“Recent research has revealed that Inpp5d was upregulated in amyloid plaque–associated microglia in 5XFAD models of familial AD and that ablation of Inpp5d in these mice reduced amyloid pathology.”
Quote in the paperSubstantial claim3 of 3 sources checked- cites [17] Tsai AP, Lin PB‐C, Dong C, et al. INPP5D expression is associated with risk for Alzheimer's disease and induced by plaque‐associated microglia. Neurobiol Dis. 2021; 153: 105303. 33631273 PMC8082515 source
The Results section reports increased Inpp5d expression in 5xFAD mice, not the effect of losing Inpp5d on amyloid pathology. The Discussion says findings from an Inpp5d-inactivated mouse model will help determine its role in disease progression; the Conclusions likewise place loss-of-function effects in future studies. Searches for loss of Inpp5d and amyloid pathology found no reported outcome. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [18] Lin PB‐C, Tsai APo‐Yi, Soni D, et al. INPP5D deficiency attenuates amyloid pathology in a mouse model of Alzheimer's disease. Alzheimer's Dement. 2023; 19(6): 2528‐ 2537. doi: 10.1002/alz.12849 36524682 source
The Abstract reports that Inpp5d haplodeficiency increased amyloid plaque clearance in 5xFAD mice, supporting an effect on amyloid pathology. The claim says “models” of amyloidosis, but the paper reports this finding in one model, 5xFAD. (LLM, conf=0.83)
Experimental — accuracy not yet measured - cites [19] Castranio EL, Hasel P, Haure‐Mirande J‐V, et al. Microglial INPP5D limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease. Alzheimer's Dement. 2023; 19(6): 2239‐ 2252. doi: 10.1002/alz.12821 36448627 PMC10481344 source
- Also stated in: § INTRODUCTION · plain
- Findingcitation
M7 shows high expression of activation marker Tyrobp.
“whereas M7 shows high expression of activation marker Tyrobp. 36 , 37 , 38”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [36] Murai N, Mitalipova M, Jaenisch R. Functional analysis of CX3CR1 in human induced pluripotent stem (iPS) cell‐derived microglia‐like cells. Eur J Neurosci. 2020; 52: 3667‐ 3678. 32579729 PMC8168698 source
The Results section on activation markers identifies TNFα, IL-6, IL-1β, CD206, IL-4 and ARG1, but does not discuss Tyrobp or M7. Searches for the quoted phrase and for Tyrobp with M7 found no passage addressing the claimed expression pattern; page numbers were unavailable in our copy. (LLM, conf=0.75)
Experimental — accuracy not yet measured - cites [37] Morillas AG, Besson VC, Lerouet D. Microglia and neuroinflammation: what place for p2ry12? Int J Mol Sci. 2021; 22: 1‐ 16. PMC7915979 33561958 source
Section 2.4 discusses P2RY12 as a marker of healthy microglia and its decrease during activation; section 4 discusses microglial activation states. Neither addresses an M7 population or Tyrobp expression. Searches for “M7 Tyrobp” and “Tyrobp activation marker microglial cluster M7” found no passage supporting the claim; page numbers were not available in our copy. (LLM, conf=0.73)
Experimental — accuracy not yet measured - cites [38] Audrain M, Haure‐Mirande J‐V, Mleczko J, et al. Reactive or transgenic increase in microglial TYROBP reveals a TREM2‐independent TYROBP–APOE link in wild‐type and Alzheimer's‐related mice. Alzheimer's Dement. 2021; 17: 149‐ 163. 33314529 PMC7938663 source
The Results (Figure 1) report increased Tyrobp expression in recruited microglia, supporting the expression part of the claim. Our copy does not identify an M7 population or show that M7 has high Tyrobp expression. The Results also distinguish recruitment from activation: Tyrobp mRNA was unchanged in activated resident microglia. (LLM, conf=0.82)
Experimental — accuracy not yet measured
- Premisecitation
In postmortem human brain tissue, dysregulation of microglial gene signatures is more common in female patients than in male patients.
“Similar observations were made in a study of postmortem human brain tissue, where dysregulation of microglial gene signatures was shown to be more common in female patients than in male patients. 40”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [40] Coales I, Tsartsalis S, Fancy N, et al. Alzheimer's disease‐related transcriptional sex differences in myeloid cells. J Neuroinflammation. 2022; 19: 1‐ 13. 36199077 PMC9535846 source
The Discussion reports that Bonham et al. inferred microglial-gene dysregulation in patients with Alzheimer’s disease to a greater extent in women than men. But this is a finding the cited paper attributes to another study; its own sex-specific gene-signature findings were primarily in postmortem microglia from donors without neurological disease, and its Results say the AD-donor samples showed no significant sex difference for the inflammatory gene sets tested. (LLM, conf=0.86)
Experimental — accuracy not yet measured
- Findingown data
M8 shows high expression of Lpl, a gene recently implicated in myelin-scavenging activated microglia.
“M8 shows high expression of Lpl, a gene recently implicated in myelin‐scavenging activated microlia. 39”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [39] Bruce KD, Gorkhali S, Given K, et al. Lipoprotein lipase is a feature of alternatively‐activated microglia and may facilitate lipid uptake in the CNS during demyelination. Front Mol Neurosci. 2018; 11: 1‐ 13. 29599706 PMC5862862 source
- Premisecitation
Lin et al. found that deletion of one copy of Inpp5d reduced plaque pathology as measured by immunohistochemical approaches.
“In contrast to the study by Castranio et al., the deletion of one copy of Inpp5d reduced plaque pathology as measured by immunohistochemical approaches.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [18] Lin PB‐C, Tsai APo‐Yi, Soni D, et al. INPP5D deficiency attenuates amyloid pathology in a mouse model of Alzheimer's disease. Alzheimer's Dement. 2023; 19(6): 2528‐ 2537. doi: 10.1002/alz.12849 36524682 source
- Findingown data
A total of 137 DEGs overlapped between heterozygous and homozygous knockout mice of both sexes.
“A total of 137 DEGs overlapped between heterozygous and homozygous knockout mice of both sexes”
Quote in the paperNot a substantial claim - Findingown data
Genes dysregulated by Inpp5d loss are enriched for multiple neurodegeneration terms.
“Affected genes are enriched for multiple neurodegeneration terms.”
- Also stated in: § Highlights · plain
“Genes dysregulated by Inpp5d loss relate to neurodegeneration.”
- Also stated in: § Loss of Inpp5d causes extensive dysregulation of genes linked to multiple forms of neurodegeneration · plain
“ontology terms for multiple neurodegenerative diseases (Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, prion disease, pathways of neurodegeneration, and Huntington's disease) were significantly enriched within DEG lists across all comparisons”
Quote in the paperSubstantial claim - Also stated in: § Highlights · plain
- Findingown data
Homozygous loss of Inpp5d causes a statistically significant increase in the number of cells in microglial cluster 4 (p = 0.039).
“Homozygous loss of Inpp5d caused a statistically significant increase in the number of cells in microglial cluster 4 (p = 0.039; Figure S2)”
Quote in the paperNot a substantial claim - Findingown data
Microglia signal mostly to other microglia and astrocytes.
“It is notable that microglia signal mostly to other microglia and astrocytes (Figure 5E).”
Quote in the paperNot a substantial claim- Rests on an assumption: Inferred ligand-receptor interactions from CellChat reflect actual cell-cell communication.
- Findingown data
In male mice, the total sum probability of interactions increased from wild-type (6.331) and heterozygous knockout (6.482) to homozygous knockout (10.628).
“Similarly, the total sum probability of interactions in the wild‐type (6.331) and heterozygous knockout (6.482) increased to 10.628 in the homozygous knockout mice.”
Quote in the paperNot a substantial claim- Rests on an assumption: Inferred ligand-receptor interactions from CellChat reflect actual cell-cell communication.
- Findingown data
In female mice, the sum probability of interactions (interaction strength) decreases from wild-type (8.279) and heterozygous knockout (8.384) to homozygous knockout (2.154).
“The sum probability of interactions (interaction strength) also decreased from wild‐type (8.279) and heterozygous knockout (8.384) to homozygous knockout (2.154) (Figure 5C).”
Quote in the paperSubstantial claim - Findingown data
Loss of microglial Inpp5d affects the transcriptome of other cell types.
“Loss of microglial Inpp5d affects the transcriptome of other cell types.”
- Also stated in: § Loss of Inpp5d causes extensive dysregulation of genes linked to multiple forms of neurodegeneration · plain
“Across both sexes, in astrocytes, 347 genes were upregulated, whereas 607 genes were downregulated; in endothelial cells, 179 genes were upregulated and 859 genes were downregulated; in microglia, 2502 genes were upregulated and 3816 genes were downregulated; and in oligodendrocytes, 281 genes were upregulated and 1021 genes were downregulated.”
Quote in the paperSubstantial claim - Also stated in: § Loss of Inpp5d causes extensive dysregulation of genes linked to multiple forms of neurodegeneration · plain
- Findingown data
Inpp5d loss without pathology has dramatic effects on gene expression.
“We report the effect of Inpp5d loss without pathology and show that this has dramatic effects on gene expression.”
Quote in the paperSubstantial claim - Findingown data
Total loss of Inpp5d in female mice collapses a conserved gene co-expression module.
“Total loss of Inpp5d in female mice collapses a conserved gene co‐expression module.”
- Also stated in: § Loss of Inpp5d has dramatic effects on gene regulatory networks in female mice compared to male mice · plain
“The eigenvalues of the Female‐1, Female‐2, and Female‐4 modules were dramatically reduced in Inpp5d −/− microglia, endothelial cells, and oligodendrocytes, respectively”
Quote in the paperSubstantial claim - Also stated in: § Loss of Inpp5d has dramatic effects on gene regulatory networks in female mice compared to male mice · plain
- Findingown data
Loss of Inpp5d has sex-specific effects on the brain transcriptome.
“Loss of Inpp5d has sex‐specific effects on the brain transcriptome.”
- Also stated in: § Highlights · plain
“Loss of Inpp5d has different effects in male and female mice.”
- Also stated in: § Loss of Inpp5d has sex‐ and genotype‐specific effects on microglial populations · plain
“Strikingly, when we plotted the proportion of cells in each cluster by sex, we detected significant differences in the proportions of M1 (p = 4.4 × 10−3), M2 (p = 0.0348) and M 3 (p = 8.4 × 10−3) microglia”
Quote in the paperSubstantial claim - Also stated in: § Highlights · plain
- Findingown data
In male Inpp5d−/− mice, VEGFA signaling from astrocytes to endothelial cells increased.
“and increases in PSAP signaling to astrocytes and VEGFA signaling from astrocytes to endothelial cells.”
Quote in the paperSubstantial claim- Rests on an assumption: Inferred ligand-receptor interactions from CellChat reflect actual cell-cell communication.
- Findingown data
In male Inpp5d−/− mice, PTN signaling from astrocytes and endothelial cells decreased.
“we observed decreases in PTN signaling from astrocytes and endothelial cells in Inpp5d −/− mice”
Quote in the paperSubstantial claim- Rests on an assumption: Inferred ligand-receptor interactions from CellChat reflect actual cell-cell communication.
- Findingown data
In female Inpp5d−/− mice, PSAP and VEGFA signaling from astrocytes to astrocytes/endothelial cells was increased.
“Conversely, prosaposin (PSAP) signaling from microglia to astrocytes, and PSAP and vascular endothelial growth factor A (VEGFA) signaling from astrocytes to astrocytes/endothelial cells, respectively, were increased (Figure 5F).”
Quote in the paperSubstantial claim- Rests on an assumption: Inferred ligand-receptor interactions from CellChat reflect actual cell-cell communication.
- Findingown data
In female Inpp5d−/− mice, inferred PTN and NCAM1 signaling from astrocytes to astrocytes was decreased.
“We found that inferred pleiotrophin (PTN) and neural cell adhesion molecule 1 (NCAM1) signaling from astrocytes to astrocytes was decreased (Figure 5F).”
Quote in the paperSubstantial claim- Rests on an assumption: Inferred ligand-receptor interactions from CellChat reflect actual cell-cell communication.
- Findingown data
In female Inpp5d−/− mice, PSAP signaling from microglia to astrocytes was increased.
“Conversely, prosaposin (PSAP) signaling from microglia to astrocytes, and PSAP and vascular endothelial growth factor A (VEGFA) signaling from astrocytes to astrocytes/endothelial cells, respectively, were increased (Figure 5F).”
Quote in the paperSubstantial claim- Rests on an assumption: Inferred ligand-receptor interactions from CellChat reflect actual cell-cell communication.
- Findingown data
Inpp5d is the most central gene in the Female-1 co-expression module.
“the gene with the highest intramodule connectivity was indeed Inpp5d”
Quote in the paperSubstantial claim - Findingown data
In male Inpp5d−/− mice, F11R signaling between microglia decreased.
“We also inferred decreased junctional adhesion molecule A (F11R) signaling between microglia”
Quote in the paperNot a substantial claim- Rests on an assumption: Inferred ligand-receptor interactions from CellChat reflect actual cell-cell communication.
- Findingown data
There were almost three times more DEGs (2874 DEGs) in female Inpp5d−/− mice than in any other comparison group.
“There were almost three times more DEGs (2874 DEGs) in female Inpp5d −/− mice than in any other comparison group”
Quote in the paperSubstantial claim - Findingown data
Six modules of coexpressed genes were identified in the female data set.
“We identified six modules of coexpressed genes in the female data set”
Quote in the paperSubstantial claim - Findingown data
In female mice, the total number of interactions between cell types decreases with loss of Inpp5d from wild-type (203 interactions) to heterozygous knockout (195 interactions) to homozygous knockout (70 interactions).
“we observed a decrease in the total number of interactions between cell types with loss of Inpp5d from wild‐type (203 interactions) to heterozygous knockout (195 interactions) to homozygous knockout (70 interactions) (Figure 5C, Table S10).”
Quote in the paperSubstantial claim - Findingown data
Inpp5d loss alters Pleotrophin (PTN), Prosaposin (PSAP), and Vascular Endothelial Growth Factor A (VEGFA) signaling probability between cell types.
“Inpp5d loss alters Pleotrophin (PTN), Prosaposin (PSAP), and Vascular Endothelial Growth Factor A (VEGFA) signaling probability between cell types.”
Quote in the paperSubstantial claim - Findingown data
In female Inpp5d−/− mice, both incoming and outgoing interaction strengths decreased dramatically in astrocytes, microglia, and endothelial cells.
“both the incoming and outgoing interaction strengths decreased dramatically in Inpp5d−/− astrocytes, microglia, and endothelial cells”
Quote in the paperSubstantial claim- Rests on an assumption: Inferred ligand-receptor interactions from CellChat reflect actual cell-cell communication.
- Findingown data
In male Inpp5d−/− mice, PSAP signaling to astrocytes increased.
“increases in PSAP signaling to astrocytes”
Quote in the paperSubstantial claim- Rests on an assumption: Inferred ligand-receptor interactions from CellChat reflect actual cell-cell communication.
- Findingown data
The eigenvalues of the Female-1, Female-2, and Female-4 modules were dramatically reduced in Inpp5d−/− microglia, endothelial cells, and oligodendrocytes, respectively.
“The eigenvalues of the Female‐1, Female‐2, and Female‐4 modules were dramatically reduced in Inpp5d −/− microglia, endothelial cells, and oligodendrocytes, respectively”
Quote in the paperSubstantial claim - Findingown data
There are no significant differences in the number of cells per cluster per genotype in the female data set.
“We observed no significant differences in the number of cells per cluster per genotype in the female data set”
Quote in the paperNot a substantial claim - Findingown data
In male mice, the number of interactions between cell types increased from wild-type (246 interactions) and heterozygous knockout (207 interactions) to homozygous knockout (359 interactions).
“The number of interactions between cell types in the wild‐type (246 interactions) and heterozygous knockout (207 interactions) increased in the homozygous knockout mice (359 interactions).”
Quote in the paperSubstantial claim- Rests on an assumption: Inferred ligand-receptor interactions from CellChat reflect actual cell-cell communication.
- Findingown data
Inpp5d is expressed exclusively in microglia.
“Given that Inpp5d is expressed exclusively in microglia (Figure S1)”
Quote in the paperSubstantial claim - Findingown data
Network analyses reveal a gene co-expression module centered around Inpp5d in female mice.
“Network analyses reveal a gene co‐expression module centered around Inpp5d in female mice.”
- Also stated in: § Loss of Inpp5d has dramatic effects on gene regulatory networks in female mice compared to male mice · hedged
“the gene with the highest intramodule connectivity was indeed Inpp5d, suggesting that Female‐1 is composed of genes coexpressed with or regulated by Inpp5d”
Quote in the paperSubstantial claim - Also stated in: § Loss of Inpp5d has dramatic effects on gene regulatory networks in female mice compared to male mice · hedged
- Findingown data
There are significant differences in cluster cell proportions between males and females.
“Of interest, we found significant differences in cluster cell proportions between males and females.”
Quote in the paperSubstantial claim - Findingown data
Among the 137 genes dysregulated in all comparisons, several have been linked to microglial activation or actin remodeling.
“Among the 137 genes dysregulated in all comparisons, several have been linked to microglial activation (Hsp90ab1, Fth1, Sall1, Irf8, Cts3, Fus, Hexb, Apoe, Tyrobp, Lyz2) or actin remodeling (Actb, Macf1, Tns1, Ssh2, Tmsb4x, Srgap2, Rcsd1)”
Quote in the paperSubstantial claim - Findingown data
In male Inpp5d−/− mice, NCAM1 signaling between astrocytes increased.
“and an increase in NCAM1 signaling between astrocytes.”
Quote in the paperSubstantial claim- Rests on an assumption: Inferred ligand-receptor interactions from CellChat reflect actual cell-cell communication.
- Findingown data
Two top marker genes for M1 are homeostatic markers Cx3cr1 and P2ry12.
“Two top marker genes for M1 are homeostatic markers Cx3cr1 and P2ry12”
Quote in the paperSubstantial claim - Findingown data
There is a striking difference in gene expression patterns between male and female mice upon deletion of Inpp5d.
“We found a striking difference in gene expression patterns between male and female mice upon the deletion of Inpp5d.”
Quote in the paperSubstantial claim - Findingown data
This module's eigenvalue was dramatically decreased in homozygous knockout mice.
“This module's eigenvalue was dramatically decreased in homozygous knockout mice”
Quote in the paperSubstantial claim- Rests on an assumption: Co-expression modules identified by hdWGCNA correspond to biologically meaningful cell states.
- Findingown data
In male mice, loss of Inpp5d did not notably decrease the module eigenvalue.
“and the loss of Inpp5d did not notably decrease the module eigenvalue (Figure S5).”
Quote in the paperSubstantial claim- Rests on an assumption: Co-expression modules identified by hdWGCNA correspond to biologically meaningful cell states.
- Findingown data
A similar module was present in male mice.
“A similar module was present in male mice”
Quote in the paperSubstantial claim- Rests on an assumption: Co-expression modules identified by hdWGCNA correspond to biologically meaningful cell states.
- Findingown data
The study reports novel reference single-cell transcriptome data sets for Inpp5d+/− and Inpp5d−/− mice using a protocol that maximized capture of microglia.
“In this article, we reported novel reference single‐cell transcriptome data sets for Inpp5d+/− and Inpp5d −/− mice using a protocol that maximized the capture of microglia.”
Quote in the paperSubstantial claim - Findingown data
A module of genes expressed in microglia centered around Inpp5d was identified in female mice.
“We identified a module of genes expressed in microglia centered around Inpp5d in female mice (Figure 4E).”
Quote in the paperSubstantial claim- Rests on an assumption: Co-expression modules identified by hdWGCNA correspond to biologically meaningful cell states.
- Findingown data
In the male module, Inpp5d was less central.
“but Inpp5d was less central”
Quote in the paperSubstantial claim- Rests on an assumption: Co-expression modules identified by hdWGCNA correspond to biologically meaningful cell states.
- Findingown data
Extensive dysregulation of gene expression in microglia and other cell types occurs upon loss of Inpp5d.
“We observed extensive dysregulation of gene expression in microglia and other cell types upon loss of Inpp5d”
Quote in the paperSubstantial claim - Findingown data
Cells in M1 were greatly decreased in Inpp5d−/− mice.
“Cells in M1 were greatly decreased in Inpp5d −/− mice”
Quote in the paperSubstantial claim - Findingown data
An Inpp5d-centric gene co-expression module in female microglia contains 5056 genes.
“We also identified an Inpp5d‐centric gene co‐expression module in female microglia containing 5056 genes”
Quote in the paperNot a substantial claim- Rests on an assumption: Co-expression modules identified by hdWGCNA correspond to biologically meaningful cell states.
- Findingown data
When data were segregated by sex, there were significant changes in cell proportions in microglial clusters 1 and 3 based on genotype.
“When the data were segregated by sex, we observed significant changes in cell proportions in microglial clusters 1 and 3 based on genotype.”
Quote in the paperSubstantial claim - Findingown data
Inpp5d is expressed only in microglia and other immune cells in the brain.
“Although we confirmed that Inpp5d is expressed only in microglia and other immune cells in the brain”
Quote in the paperSubstantial claim - Findingown data
Many of the dysregulated genes are implicated in diseases other than AD.
“we were surprised by how many of these genes were implicated in diseases other than AD (Figure 3B).”
Quote in the paperSubstantial claim - Findingnone given
The study determined the consequences of a total loss of Inpp5d at single-cell resolution in both male and female mice.
“In conclusion, we determined the consequences of a total loss of Inpp5d at single‐cell resolution in both male and female mice.”
Quote in the paperSubstantial claim - Interpretationown data
The normal function of Inpp5d is entangled with mechanisms involved in neurodegeneration.
“Our data suggest that the normal function of Inpp5d is entangled with mechanisms involved in neurodegeneration.”
Quote in the paperSubstantial claim - Interpretationown data
The Female-1 module is composed of genes coexpressed with or regulated by Inpp5d.
“suggesting that Female‐1 is composed of genes coexpressed with or regulated by Inpp5d”
Quote in the paperSubstantial claim - Interpretationown data
Loss of Inpp5d in microglia affects signaling in other cell types.
“suggesting that the loss of Inpp5d in microglia affects signaling in other cell types (Figure 5D).”
Quote in the paperSubstantial claim- Rests on an assumption: Inferred ligand-receptor interactions from CellChat reflect actual cell-cell communication.
- Premisecitation
Inpp5d is genetically associated with Alzheimer's disease risk.
“Inpp5d is genetically associated with Alzheimer's disease risk.”
- Also stated in: § INTRODUCTION · plain
“a meta‐analysis of two AD GWAS (n = 54,162) revealed an intronic single‐nucleotide polymorphism (SNP; rs35349669) in INPP5D that is associated with AD risk.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Lambert J‐C, Ibrahim‐Verbaas CA, Harold D, et al. Meta‐analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013; 45: 1452‐ 1458. 24162737 PMC3896259 source
- Also stated in: § INTRODUCTION · plain
- Interpretationreasoning
These data represent a baseline effect of Inpp5d loss.
“Therefore, these data represent a baseline effect of Inpp5d loss”
Quote in the paperSubstantial claim - Interpretationreasoning
Inpp5d expression may affect the ability of microglia to clear protein aggregates in other neurodegenerative diseases.
“Thus, Inpp5d expression may affect the ability of microglia to clear protein aggregates in other neurodegenerative diseases.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Downregulation of PTN signaling through loss of Inpp5d could enhance neuroinflammation.
“Downregulation of this signaling pathway through the loss of Inpp5d could, therefore, enhance neuroinflammation.”
Quote in the paperSubstantial claim- Rests on an assumption: Inferred ligand-receptor interactions from CellChat reflect actual cell-cell communication.
- Interpretationown data
This module is composed of genes whose expression correlates tightly with Inpp5d.
“confirming that this module is composed of genes whose expression correlates tightly with Inpp5d.”
Quote in the paperSubstantial claim- Rests on an assumption: Co-expression modules identified by hdWGCNA correspond to biologically meaningful cell states.
- Interpretationown data
There is an opposite direction of NCAM1 communication probability between the astrocytes of each sex in Inpp5d−/− mice.
“whereas there is an opposite direction of NCAM1 communication probability between the astrocytes of each sex.”
Quote in the paperSubstantial claim- Rests on an assumption: Inferred ligand-receptor interactions from CellChat reflect actual cell-cell communication.
- Interpretationown data
Inpp5d may exert greater control over microglial gene regulation and function in female mice than in male mice.
“These contrasting findings in hdWGCNA between female and male mice, coupled with the elevated number of differentially expressed genes in female Inpp5d null mice, suggest that Inpp5d may exert greater control over microglial gene regulation and function in female mice than in male mice.”
Quote in the paperSubstantial claim- Rests on an assumption: Co-expression modules identified by hdWGCNA correspond to biologically meaningful cell states.
- Interpretationreasoning
Inpp5d loss drives a shift away from a homeostatic state.
“This suggests that Inpp5d loss drives a shift away from a homeostatic state.”
Quote in the paperSubstantial claim - Interpretationreasoning
M1 may represent homeostatic microglia.
“As the largest cluster in healthy young mice, M1 may represent homeostatic microglia.”
Quote in the paperSubstantial claim - Premisecitation
Iguchi et al. found that at 9 months of age, Inpp5d depletion increased microgliosis and plaque engagement in male mice.
“At 9 months of age, Inpp5d depletion increased microgliosis and plaque engagement in male mice.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Iguchi A, Takatori S, Kimura S, et al. INPP5D modulates TREM2 loss‐of‐function phenotypes in a β‐amyloidosis mouse model. iScience. 2023; 26: 106375. 37035000 PMC10074152 source
- Interpretationreasoning
Deletion of Inpp5d affects the transcriptome of non-microglial cells.
“its deletion seems to affect the transcriptome of non‐microglial cells.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 18
- May combine two claims. 21
Classified as probably not a substantial claim.
PremisecitationCellChat can predict the probability of 2021 validated molecular interactions between receptors and ligands across groups of cells.
“CellChat can predict the probability of 2021 validated molecular interactions between receptors and ligands across groups of cells (Figure 5A–B).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [28] Jin S, Guerrero‐Juarez CF, Zhang L, et al. Inference and analysis of cell‐cell communication using CellChat. Nat Commun. 2021; 12: 1‐ 20. 33597522 PMC7889871 source
May combine two claims.
PremisecitationElevated PTN is detected in the substantia nigra of patients with Parkinson's disease and in the CSF of patients with AD.
“Elevated PTN is detected in the substantia nigra of patients with Parkinson's disease and in the cerebrospinal fluid (CSF) of patients with AD. 41 , 42”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [41] Marchionini DM, Lehrmann E, Chu Y, et al. Role of heparin binding growth factors in nigrostriatal dopamine system development and Parkinson's disease. Brain Res. 2007; 1147: 77‐ 88. 17368428 source
- cites [42] Skillbäck T, Mattsson N, Hansson K, et al. A novel quantification‐driven proteomic strategy identifies an endogenous peptide of pleiotrophin as a new biomarker of Alzheimer's disease. Sci Rep. 2017; 7: 1‐ 12. 29042634 PMC5645330 source
The Results (Validation of PTN 151–166 as a biomarker of AD; page unavailable) report elevated CSF levels in AD patients, supporting the AD portion of the sentence. The measured substance was the PTN 151–166 peptide, not full-length PTN; the paper does not establish elevated PTN in the substantia nigra of patients with Parkinson’s disease. (LLM, conf=0.86)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationMicroglial activation and actin remodeling are processes that can be mediated by Inpp5d.
“which are both processes that can be mediated by Inpp5d. 6 , 20”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [6] Liu Q, Sasaki T, Kozieradzki I, et al. SHIP is a negative regulator of growth factor receptor‐mediated PKB/Akt activation and myeloid cell survival. Genes Dev. 1999; 13: 786‐ 791. 10197978 PMC316591 source
The paper’s Abstract (page unavailable) says PI3K and phospholipid-regulated signaling are implicated in cytoskeletal reorganization, and the SHIP-regulates-PKB section describes SHIP’s role in that signaling pathway. This provides indirect support for a connection to actin remodeling, but the paper does not show SHIP mediating actin remodeling or address microglial activation. (LLM, conf=0.73)
Experimental — accuracy not yet measured - cites [20] Iguchi A, Takatori S, Kimura S, et al. INPP5D modulates TREM2 loss‐of‐function phenotypes in a β‐amyloidosis mouse model. iScience. 2023; 26: 106375. 37035000 PMC10074152 source
Classified as probably not a substantial claim.
PremisecitationAstrocyte-derived PTN is an anti-inflammatory, neuroprotective factor secreted by reactive astrocytes.
“Accumulating evidence points to astrocyte‐derived PTN as an anti‐inflammatory, neuroprotective factor secreted by reactive astrocytes. 43 , 44”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [43] Linnerbauer M, Lößlein L, Farrenkopf D, et al. Astrocyte‐derived pleiotrophin mitigates late‐stage autoimmune CNS inflammation. Front Immunol. 2022; 12: 1‐ 14. PMC8762329 35046956 source
- cites [44] Iseki K, Hagino S, Mori T, et al. Increased syndecan expression by pleiotrophin and FGF receptor‐expressing astrocytes in injured brain tissue. Glia. 2002; 39: 1‐ 9. 12112370 source
May combine two claims.
PremisecitationPSAP is secreted by microglia and astrocytes in humans and predominantly by microglia in mice.
“PSAP is secreted by microglia and astrocytes in humans and predominantly by microglia in mice. 45 , 46”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [45] Zhang Ye, Chen K, Sloan SA, et al. An RNA‐sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci. 2014; 34: 11929‐ 11947. 25186741 PMC4152602 source
The purification and RNA-Seq sections describe mouse cortical cell populations, but do not address PSAP secretion or compare its cellular sources in humans and mice. Searches for PSAP, prosaposin, and human–mouse glial secretion found no passage supporting the claim in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites [46] Zhang Ye, Sloan SA, Clarke LE, et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron. 2016; 89: 37‐ 53. 26687838 PMC4707064 source
The Results passages on human astrocyte transcriptomes and human–mouse functional differences do not address PSAP secretion or compare its cellular sources across species. Searches of our copy for “PSAP,” “prosaposin,” and secretion by microglia and astrocytes found no relevant passage; page numbers were not available. (LLM, conf=0.74)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPrevious studies of Inpp5d in AD have employed APP transgenic or knock-in models.
“Previous studies of Inpp5d in AD have employed APP transgenic or knock‐in models to determine the effect of Inpp5d depletion on amyloid pathology. 18 , 19 , 20 , 49”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [18] Lin PB‐C, Tsai APo‐Yi, Soni D, et al. INPP5D deficiency attenuates amyloid pathology in a mouse model of Alzheimer's disease. Alzheimer's Dement. 2023; 19(6): 2528‐ 2537. doi: 10.1002/alz.12849 36524682 source
- cites [19] Castranio EL, Hasel P, Haure‐Mirande J‐V, et al. Microglial INPP5D limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease. Alzheimer's Dement. 2023; 19(6): 2239‐ 2252. doi: 10.1002/alz.12821 36448627 PMC10481344 source
- cites [20] Iguchi A, Takatori S, Kimura S, et al. INPP5D modulates TREM2 loss‐of‐function phenotypes in a β‐amyloidosis mouse model. iScience. 2023; 26: 106375. 37035000 PMC10074152 source
May combine two claims.
PremisecitationIn astrocytes, PSAP promotes motility and neuroprotective function, and is upregulated in the brains of patients with AD.
“In astrocytes, it promotes motility and neuroprotective function, and is upregulated in the brains of patients with AD. 47 , 48”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [47] Liu B, Mosienko V, Vaccari Cardoso B, et al. Glio‐ and neuro‐protection by prosaposin is mediated by orphan G‐protein coupled receptors GPR37L1 and GPR37. Glia. 2018; 66: 2414‐ 2426. 30260505 PMC6492175 source
The Results section on astrocyte motility reports that PSAP depletion slowed movement in a scratch assay, while the Results section on oxidative stress links PSAP signaling in astrocytes to protection of co-cultured neurons. The paper does not report PSAP upregulation in the brains of patients with AD; its reported increase was in culture media after neurons were stressed. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [48] Mendsaikhan A, Tooyama I, Bellier J‐P, et al. Characterization of lysosomal proteins Progranulin and Prosaposin and their interactions in Alzheimer's disease and aged brains: increased levels correlate with neuropathology. Acta Neuropathol Commun. 2019; 7: 1‐ 26. PMC6925443 31864418 source
The Results report increased PSAP protein in AD brain samples, and the Introduction describes PSAP as having neuroprotective properties. However, the paper does not report that PSAP promotes astrocyte motility or establish a neuroprotective function specifically in astrocytes; the Results find only limited PSAP staining in those cells. The indexed passages provide section labels but no page numbers. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationCastranio et al. observed increased amyloid plaque pathology at 6 to 6.5 months of age using immunohistochemistry despite no change in Aβ levels measured by ELISA.
“They observed increased amyloid plaque pathology at 6 to 6.5 months of age using immunohistochemistry despite no change in Aβ levels measured by ELISA. 19”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [19] Castranio EL, Hasel P, Haure‐Mirande J‐V, et al. Microglial INPP5D limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease. Alzheimer's Dement. 2023; 19(6): 2239‐ 2252. doi: 10.1002/alz.12821 36448627 PMC10481344 source
Classified as probably not a substantial claim.
PremisecitationSex has effects on microglial morphology, gene expression, and function.
“There is some precedent for sex having effects on microglial morphology, gene expression, and function. 33 , 34 , 35”
Quote in the paperSubstantial claim2 of 3 sources checked- cites [33] Hanamsagar R, Alter MD, Block CS, Sullivan H, Bolton JL, Bilbo SD. Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity. Glia. 2017; 65: 1504‐ 1520. 28618077 PMC5540146 source
- cites [34] Guneykaya D, Ivanov A, Hernandez DP, et al. Transcriptional and translational differences of microglia from male and female brains. Cell Rep. 2018; 24: 2773‐ 2783. e6. 30184509 source
- cites [35] Villa A, Gelosa P, Castiglioni L, et al. Sex‐specific features of microglia from adult mice. Cell Rep. 2018; 23: 3501‐ 3511. 29924994 PMC6024879 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationSamuels et al. found that amyloid levels were not changed but microglial number and engagement with plaques increased.
“Amyloid levels were not changed but microglial number and engagement with plaques increased.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [49] Samuels JD, Moore KA, Ennerfelt HE, et al. The Alzheimer's disease risk factor INPP5D restricts neuroprotective microglial responses in amyloid beta‐mediated pathology. Alzheimer's Dement. 2023; 19(11): 1‐ 14. doi: 10.1002/alz.13089 PMC10576836 37061460 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIguchi et al. provides evidence that Inpp5d loss increases glial engagement with plaques, as also observed by both Lin et al. and Samuels et al.
“Iguchi et al. provides evidence that Inpp5d loss increases glial engagement with plaques, as also observed by both Lin et al. and Samuels et al.”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [20] Iguchi A, Takatori S, Kimura S, et al. INPP5D modulates TREM2 loss‐of‐function phenotypes in a β‐amyloidosis mouse model. iScience. 2023; 26: 106375. 37035000 PMC10074152 source
- cites [18] Lin PB‐C, Tsai APo‐Yi, Soni D, et al. INPP5D deficiency attenuates amyloid pathology in a mouse model of Alzheimer's disease. Alzheimer's Dement. 2023; 19(6): 2528‐ 2537. doi: 10.1002/alz.12849 36524682 source
- cites [49] Samuels JD, Moore KA, Ennerfelt HE, et al. The Alzheimer's disease risk factor INPP5D restricts neuroprotective microglial responses in amyloid beta‐mediated pathology. Alzheimer's Dement. 2023; 19(11): 1‐ 14. doi: 10.1002/alz.13089 PMC10576836 37061460 source
May combine two claims.
Findingown dataIn male mice, Inpp5d−/− is associated with a significant decrease in cell proportions in microglial cluster 1 (p = 0.0129), and Inpp5d+/− with a significant increase in microglial cluster 3 (p = 0.0323).
“compared to wild‐type, there was a significant decrease in cell proportions from male Inpp5d−/− mice in microglial cluster 1 (p = 0.0129), and a significant increase in cell proportions from male Inpp5d+/− mice in microglial cluster 3 (p = 0.0323)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThere are significant differences in the proportions of M1 (p = 4.4 × 10−3), M2 (p = 0.0348), and M3 (p = 8.4 × 10−3) microglia by sex.
“we detected significant differences in the proportions of M1 (p = 4.4 × 10−3), M2 (p = 0.0348) and M 3 (p = 8.4 × 10−3) microglia”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataThe eigenvalue of the Female-2 module also decreased in Inpp5d+/− endothelial cells, whereas the eigenvalue of the Female-3 module increased only in Inpp5d+/− astrocytes.
“The eigenvalue of the Female‐2 module also decreased in Inpp5d +/− endothelial cells, whereas the eigenvalue of the Female‐3 module increased only in Inpp5d+/− astrocytes.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataThere are overlaps in DEGs between male and female Inpp5d−/− mice (543 DEGs), between Inpp5d+/− and Inpp5d−/− in female mice (448 DEGs), and between Inpp5d+/− and Inpp5d−/− in male mice (388 DEGs).
“there were overlaps in DEGs between male and female Inpp5d −/− mice (543 DEGs), Inpp5d +/− and Inpp5d −/− DEGs in female mice (448 DEGs), and Inpp5d +/− and Inpp5d −/− DEGs in male mice (388 DEGs)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataEach co-expression module was strikingly enriched in a particular cell type; the Female-1 module was highly expressed in microglia.
“There was striking enrichment of each module in a particular cell type; for example, the Female‐1 module was highly expressed in microglia”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn male Inpp5d−/− mice, there is a general increase in interaction strength, with the greatest increase in astrocytes and endothelial cells.
“initially observed the opposite of what we observed in the female data set—a general increase in interaction strength in Inpp5d −/− mice, with the greatest increase occurring in astrocytes and endothelial cells (Figure S9).”
Quote in the paperSubstantial claim- Rests on an assumption: Inferred ligand-receptor interactions from CellChat reflect actual cell-cell communication.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataAfter correction for ambient RNA contamination, doublet inference and removal, and quality control, 57,742 cells were taken forward for analysis.
“After correction for ambient RNA contamination, doublet inference and removal, and quality control (see Methods), 57,742 cells were taken forward for analysis”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductown dataThe selective expression of Inpp5d in microglial clusters and the total loss of expression in Inpp5d−/− mice were confirmed.
“We confirmed the selective expression of Inpp5d in microglial clusters and the small number of myeloid cells and erythrocytes present in our study (Figure S1), as well as the total loss of expression in Inpp5d −/− mice.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataCell viability was >94%.
“Cell viability was >94%.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisenone givenCastriano and Lin used regional spatial transcriptomics, which measure gene expression in regions of a slide-mounted sample rather than single cells.
“Castriano and Lin used regional spatial transcriptomics. These technologies measure gene expression in regions of a slide‐mounted sample, rather than single cells.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Premisenone givenSamuels et al. performed a single-nucleus 3′-RNA-sequencing experiment with n = 3 biological replicates pooled into n = 1 technical replicate per genotype.
“Samuels et al. performed a single‐nucleus 3′‐RNA‐sequencing experiment with n = 3 biological replicates pooled into n = 1 technical replicate per genotype.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningDue to differences across the four studies, it is difficult to draw firm conclusions on the role of Inpp5d in Alzheimer's pathology or compare these works with our own.
“Due to the differences across these four studies, it is difficult to draw firm conclusions on the role of Inpp5d in Alzheimer's pathology or compare these works with our own.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataDecreases in PTN and increases in PSAP and VEGFA signaling may occur in both female and male Inpp5d−/− mice.
“Taken together, these findings indicate that decreases in PTN and increases in PSAP and VEGFA signaling may occur in both female and male Inpp5d −/− mice”
Quote in the paperSubstantial claim- Rests on an assumption: Inferred ligand-receptor interactions from CellChat reflect actual cell-cell communication.
Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
InterpretationreasoningCytoskeletal remodeling likely mediates chemotaxis, surveillance, and phagocytosis in microglia.
“It seems likely that cytoskeletal remodeling would mediate chemotaxis, surveillance, and phagocytosis in microglia”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductown dataSample size was reduced to n = 2 per genotype and sex, and variance across proportions in clusters M1 and M3 is high.
“as our sample size was reduced to n = 2 per genotype and sex, and as variance across proportions in clusters M1 and M3 are high”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningUpregulation of PSAP expression in astrocytes and microglia may promote astrocyte reactivity and be neuroprotective.
“These findings indicate that upregulation of PSAP expression in astrocytes and microglia may promote astrocyte reactivity and be neuroprotective.”
Quote in the paperSubstantial claim- Rests on an assumption: Inferred ligand-receptor interactions from CellChat reflect actual cell-cell communication.
Probably not a substantial claim: may not pass S4 (based). May combine two claims.
Premisenone givenNo study has modeled the effect of total loss of Inpp5d, as this leads to death before sufficient AD-like pathology has developed in mouse models.
“No study has modeled the effect of total loss of Inpp5d, as this leads to death before sufficient AD‐like pathology has developed in mouse models.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationown dataM1 cells seem to be redistributed, albeit not significantly, across M7 and M8.
“and seem to be redistributed, albeit not significantly, across M7 and M8.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningChanges in the activity of these pathways based on sex and genotype could explain the changes observed in non-microglial cell types.
“Changes in the activity of these pathways based on sex and genotype could explain the changes we observed in the non‐microglial cell types we discussed.”
Quote in the paperNot a substantial claim- Rests on an assumption: Inferred ligand-receptor interactions from CellChat reflect actual cell-cell communication.
Probably not a substantial claim: may not pass S2 (checkable).
Interpretationown dataThe dysregulated genes, otherwise masked by haplosufficiency of Inpp5d, will provide new leads for further investigating their roles in microglial function and neurodegenerative diseases.
“The dysregulated genes, otherwise masked by haplosufficiency of Inpp5d, will provide new leads for further investigating their roles in microglial function and neurodegenerative diseases.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.
Premisenone givenOur single-cell protocol enriches for microglia, whereas single-nucleus suspensions contain many neuronal nuclei with low numbers of microglia.
“Our single‐cell protocol enriches for microglia, whereas single‐nucleus suspensions contain many neuronal nuclei with low numbers of microglia.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Wild-type mouse brain transcriptomes are a valid model for human brain before Alzheimer's disease pathology.
“This study design with wild‐type mice is a critical step in understanding the function of Inpp5d without the confounding effect of amyloid pathology on cell transcriptomes, as is the case in humans before AD pathology starts.”
The paper relies on this without support.
Loss of Inpp5d function is the mechanism by which INPP5D variants affect Alzheimer's disease risk.
“Inpp5d is genetically associated with Alzheimer's disease risk. Loss of Inpp5d alters amyloid pathology in models of amyloidosis.”
“Although previous work has focused on reducing the expression of Inpp5d in mouse models of amyloid, we aimed to determine the effects of both partial and total Inpp5d loss on the brain transcriptome”
The paper relies on this without support.
Inferred ligand-receptor interactions from CellChat reflect actual cell-cell communication.
“CellChat can predict the probability of 2021 validated molecular interactions between receptors and ligands across groups of cells (Figure 5A–B).”
The paper relies on this without support.
Co-expression modules identified by hdWGCNA correspond to biologically meaningful cell states.
“hdWGCNA is an unsupervised method of identifying groups of genes associated with cell states.”
The paper relies on this without support.
Mouse Inpp5d loss effects are relevant to human INPP5D in Alzheimer's disease.
“Given the increasing evidence that microglia play a critical role in AD pathogenesis 30 and that Inpp5d is exclusively expressed in microglia, we believe that our data will be invaluable resources for the research community for designing future experiments.”
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.
Inpp5d expression is described as both exclusive and nonexclusive to microglia
MinorThe results say Inpp5d is expressed exclusively in microglia, but earlier report its expression in myeloid cells and erythrocytes as well.
“Given that Inpp5d is expressed exclusively in microglia (Figure S1), we decided to infer outgoing signaling from microglia to other cell types.”
“We confirmed the selective expression of Inpp5d in microglial clusters and the small number of myeloid cells and erythrocytes present in our study (Figure S1), as well as the total loss of expression in Inpp5d −/− mice.”
Male cluster changes are assigned to the female panel
MinorThe results cite Figure 2A for changes in male mice, but the figure caption identifies panel A as female data and panel B as male data.
“Of interest, compared to wild‐type, there was a significant decrease in cell proportions from male Inpp5d−/− mice in microglial cluster 1 (p = 0.0129), and a significant increase in cell proportions from male Inpp5d+/− mice in microglial cluster 3 (p = 0.0323) (Figure 2A).”
“(A) Proportions of cells in each cluster in female data. (B) Proportions of cells in each cluster in male data.”
Figure 5D is cited for gene modules but depicts signaling
MinorThe cited panel concerns incoming and outgoing signaling interactions, not gene-module preservation.
“We found that the loss of a microglial‐expressed gene can cause changes in gene module preservation in other cell types (Figure 5D).”
“(D) Numbers and strengths of incoming and outgoing interactions decrease in all cell types on total loss of Inpp5d in female mice.”
Cites
WGCNA: an R package for weighted correlation network analysis
Langfelder, P., & Horvath, S. (2008) · BMC Bioinformatics · doi:10.1186/1471-2105-9-559 · Cited by 27,252 · see citing works
Integrated analysis of multimodal single-cell data
Hao, Y., Hao, S., Andersen-Nissen, E., Mauck, W. M., Zheng, S., Butler, A., Lee, M. J., Wilk, A. J., Darby, C., Zagar, M., et al. (2020) · doi:10.1101/2020.10.12.335331 · Cited by 15,508 · see citing works
Inference and analysis of cell-cell communication using CellChat
Jin, S., Guerrero-Juarez, C. F., Zhang, L., Chang, I., Ramos, R., Kuan, C.-H., Myung, P., Plikus, M. V., & Nie, Q. (2021) · Nature Communications · doi:10.1038/s41467-021-21246-9 · Cited by 8,409 · see citing works
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 · see citing works
McGinnis, C. S., Murrow, L. M., & Gartner, Z. J. (2019) · Cell Systems · doi:10.1016/j.cels.2019.03.003 · Cited by 4,521 · see citing works
Meta-Analysis of 74,046 Individuals Identifies 11 New Susceptibility Loci for Alzheimer’s Disease
(EADI), E. A. D. I., Lambert, J.-C., (GERAD), G. A. E. R. I. A. D., Alzheimer's Disease Genetic Consortium (ADGC), (CHARGE), C. F. H. A. A. R. I. G. E., Ibrahim-Verbaas, C. A., Harold, D., Naj, A. C., Sims, R., Bellenguez, C., et al. (2013) · Nature Genetics · doi:10.1038/ng.2802 · Cited by 4,336 · see citing works
Zhang, Y., Sloan, S. A., Clarke, L. E., Caneda, C., Plaza, C. A., Blumenthal, P. D., Vogel, H., Steinberg, G. K., Edwards, M. S. B., Li, G., et al. (2016) · Neuron · doi:10.1016/j.neuron.2015.11.013 · Cited by 2,295 · cited 1× · see citing works
“45,46 In astrocytes, it promotes motility and neuroprotective function, and is upregulated in the brains of patients with AD.”
SoupX removes ambient RNA contamination from droplet-based single-cell RNA sequencing data
Young, M. D., & Behjati, S. (2020) · GigaScience · doi:10.1093/gigascience/giaa151 · Cited by 1,619 · see citing works
Mapping the Mouse Cell Atlas by Microwell-Seq
Han, X., Wang, R., Zhou, Y., Fei, L., Sun, H., Lai, S., Saadatpour, A., Zhou, Z., Chen, H., Ye, F., et al. (2018) · Cell · doi:10.1016/j.cell.2018.02.001 · Cited by 1,597 · see citing works
Alzheimer’s Disease Risk Genes and Mechanisms of Disease Pathogenesis
Karch, C. M., & Goate, A. M. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.05.006 · Cited by 1,357 · see citing works
hdWGCNA identifies co-expression networks in high-dimensional transcriptomics data
Morabito, S., Reese, F., Rahimzadeh, N., Miyoshi, E., & Swarup, V. (2023) · Cell Reports Methods · doi:10.1016/j.crmeth.2023.100498 · Cited by 773 · see citing works
Sex-specific features of microglia from adult mice
Villa, A., Gelosa, P., Castiglioni, L., Cimino, M., Rizzi, N., Pepe, G., Lolli, F., Marcello, E., Sironi, L., Vegeto, E., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.05.048 · Cited by 651 · cited 1× · see citing works
“35 Although there are ways of integrating data to remove the effectsofsuchvariables,we decidedagainstthisanalysisapproach to avoid the loss of findings linked to sex as an important biological variable.”
Single-nucleus chromatin accessibility and transcriptomic characterization of Alzheimer’s disease
Morabito, S., Miyoshi, E., Michael, N., Shahin, S., Martini, A. C., Head, E., Silva, J., Leavy, K., Perez-Rosendahl, M., & Swarup, V. (2021) · Nature Genetics · doi:10.1038/s41588-021-00894-z · Cited by 643 · see citing works
Damen, J. E., Liu, L., Rosten, P., Humphries, R. K., Jefferson, A. B., Majerus, P. W., & Krystal, G. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.4.1689 · Cited by 633 · see citing works
Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk
Efthymiou, A. G., & Goate, A. M. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0184-x · Cited by 562 · cited 1× · see citing works
“Given the increasing evidence that microglia play a critical role in AD pathogenesis 30 and that Inpp5d is exclusively expressed in microglia, we believe that our data will be invaluable resources for the research community for designing future experiments.”
Transcriptional and Translational Differences of Microglia from Male and Female Brains
Guneykaya, D., Ivanov, A., Hernandez, D. P., Haage, V., Wojtas, B., Meyer, N., Maricos, M., Jordan, P., Buonfiglioli, A., Gielniewski, B., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.08.001 · Cited by 477 · see citing works
p150Ship, a signal transduction molecule with inositol polyphosphate-5-phosphatase activity.
Lioubin, M. N., Algate, P. A., Tsai, S., Carlberg, K., Aebersold, A., & Rohrschneider, L. R. (1996) · Genes & Development · doi:10.1101/gad.10.9.1084 · Cited by 418 · see citing works
Hanamsagar, R., Alter, M. D., Block, C. S., Sullivan, H., Bolton, J. L., & Bilbo, S. D. (2017) · Glia · doi:10.1002/glia.23176 · Cited by 384 · see citing works
Liu, Q., Sasaki, T., Kozieradzki, I., Wakeham, A., Itie, A., Dumont, D. J., & Penninger, J. M. (1999) · Genes & Development · doi:10.1101/gad.13.7.786 · Cited by 341 · cited 1× · see citing works
“6,20 It seems likely that cytoskeletal remodeling wouldmediatechemotaxis,surveillance,andphagocytosisinmicroglia, and drugs affecting the activity of these genes may be useful in studies of amyloid clearance.”
Hanamsagar, R., Alter, M. D., Block, C. L., Sullivan, H. K., Bolton, J. L., & Bilbo, S. D. (2017) · Glia · doi:10.1002/glia.23277 · Cited by 297 · see citing works
Microglia and Neuroinflammation: What Place for P2RY12?
Gómez Morillas, A., Besson, V. C., & Lerouet, D. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22041636 · Cited by 214 · see citing works
Pauls, S. D., & Marshall, A. J. (2017) · European Journal of Immunology · doi:10.1002/eji.201646795 · Cited by 118 · cited 1× · see citing works
“15 In the brain, Inpp5d is thought to be expressed mainly in microglia, which serve as the brain’s resident immune cells and are currently thoughttobemajorplayersinpredisposingagainst,respondingto,and regulating AD pathology.”
Tsai, A. P., Lin, P. B.-C., Dong, C., Moutinho, M., Casali, B. T., Liu, Y., Lamb, B. T., Landreth, G. E., Oblak, A. L., & Nho, K. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105303 · Cited by 104 · see citing works
Self-citationLiu, B., Mosienko, V., Vaccari Cardoso, B., Prokudina, D., Huentelman, M., Teschemacher, A. G., & Kasparov, S. (2018) · Glia · doi:10.1002/glia.23480 · Cited by 96 · see citing works
Bruce, K. D., Gorkhali, S., Given, K., Coates, A. M., Boyle, K. E., Macklin, W. B., & Eckel, R. H. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2018.00057 · Cited by 94 · cited 1× · see citing works
“39 This suggests that Inpp5d loss drives a shift away from a homeostatic state.”
Negative signaling in B cells causes reduced Ras activity by reducing Shc-Grb2 interactions
Tridandapani, S., Chacko, G. W., Brocklyn, J. R. V., & Coggeshall, K. M. (1997) · The Journal of Immunology · doi:10.4049/jimmunol.158.3.1125 · Cited by 90 · cited 1× · see citing works
“9 During development, Inpp5d 14 In summary, SHIP-1 is an important regulator of peripheral immune cell proliferation and functions through both its phosphatase activity and as a molecular scaffold in signaling complexes.”
Iseki, K., Hagino, S., Mori, T., Zhang, Y., Yokoya, S., Takaki, H., Tase, C., Murakawa, M., & Wanaka, A. (2002) · Glia · doi:10.1002/glia.10078 · Cited by 78 · cited 1× · see citing works
“43,44 Downregulation of this signaling pathway through the loss of Inpp5d could, therefore, enhance neuroinflammation.”
Castranio, E. L., Hasel, P., Haure‐Mirande, J., Ramirez Jimenez, A. V., Hamilton, B. W., Kim, R. D., Glabe, C. G., Wang, M., Zhang, B., Gandy, S., et al. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.12821 · Cited by 74 · cited 1× · see citing works
“19 Recently, haploinsufficiency of Inpp5d was shown to rescue microglial function in NLGF mice lacking both copies of Tyrobp .”
Marchionini, D. M., Lehrmann, E., Chu, Y., He, B., Sortwell, C. E., Becker, K. G., Freed, W. J., Kordower, J. H., & Collier, T. J. (2007) · Brain Research · doi:10.1016/j.brainres.2007.02.028 · Cited by 69 · cited 1× · see citing works
“41,42 Accumulating evidence points to astrocyte-derived PTN as an anti-inflammatory, neuroprotective factor secreted by reactive astrocytes.”
Audrain, M., Haure‐Mirande, J., Mleczko, J., Wang, M., Griffin, J. K., St George‐Hyslop, P. H., Fraser, P., Zhang, B., Gandy, S., & Ehrlich, M. E. (2021) · Alzheimer's & Dementia · doi:10.1002/alz.12256 · Cited by 65 · cited 1× · see citing works
“Two 36–38 M8 shows high expression of Lpl , a gene recently implicated in myelin-scavenging activated microlia.”
Skillbäck, T., Mattsson, N., Hansson, K., Mirgorodskaya, E., Dahlén, R., van der Flier, W., Scheltens, P., Duits, F., Hansson, O., Teunissen, C., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-13831-0 · Cited by 61 · see citing works
Pan-SHIP1/2 inhibitors promote microglia effector functions essential for CNS homeostasis
Pedicone, C., Fernandes, S., Dungan, O. M., Dormann, S. M., Viernes, D. R., Adhikari, A. A., Choi, L. B., De Jong, E. P., Chisholm, J. D., & Kerr, W. G. (2020) · Journal of Cell Science · doi:10.1242/jcs.238030 · Cited by 61 · cited 1× · see citing works
“31,32 No study has modeled the effect of total loss of Inpp5d , as this leads to death before sufficient AD-like pathology has developed in mouse models.”
Harmer, S. L., & DeFranco, A. L. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.17.12183 · Cited by 60 · cited 1× · see citing works
“8 SHC and GRB2 are upstreamofRasactivation,andtheirsequestrationbySHIP-1hasbeen proposedtofurtherinhibitcellproliferationthroughtheMitogenActi-vated Protein Kinase (MAPK) pathway.”
Mendsaikhan, A., Tooyama, I., Bellier, J.-P., Serrano, G. E., Sue, L. I., Lue, L.-F., Beach, T. G., & Walker, D. G. (2019) · Acta Neuropathologica Communications · doi:10.1186/s40478-019-0862-8 · Cited by 57 · cited 1× · see citing works
“47,48 These findings indicate that upregulation of PSAP expression in astrocytes and microglia may promote astrocyte reactivity and be neuroprotective.”
<i>INPP5D</i> deficiency attenuates amyloid pathology in a mouse model of Alzheimer's disease
Lin, P. B., Tsai, A. P., Soni, D., Lee‐Gosselin, A., Moutinho, M., Puntambekar, S. S., Landreth, G. E., Lamb, B. T., & Oblak, A. L. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.12849 · Cited by 54 · see citing works
Self-citationKarahan, H., Smith, D. C., Kim, B., Dabin, L. C., Al-Amin, M. M., Wijeratne, H. R. S., Pennington, T., Viana di Prisco, G., McCord, B., Lin, P. B.-C., et al. (2021) · Science Advances · doi:10.1126/sciadv.abe3954 · Cited by 53 · see citing works
Self-citationAlzheimer’s disease-related transcriptional sex differences in myeloid cells
Coales, I., Tsartsalis, S., Fancy, N., Weinert, M., Clode, D., Owen, D., & Matthews, P. M. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02604-w · Cited by 49 · cited 1× · see citing works
“40 We were also interested in investigating the differences in gene expression in cell types that do not express Inpp5d .”
Samuels, J. D., Moore, K. A., Ennerfelt, H. E., Johnson, A. M., Walsh, A. E., Price, R. J., & Lukens, J. R. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.13089 · Cited by 46 · see citing works
Targeted genetic analysis of cerebral blood flow imaging phenotypes implicates the INPP5D gene
Yao, X., Risacher, S. L., Nho, K., Saykin, A. J., Wang, Z., & Shen, L. (2019) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2019.06.003 · Cited by 40 · see citing works
INPP5D modulates TREM2 loss-of-function phenotypes in a β-amyloidosis mouse model
Iguchi, A., Takatori, S., Kimura, S., Muneto, H., Wang, K., Etani, H., Ito, G., Sato, H., Hori, Y., Sasaki, J., et al. (2023) · iScience · doi:10.1016/j.isci.2023.106375 · Cited by 37 · cited 3× · see citing works
“6,20 It seems likely that cytoskeletal remodeling wouldmediatechemotaxis,surveillance,andphagocytosisinmicroglia, and drugs affecting the activity of these genes may be useful in studies of amyloid clearance.”
Murai, N., Mitalipova, M., & Jaenisch, R. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.14879 · Cited by 33 · cited 1× · see citing works
“Two 36–38 M8 shows high expression of Lpl , a gene recently implicated in myelin-scavenging activated microlia.”
Astrocyte-Derived Pleiotrophin Mitigates Late-Stage Autoimmune CNS Inflammation
Linnerbauer, M., Lößlein, L., Farrenkopf, D., Vandrey, O., Tsaktanis, T., Naumann, U., & Rothhammer, V. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2021.800128 · Cited by 33 · cited 1× · see citing works
“43,44 Downregulation of this signaling pathway through the loss of Inpp5d could, therefore, enhance neuroinflammation.”
Iyer, S., Brooks, R., Gumbleton, M., & Kerr, W. G. (2014) · Stem Cells and Development · doi:10.1089/scd.2014.0501 · Cited by 20 · see citing works
Liu, Y., Zeng, X., Wang, Z., Zhang, N., Fan, D., & Yuan, H. (2015) · Magnetic Resonance Imaging · doi:10.1016/j.mri.2015.05.001 · Cited by 20 · see citing works
Role of SHIP1 in Invariant NKT Cell Development and Functions
Anderson, C., Salter, A. I., Toussaint, L. E., et al. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500567 · Cited by 13 · cited 1× · see citing works
“9 During development, Inpp5d 14 In summary, SHIP-1 is an important regulator of peripheral immune cell proliferation and functions through both its phosphatase activity and as a molecular scaffold in signaling complexes.”
Sun, X., Li, Z., Niu, Y., et al. (2019) · Cell Proliferation · doi:10.1111/cpr.12638 · Cited by 12 · see citing works
So, E. Y., Sun, C., Reginato, A. M., Dubielecka, P. M., Ouchi, T., & Liang, O. D. (2019) · Cancer Biology & Therapy · doi:10.1080/15384047.2018.1523846 · Cited by 10 · see citing works
Lipid phosphatase SHIP‐1 regulates chondrocyte hypertrophy and skeletal development
So, E. Y., Sun, C., Wu, K. Q., Driesman, A. S., Leggett, S. E., Isaac, M., Spangler, T., Dubielecka, P. M., Reginato, A. M., & Liang, O. D. (2019) · Journal of Cellular Physiology · doi:10.1002/jcp.29063 · Cited by 9 · see citing works
Suwa, A., Nishida, K., Utsunomiya, K., Nonen, S., Yoshimura, M., Takekita, Y., Wakeno, M., Tajika, A., Yoshino, M., Koshikawa, Y., et al. (2015) · Dementia and Geriatric Cognitive Disorders Extra · doi:10.1159/000440714 · Cited by 7 · see citing works
Richardson, T. I., Jesudason, C. D., Lobb, K. L., Durst, G. L., Clayton, B., Massey, S. M., Beck, D. E., Zhang, Z., Dong, J., Lin, J., et al. (2022) · Alzheimer s & Dementia · doi:10.1002/alz.068781 · Cited by 2 · cited 1× · see citing works
“31,32 No study has modeled the effect of total loss of Inpp5d , as this leads to death before sufficient AD-like pathology has developed in mouse models.”
Self-citation
Flagged first, then by citations
1 of the 51 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Kloske, C. M., Mahinrad, S., Barnum, C. J., Batista, A. F., Bradshaw, E. M., Butts, B., Carrillo, M. C., Chakrabarty, P., Chen, X., Craft, S., et al. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.14291 · Cited by 6 · see citing works
“89 In particular, previous use of spatial transcriptomics to investigate Cx3cr1-dependent deletion of Inpp5d , when crossed with APP/PS1 amyloidosis mice, highlighted an extended gene expression signature associated with plaques and identified CST7 (cystatin F) as a novel marker of plaques.”
Self-citationJiang, T., Zhuang, Y., Jian, J., Wang, J., Ding, Z., Liu, W., Wu, T., & Yang, M. (2025) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2025.111633 · Cited by 4 · see citing works
Prosaposin in CNS health and disease, metabolic stress and exercise adaptation
Taha, H. B., Zhu, S., & Wang, E. (2026) · Journal of Molecular Medicine · doi:10.1007/s00109-026-02643-3 · Cited by 5 · see citing works
Karahan, H., Hartigan, K., Al‐Amin, M. M., John, S. K., McCord, B., Wijeratne, H. R. S., Acri, D. J., Smith, D. C., Dabin, L. C., Cordero, H. M. R., et al. (2025) · Alzheimer's & Dementia · doi:10.1002/alz.70949 · Cited by 2 · see citing works
Self-citationJesudason, C. D., Rangel‐Barajas, C., Beach, C. J., Beck, D. E., Caballero-Floran, I., Clayton, B., Silva, L. D., David, J. C., Doolen, S., Faulkner, A. N., et al. (2026) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6c00010 · Cited by 1 · see citing works
Self-citationNRF2 deficit prevents pathologic Tau seeding and spreading in an induced tauopathy mouse model
López-Sampere, Y., Mengod, P., Roca-Pereira, S., Vinyals, A., Mato-Blanco, X., Vela-Martínez, M., Dakterzada, F., Romero, L., Santamaría, E., Fernández‐Irigoyen, J., et al. (2026) · Redox Biology · doi:10.1016/j.redox.2026.104068
“The downregulation of Inpp5d , a negative regulator of micro-glial activation, may indicate a shift toward a more proinflammatory or dysregulated microglial state [81].”
Xi, R., Zheng, X., Zhao, J., & Fu, Y. (2026) · Journal of Neuroinflammation · doi:10.1186/s12974-026-03819-x · Cited by 1 · see citing works
“In addition, in normal adult brains or after traumatic brain injury, SHIP1 deficiency triggers excessive microglial activation and intensifies chronic inflammatory responses, thereby impeding neuro-reparative processes [34, 153, 165].”
APOE4 and INPP5D converge on membrane mechanics to regulate endocytosis in human astrocytesPreprint
Gevorgyan, A. S., Gordon, L. M., Combs, C. A., Lita, A., Yang, L. G., Cuní‐López, C., Root, J. T., Larion, M., Taraska, J. W., & Narayan, P. S. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.05.22.726347
Zhang, Y., Zhang, A., Seo, S., Fredrickson, C., Jung, M., Shan, X., Phu, L., Cramer, A. L., Sánchez-Priego, C., Kulkarni, V. V., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.07.749934 · Cited by 1 · see citing works
- Authors
- Dabin, L. C., Kersey, H., Kim, B., Acri, D. J., Sharify, D., Lee‐Gosselin, A., Lasagna‐Reeves, C. A., Oblak, A. L., Lamb, B. T., & Kim, J.
- Affiliations
- Indiana University Indianapolis (US)
- Department of Medical & Molecular Genetics Indiana University School of Medicine Indianapolis Indiana USA
- Corresponding author
- Kim, Jungsu
- ORCID
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2024-06-26
- Volume
- 20
- Issue
- 8
- Pages
- 5311-5323
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC11350029
- OpenAlex
- W4400046482
- Semantic Scholar
- b5b161d1c1dae936d3925fa9d91f2f4e504cadfc
- Cited by
- 10
- References
- 51
- Citations by year
- 2026: 6 · 2025: 2 · 2024: 2
- FWCI
- 1.34
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia (publishedVersion, cc-by)
- PubMed (publishedVersion)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by)
- PubMed Central (submittedVersion, cc-by)
- Funders
- National Institutes of Health (R01AG077829, R01AG071281, R21AG072738, RF1AG074543)
- Lilly Endowment
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- INPP5D, Alzheimer's disease risk
- MeSH terms
- Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Female, Male, Neuroglia, Sex Factors, Microglia, Mice, Transcriptome
About these checks
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.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-17.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-17.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
