The DOI matches its Crossref record; 75 of the 75 references it cites were found in a registry or an index; none of the 45 sources its claims cite is checked for support yet.
Amyloid clearance defect in ApoE4 astrocytes is reversed by epigenetic correction of endosomal pH
Open accessPublished version of a preprint
Abstract
Significance: Alzheimer’s disease is the most common cause of dementia in the elderly. Most cases occur sporadically, with 40–65% of patients carrying at least one copy of the E4 allele of Apolipoprotein E. Because no drug exists that can halt disease progress, there is strong interest in understanding the presymptomatic role of endosomes. We show that excessive endosomal acidification in ApoE4 astrocytes is caused by downregulation of the Na + /H + exchanger NHE6 and results in defective clearance of amyloid beta (Aβ) peptide by intracellular sequestration of the LRP1 receptor. Epigenetic modifiers restore NHE6 expression to alkalinize endosomal pH, increase surface expression of LRP1, and correct Aβ clearance in astrocytes. Thus, endosomal pH emerges as a target for the correction of amyloid disorders.
Overview
AI snapshot
Written from the paper’s full text.
TL;DR
In ApoE4 astrocytes, selective downregulation of the endosomal Na+/H+ exchanger NHE6 causes endosomal hyperacidification, trapping LRP1 intracellularly and impairing Aβ clearance. Restoring NHE6—by ectopic expression or broad-spectrum HDAC inhibitors—normalizes endosomal pH, increases surface LRP1, and rescues Aβ clearance to ApoE3-like levels.
Key findings
- ApoE4 astrocytes showed 78% lower cell-associated Aβ than ApoE3 astrocytes, with lower Aβ at all time points (53% at 1 h, 59% at 4 h, 65% at 16 h), while transferrin uptake was 1.5–2-fold higher and dextran uptake did not differ.
- Surface LRP1 was reduced in ApoE4 astrocytes by ~50% (biotinylation), ~43% (flow cytometry), and ~49% (confocal), and surface Aβ binding was 66% lower, despite no differences in LRP1 transcript or total protein.
- Endosomal pH in ApoE4 astrocytes was reduced by ~0.84 pH unit, lysosomal pH was elevated by >1 pH unit, and monensin raised endosomal pH from 5.38±0.01 to 5.74±0.03 and restored Aβ clearance.
- NHE6 transcript was ~56% lower in ApoE4 knock-in astrocytes; NHE6 KO mouse brains had elevated Aβ; ectopic NHE6 restored Aβ clearance and increased surface LRP1 (~2.5-fold by imaging, ~5.7-fold by biotinylation). Broad-spectrum HDAC inhibitors restored NHE6, with TSA and SAHA EC50 values of 6.50±0.36 µM and 6.81±0.53 µM, and corrected Aβ clearance up to 92.4% of ApoE3 levels (R²=0.7884 between Aβ clearance and NHE6 fold-change).
Methods
- Isogenic ApoE3/ApoE4 knock-in immortalized astrocytes and ApoE KO astrocytes were used with fluorescent Aβ40 uptake/clearance assays, flow cytometry, confocal microscopy, surface biotinylation, pH-sensitive reporters, qPCR, Western blotting, lentiviral NHE6/NHE9 expression, and a nine-drug HDAC inhibitor panel.
- Human bioinformatics included GSE5281 (15 LOAD, 12 controls), GSE15222 (n=363), and a meta-analysis of nine studies comprising 103 AD and 87 control post-mortem brains; NHE6 KO male mice (Slc9a6−/Y) versus wild-type male controls were used for brain Aβ40 ELISA, with on average five mice per genotype.
- Statistical analysis used Student’s t test, ANOVA, and linear regression in GraphPad Prism; data are presented as mean ± SD.
Limitations
- The paper states that the precise pH-mediated perturbation in trafficking remains to be determined, and that future work could test HDAC inhibitor efficacy on amyloid pathology in well-defined animal models.
- Evident from the text: the mechanistic rescue experiments are primarily in immortalized astrocyte cell culture, while in vivo evidence is limited to elevated Aβ in NHE6 KO mouse brain rather than ApoE4-specific HDAC inhibitor treatment.
- Evident from the text: human evidence for NHE6 downregulation in ApoE4 is based on transcriptomic datasets and post-mortem brain analyses, which are associative rather than direct causal tests in human tissue.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
0 of 45 cited sources checked · 0 supported · 0 flagged
- Findingown data
The NHE6 KO mouse model shows elevated Aβ in the brain.
“In vivo, the NHE6 KO mouse model shows elevated Aβ in the brain.”
Quote in the paperSubstantial claim- Rests on an assumption: Elevated brain Aβ in NHE6 KO mice reflects a role for NHE6 in amyloid pathology relevant to AD.
- Findingown data
Epigenetic restoration of NHE6 expression with HDAC inhibitors normalized ApoE4-specific defects in endosomal pH, LRP1 trafficking and amyloid clearance.
“Epigenetic restoration of NHE6 expression with histone deacetylase inhibitors normalized ApoE4-specific defects in endosomal pH, LRP1 trafficking and amyloid clearance.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
There was significantly lower cell-associated Aβ in ApoE4 cells relative to ApoE3 at all time points.
“Consistent with defective uptake, there was significantly lower cell-associated Aβ in ApoE4 cells relative to ApoE3 at all time points (Fig. 1C, Fig. S1F).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
Broad-spectrum HDAC inhibitors (sodium butyrate, sodium valproate, LBH589, TSA, and SAHA) resulted in significant restoration of NHE6 expression levels in ApoE4 astrocytes to levels comparable to ApoE3.
“broad-spectrum drugs inhibiting both classes, including sodium butyrate, sodium valproate, LBH589, 5 TSA, and SAHA (vorinostat), resulted in significant restoration of NHE6 expression levels in ApoE4 astrocytes to levels comparable to ApoE3 astrocytes (Fig. 5C).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
ApoE4 cells expressing ectopic NHE6 had ∼2.5-fold higher LRP1 staining compared to vector-transfected ApoE4 astrocytes.
“Compared to the weak surface LRP1 staining in vector-transfected ApoE4 astrocytes, we observed prominent, ∼2.5-fold higher LRP1 staining in ApoE4 cells expressing ectopic NHE6 (Fig. 4F).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
Surface-bound ligand (fluorescent Aβ) measured by confocal microscopy was 66% lower in ApoE4 astrocytes.
“In a fourth approach, surface-bound ligand (fluorescent Aβ) measured by confocal microscopy was 66% lower in ApoE4 astrocytes (Fig. 1E).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
Aβ clearance was not restored in ApoE4 astrocytes transfected with NHE9.
“Remarkably, Aβ clearance was restored to ApoE3 levels in ApoE4 astrocytes transfected with NHE6 (Fig. 4E), but not with NHE9 (Fig. S3E-F), pointing to 5 an isoform-specific role for NHE6 in Aβ clearance.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
Uptake of dextran by fluid-phase endocytosis was not different between ApoE genotypes.
“Uptake of dextran by fluid-phase endocytosis was not different between ApoE genotypes (Fig. 1F).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
Surface biotinylation revealed that plasma membrane expression of LRP1 receptor in ApoE4 astrocytes was lower by ∼50%.
“First, surface biotinylation revealed that plasma membrane expression of LRP1 receptor in ApoE4 astrocytes was lower by ∼50% (Fig. 1B).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
Monensin treatment restored Aβ clearance in ApoE4 astrocytes to ApoE3 levels.
“Concomitantly, monensin treatment restored Aβ clearance in ApoE4 astrocytes to ApoE3 levels, as shown by flow cytometry analysis (Fig. 3F).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
Broad-spectrum HDAC inhibitors (e.g., TSA and SAHA) that significantly restored NHE6 expression elicited proportionally complete correction of defective Aβ clearance in ApoE4 astrocytes to levels similar (up to 92.4%) to ApoE3 cells.
“Notably, broad-spectrum HDAC inhibitors (e.g.TSA and SAHA) that significantly restored NHE6 expression also elicited proportionally complete correction of defective Aβ clearance in ApoE4 astrocytes to levels similar (up to 92.4%)”
Quote in the paperSubstantial claim - Findingown data
HDAC4 nuclear colocalization was higher in ApoE4 astrocytes (Pearson's correlation coefficient 0.51±0.02) than ApoE3 (0.17±0.01).
“Note prominent overlap between HDAC4 and DAPI, consistent with increased nuclear 10 translocation, in ApoE4 astrocytes (Pearson's correlation coefficient= ApoE3: 0.17±0.01 vs. ApoE4: 0.51±0.02;n=150/condition; ****p=4.6X10-44 ; Student's t-test).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
Aβ clearance was restored to ApoE3 levels in ApoE4 astrocytes transfected with NHE6.
“Remarkably, Aβ clearance was restored to ApoE3 levels in ApoE4 astrocytes transfected with NHE6 (Fig. 4E), but not with NHE9 (Fig. S3E-F), pointing to 5 an isoform-specific role for NHE6 in Aβ clearance.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
Cell-associated Aβ was reduced by 78% in ApoE4 astrocytes relative to ApoE3.
“Strikingly, cell-associated Aβ was reduced by 78% in ApoE4 astrocytes, relative to ApoE3 (Fig. 1B).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
NHE6 colocalizes with EEA1 and LRP1.
“Colocalization of NHE6 with EEA1 and LRP1 (Fig. S3G-H) suggested a potential role for NHE6 in endosomal recycling of LRP1 receptors.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
Cytoplasmic pH showed no significant differences between the two ApoE isotypes.
“Cytoplasmic pH showed no significant differences between the two ApoE isotypes (Fig. 3D).”
Quote in the paperNot a substantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingcitation
There is no difference in brain LRP1 gene expression at different stages of AD compared with normal controls in publicly available microarray data.
“However, we found no difference in brain LRP1 gene expression at different stages of AD (incipient, 10 moderate, and severe), as compared with normal controls, in publicly available microarray data 22 (Fig. S2A-B).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [22]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Findingown data
Surface biotinylation showed ∼5.7-fold higher surface LRP1 levels in ApoE4 cells with restored NHE6 expression compared to empty vector.
“Similar results were obtained in surface biotinylation experiments that showed robust ∼5.7-fold higher surface LRP1 levels in ApoE4 cells with restored NHE6 expression, compared to transfection with empty vector (Fig. S3I).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
There is a prominent linear relationship between Aβ clearance and the fold-change in NHE6 expression elicited by DMSO and nine HDAC inhibitors in ApoE4 astrocytes (R2=0.7884; p<0.0001).
“Note prominent linear relationship between Aβ clearance and the fold-change in NHE6 expression (R 2 =0.7884; p<0.0001) elicited by DMSO and nine HDAC inhibitors.”
- Also stated in: § HDAC nuclear translocation · plain
“We observed a prominent linear relationship between Aβ clearance and the fold-change in NHE6 expression (R 2 =0.7884;Fig. 5F) elicited by the panel of nine HDAC inhibitors.”
Quote in the paperSubstantial claim - Also stated in: § HDAC nuclear translocation · plain
- Findingown data
Cell-associated TFN was 1.5-2 fold higher in ApoE4 cells relative to ApoE3.
“In contrast, cell-associated TFN was 1.5-2 fold higher in ApoE4 cells relative to ApoE3 as measured by flow cytometry (Fig. 1D) and confocal microscopy (Fig. 1E).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
Neither TSA nor SAHA significantly altered NHE9 levels.
“Neither TSA nor SAHA significantly altered NHE9 levels (Fig. S4D).”
Quote in the paperNot a substantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
ApoE4 cells treated with SAHA showed prominent vesicular Aβ staining relative to vehicle control.
“ApoE4 cells treated with SAHA showed prominent, vesicular Aβ staining relative to vehicle control (Fig. 5G).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
Fractional colocalization of HDAC4 with DAPI revealed prominent overlap, consistent with increased nuclear translocation in ApoE4 astrocytes.
“Fractional colocalization 25 of HDAC4 with DAPI revealed prominent overlap, consistent with increased nuclear translocation in ApoE4 astrocytes (Fig. 5B).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
Lysosomal pH in ApoE4 astrocytes was elevated by >1 pH unit relative to ApoE3.
“In contrast, we observed >1 pH unit elevation of lysosomal pH in ApoE4 astrocytes (Fig. 3C).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
SAHA treatment increases Aβ internalization by ApoE4 astrocytes.
“Representative FACS histogram demonstrating increase Aβ internalization by ApoE4 with SAHA treatment is shown on the right.”
Quote in the paperSubstantial claim - Findingown data
TSA treatment (5 μM for 12 h) corrects hyperacidic endosomal pH in ApoE4 astrocytes relative to DMSO treatment.
“HDAC inhibition by TSA 20 treatment (5µM for 12h) corrected hyperacidic endosomal pH in ApoE4 astrocyte, relative to DMSO treatment (**p=0.0014;n=3; Student's t-test).”
Quote in the paperSubstantial claim - Findingown data
Monensin treatment (50μM for 1 h) elevated endosomal pH in ApoE4 knock-in astrocytes from 5.38±0.01 to 5.74±0.03 relative to vehicle-treated control.
“Thus, monensin treatment (50µM for 1 h) elevated endosomal pH in ApoE4 knock-in astrocytes from 5.38±0.01 to 5.74±0.03,relative to the vehicle treated control (Fig. 3E).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingcitation
An independent large human brain transcriptome dataset (n=363, GSE15222) shows ApoE4 isotype-specific differential gene expression of NHE6 in aging brain.
“We validated these findings using an independent, large human brain transcriptome dataset (n=363, GSE15222) to show ApoE4 isotype-specific differential 15 gene expression of NHE6 in aging brain 34 (Fig. 4B).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [34]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Findingown data
Amyloid Aβ levels were elevated in mouse brains from NHE6 KO.
“Consistent with this hypothesis, amyloid Aβ levels were found to be elevated in mouse brains from NHE6 KO (Fig. 4C), together with diminished brain weight (Fig. S3C), suggesting an underlying neurodegenerative pathology.”
Quote in the paperSubstantial claim- Rests on an assumption: Elevated brain Aβ in NHE6 KO mice reflects a role for NHE6 in amyloid pathology relevant to AD.
- Findingown data
Inhibitors of class I (CI994) or class II (MC1568) HDACs resulted in minimal changes in NHE6 expression.
“Whereas inhibitors of class I (CI994) or class II (MC1568) HDACs resulted in minimal changes in NHE6 expression,”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
Other narrow spectrum HDAC inhibitors tubacin and clioquinol had no significant effect on NHE6.
“Other narrow spectrum HDAC inhibitors studied here (tubacin and clioquinol) had no significant effect.”
Quote in the paperNot a substantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
Total LRP1 protein expression normalized to β-actin does not differ significantly between ApoE3 and ApoE4 astrocytes (p=0.585; n=3).
“Representative Western blot (F) and quantification of three biological replicates (G) showing total LRP1 protein expression normalized to β-actin levels between ApoE3 and ApoE4 astrocytes (p=0.585;n=3; Student's t-test).”
Quote in the paperNot a substantial claim - Findingnone given
In vivo Aβ levels were significantly higher in the brains of NHE6 KO mice.
“Consistent with a role in amyloid pathology, in vivo Aβ levels were found to be significantly higher in the brains of NHE6 KO mice.”
Quote in the paperSubstantial claim- Rests on an assumption: Elevated brain Aβ in NHE6 KO mice reflects a role for NHE6 in amyloid pathology relevant to AD.
- Findingown data
Confocal microscopy showed ∼49% lower LRP1 surface labeling by antibody in ApoE4.
“Third, this was confirmed by confocal microscopy showing ∼49% lower LRP1 surface labeling by antibody in ApoE4 (Fig. 1D).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
TSA and SAHA stimulated acetylation of histone H3 and H4 in ApoE4 astrocytes following 60 minutes of treatment.
“We confirmed that both TSA and SAHA stimulated acetylation of histone H3 and H4 in ApoE4 astrocytes following 60 minute of treatment (Fig. S4E-F).”
Quote in the paperNot a substantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
TSA and SAHA elicited dose dependent NHE6 increases with EC50 of 6.50±0.36μM and 6.81±0.53μM respectively.
“Both TSA and SAHA elicited dose dependent NHE6 increases with half-maximal response (EC 50 ) of 6.50±0.36µMand 6.81±0.53µM(Fig. S4B-C), 10 respectively, comparable to their therapeutic plasma concentrations 36 .”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [36]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
TSA treatment (5 μM for 12 h) does not affect lysosomal pH in ApoE4 astrocytes relative to DMSO treatment.
“TSA treatment (5µM for 12h) did not affect lysosomal pH in ApoE4 astrocyte, relative to DMSO treatment (p=0.797;n=3; Student's t-test).”
Quote in the paperSubstantial claim - Findingown data
Endosomal pH in ApoE4 astrocytes was strongly reduced by ∼0.84 pH unit relative to ApoE3.
“Endosomal pH in ApoE4 astrocytes was strongly reduced by ∼0.84 pH unit, relative ApoE3 (Fig. 3B).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingcitation
Analysis of GSE5281 comprising 15 LOAD and 12 matched control post-mortem brains revealed that genes involved in hydrogen ion transmembrane transport, including NHE6 and V-ATPase subunits, comprised 10% of the top 100 down regulated genes, with highest enrichment scores (>15-fold).
“analysis of a publicly available microarray dataset (GSE5281) comprising a total of 15 sporadic, late-onset AD (LOAD) and 12 matched control post-mortem brains 31 revealed that genes involved in hydrogen ion transmembrane transport, including the endosomal NHE6 and V-ATPase subunits, 10 comprised 10% of the top 100 down regulated genes, exhibiting highest enrichment scores (>15-fold; Fig. S3A).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Findingown data
TSA or SAHA treatment does not affect cell viability in ApoE4 astrocytes.
“TSA or SAHA treatment in ApoE4 astrocytes did not affect cell viability measured using trypan blue exclusion.”
Quote in the paperNot a substantial claim - Findingown data
There were no concomitant changes in LRP1 transcript or total protein expression levels with restored NHE6.
“We confirmed that there were no concomitant changes in LRP1 transcript (Fig. S3J) or total protein expression levels (Fig. S3I), suggesting that increased surface LRP1 was due to posttranslational 15 redistribution of the existing cellular LRP1 pool.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
Narrow-spectrum HDAC inhibitors tubacin and clioquinol have no significant effect on NHE6 expression in ApoE4 astrocytes.
“Other narrow spectrum HDAC inhibitors studied here (tubacin/TUB and clioquinol) had no significant effect.”
Quote in the paperSubstantial claim - Findingown data
TSA or SAHA treatment does not significantly change NHE9 expression in ApoE4 astrocytes.
“qPCR analysis revealed no significant changes in NHE9 expression with TSA or SAHA treatment of ApoE4 astrocytes.”
Quote in the paperNot a substantial claim - Findingown data
There were no differences in LRP1 transcript and total protein expression between ApoE3 and ApoE4 astrocytes.
“Consistent with these findings, we observed no 15 differences in LRP1 transcript and total protein expression between ApoE3 and ApoE4 astrocytes (Fig. S2E-G).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingnone given
LRP1 gene expression does not differ significantly between ApoE3 and ApoE4 astrocytes.
“LRP1 gene expression showing no significant difference between ApoE3 and ApoE4”
Quote in the paperNot a substantial claim - Findingown data
Flow cytometry showed a reduction of LRP1-positive cells by ~43% in ApoE4.
“Second, an antibody directed against an external epitope of LRP1 to quantify surface expression in live cells by flow cytometry analysis showed a reduction of LRP1-positive 25 cells by ~43% (Fig. 1C).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
Meta-analysis of nine independent gene expression studies showed no significant changes in LRP1 gene expression in AD.
“Meta-analysis of nine independent gene expression studies from anatomically and functionally distinct brain regions, comprising a total of 103 AD and 87 control post-mortem brains also showed no significant changes in LRP1 gene expression in AD (Fig. S2C-D).”
Quote in the paperSubstantial claim - Findingown data
Western blots of nuclear fractions showed higher HDAC4 in ApoE4 astrocytes relative to ApoE3.
“This was independently verified in Western blots of nuclear fractions, which showed higher HDAC4 in ApoE4 astrocytes relative to ApoE3 (Fig. S4A).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
Broad-spectrum HDAC inhibitors (sodium butyrate, sodium valproate, LBH589, TSA, and SAHA) significantly restore NHE6 expression in ApoE4 astrocytes to levels comparable to ApoE3 astrocytes.
“Broad-spectrum drugs inhibiting both classes, including sodium butyrate, sodium valproate, LBH589, TSA, and SAHA, resulted in significant restoration of NHE6 expression levels in ApoE4 astrocytes to levels comparable to ApoE3 astrocytes (****p<0.0001;n=3; Student's t-test).”
Quote in the paperSubstantial claim - Findingown data
NHE6 transcript was similar in ApoE KO mouse astrocytes and ApoE KO astrocytes with knock-in of human ApoE3, but was ∼56% reduced in ApoE4 knock-in cells.
“Although NHE6 transcript was similar in ApoE KO mouse astrocytes and ApoE KO astrocytes with knock-in of human ApoE3, it was ∼56% reduced in ApoE4 knock-in cells (Fig. 4C).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
HDAC inhibitors with lower induction of NHE6 expression (e.g., MC1568 and tubacin) conferred minimal changes in Aβ clearance.
“HDAC inhibitors with lower induction of NHE6 expression (e.g.MC1568 and tubacin) conferred minimal changes in Aβ clearance.”
- Also stated in: § HDAC nuclear translocation · plain
“HDAC inhibitors with lower induction of NHE6 expression (e.g.MC1568 and tubacin) conferred minimal 25 changes in Aβ clearance.”
Quote in the paperSubstantial claim - Also stated in: § HDAC nuclear translocation · plain
- Findingown data
SAHA-treated ApoE4 cells show prominent vesicular Aβ staining, in contrast to faint diffuse staining in vehicle control.
“Note prominent, vesicular Aβ staining in SAHA treated ApoE4 cells, in contrast to faint, diffuse staining in vehicle control (****p=9.9X10-13 ; n=160/condition; Student's t-test).”
Quote in the paperSubstantial claim - Findingown data
Lentiviral vector mediated expression of NHE6 alkalinized the endosomal lumen in ApoE4 astrocytes.
“Similar to monensin treatment, lentiviral vector mediated expression of NHE6 alkalinized the endosomal lumen in ApoE4 astrocytes (Fig. S3D).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Findingown data
NHE6 KO mouse brains had diminished brain weight.
“together with diminished brain weight (Fig. S3C)”
Quote in the paperNot a substantial claim- Rests on an assumption: Elevated brain Aβ in NHE6 KO mice reflects a role for NHE6 in amyloid pathology relevant to AD.
- Findingown data
ApoE4 astrocytes have cargo-specific defects in endocytosis.
“ApoE4 astrocytes have cargo specific defects in endocytosis”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Premisecitation
Endosomal aberrations constitute the earliest detectable brain cytopathology, emerging before cognitive dysfunction in neurodegenerative disorders including Alzheimer disease, Niemann-Pick Type C and Down syndrome.
“In this context, endosomal aberrations constitute the earliest detectable brain cytopathology, emerging before cognitive dysfunction is apparent in neurodegenerative disorders, including Alzheimer disease, Niemann-Pick Type C and Down syndrome 4, 5, 15 6, 7 .”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [4]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [5]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [6]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [7]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
Aberrant accumulation of endosomal protons in ApoE4 astrocytes traps the LRP1 receptor in non-productive intracellular compartments, leading to loss of surface expression and Aβ clearance.
“Here, we show that aberrant accumulation of endosomal protons in ApoE4 astrocytes traps the LRP1 receptor in non-productive intracellular compartments, leading to loss of surface expression and Aβ clearance.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Premisecitation
Prominent pre-symptomatic endosomopathy of the brain, evidenced by enlarged and more numerous endosomes, has been observed in the ApoE4 genotype.
“Importantly, prominent pre-symptomatic endosomopathy of the brain, evidenced by enlarged and more numerous endosomes, has been observed in the ApoE4 genotype 9,10,11 , the strongest known genetic risk factor influencing susceptibility to sporadic, late-onset AD (LOAD) 12,13 .”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [12]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [13]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
Hyperacidification of endosomal pH in ApoE4 brain and astrocytes is caused by selective down regulation of NHE6.
“Hyperacidification of endosomal pH is caused by 10 selective down regulation of the Na + /H + exchanger NHE6, which functions as a critical proton leak pathway, in ApoE4 brain and astrocytes.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Interpretationcitation
Endosomal pH may be a critical mechanistic link between neurodevelopmental and neurodegenerative disorders.
“We suggest that endosomal pH may be a critical mechanistic link between neurodevelopmental and neurodegenerative disorders.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Premisecitation
In AD patients with ApoE4/4 genotype, NHE6 was among the transcripts differentially down regulated in hippocampus, by up to ~4-fold compared to ApoE3/3.
“In AD patients with ApoE4/4 genotype, NHE6 was among the transcripts differentially down regulated in hippocampus, by up to ~4-fold compared to ApoE3/3 32,33 .”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [32]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [33]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Premisecitation
Reports of increased nuclear translocation of multiple HDACs in ApoE4 isotype relative to ApoE3 in post-mortem brains and neurons suggested a mechanistic basis.
“Reports of increased nuclear translocation of multiple histone deacetylases (HDACs) in ApoE4 isotype, relative to ApoE3 (Fig. 5A), in post-mortem brains and neurons suggested a mechanistic basis for our observations 35 .”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [35]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationown data
A profound dysregulation of endosomal pH in humanized mouse ApoE4 astrocytes leads to intracellular sequestration and cell surface loss of the Aβ receptor LRP1.
“Here we show that a profound dysregulation of endosomal pH in humanized mouse ApoE4 astrocytes leads to intracellular sequestration and cell surface loss of the Aβ receptor, LRP1.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Interpretationown data
ApoE isotype-specific alterations in receptor recycling determine LRP1 surface expression and cellular Aβ uptake.
“Thus, ApoE isotypespecific alterations in receptor recycling determine LRP1 surface expression and cellular Aβ uptake, revealing a new pharmacological target for amyloid clearance defects in the pathological ApoE4 genotype.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Interpretationown data
Increased surface LRP1 with restored NHE6 was due to posttranslational redistribution of the existing cellular LRP1 pool.
“We confirmed that there were no concomitant changes in LRP1 transcript (Fig. S3J) or total protein expression levels (Fig. S3I), suggesting that increased surface LRP1 was due to posttranslational 15 redistribution of the existing cellular LRP1 pool.”
Quote in the paperNot a substantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Interpretationown data
These large transcript differences could account for the observed ApoE-isotype specific shifts in endo-lysosomal pH.
“These large transcript differences could account for the observed ApoE-isotype specific shifts in endo-lysosomal pH.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Interpretationreasoning
NHE6 is a novel ApoE effector.
“In summary, we identify NHE6 as a novel ApoE effector and suggest potential therapeutic options in the treatment of amyloid disorders.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Premisecitation
Network analysis of 1697 genes in a late-onset AD dataset identified NHE6 as a top-five hub transcript in AD, with 202 network connections.
“One clue emerged from network analysis of 1697 genes in a late-onset AD dataset (Cases n=176, Controls=188), in which the endosomal Na + /H + exchanger NHE6 20 (SLC9A6) was identified as a top-five hub transcript in AD, with 202 network connections and a plethora of potential downstream effects 34 .”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [34]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationcitation
These findings could have implications for Christianson syndrome patients who have loss of function mutations in NHE6 and exhibit age-dependent hallmarks of neurodegeneration.
“These findings could have implications for Christianson 5 syndrome patients who have loss of function mutations in NHE6 and exhibit agedependent hallmarks of neurodegeneration 17,18 .”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [17]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [18]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationreasoning
It is likely that hyper-acidification of early and recycling endosomes redistributes plasma membrane proteins to the lysosome at the expense of recycling to the cell surface.
“It is likely that hyper-acidification of early and recycling endosomes redistributes plasma membrane proteins to the lysosome at the expense of recycling to the cell surface.”
Quote in the paperNot a substantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Interpretationown data
Diminished NHE6 expression is a major underlying cause for defective Aβ clearance in ApoE4 astrocytes.
“Taken together, our data point to diminished NHE6 expression as a major underlying cause for defective Aβ clearance in ApoE4 astrocytes.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Interpretationown data
Differential effects of ApoE3 and ApoE4 genotypes on nucleo-cytoplasmic shuttling of HDACs lead to a novel molecular mechanism for ApoE4-associated down regulation of NHE6 in post-mortem brain and astrocyte models.
“Taken together, these findings 30 reveal differential effects of ApoE3 and ApoE4 genotypes on nucleo-cytoplasmic shuttling of the HDACs leading to a novel molecular mechanism, with clinical implication, for ApoE4 associated down regulation of NHE6 in post-mortem brain and astrocyte models.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Interpretationreasoning
NHE6 is a novel and important ApoE4 effector in astrocytes.
“Thus, NHE6 is a novel and important ApoE4 effector in astrocytes (Fig. 6).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Interpretationown data
Defective pH regulation could underlie the observed Aβ clearance defects.
“This was independently confirmed by confocal microscopy (Fig. 3G), suggesting that defective pH regulation 25 could underlie the observed Aβ clearance defects.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Study design and conductown data
TSA or SAHA treatment in ApoE4 astrocytes did not significantly affect cell viability measured using trypan blue exclusion.
“Of note, TSA or SAHA treatment in ApoE4 astrocytes did not significantly affect cell viability measured using trypan blue exclusion (Fig. S4G).”
Quote in the paperNot a substantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Interpretationown data
NHE6 has a critical role in the uptake and clearance of soluble, secreted Aβ in astrocytes.
“In this study, we demonstrate a critical role for NHE6 in the uptake and 5 clearance of soluble, secreted Aβ in astrocytes.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Interpretationown data
Increased nuclear translocation of HDAC4 in ApoE4 astrocytes is linked to down regulation of NHE6 expression.
“Here, we link increased nuclear translocation of HDAC4 in ApoE4 astrocytes to down regulation of NHE6 expression.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- Interpretationreasoning
The amelioration of AD pathogenesis observed in vitro and in vivo by small molecule inhibitors of HDACs may be mediated, in part, by NHE6.
“Thus, the amelioration of AD pathogenesis observed in vitro and in vivo by 25 small molecule inhibitors of HDACs may be mediated, in part, by NHE6.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
- It may state two separate claims as one. 14
- Probably not a substantial claim. 16
It may state two separate claims as one.
Findingown dataHDAC inhibitors that restore NHE6 expression also restore surface expression of LRP1 and correct defective amyloid clearance in ApoE4 astrocytes to non-pathological ApoE3 levels.
“HDAC inhibitors that restore NHE6 expression also restore surface expression of LRP1 and effectively correct defective amyloid clearance in ApoE4 astrocytes to non-pathological ApoE3 levels.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
It may state two separate claims as one.
Findingown dataTSA treatment (5μM for 12h) significantly elevated endosomal pH without effect on lysosomal pH in ApoE4 astrocytes.
“TSA treatment (5µM for 12h) exhibited a compartment-specific effect of significantly elevating endosomal pH (Fig. 5D) without effect on lysosomal pH (Fig. 5E).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
It may state two separate claims as one.
Findingown dataBroad-spectrum HDAC inhibitors restore NHE6 expression, normalize endosomal pH and correct Aβ clearance defects in ApoE4 astrocytes.
“We show that broad-spectrum HDAC inhibitors restore NHE6 expression, normalize endosomal pH and correct Aβ clearance defects in ApoE4 astrocytes.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
It may state two separate claims as one.
PremisecitationApoE4 potentiates pre-symptomatic endosomal dysfunction and defective clearance of Aβ.
“The strongest genetic risk factor in sporadic AD is the ε4 allele of Apolipoprotein E (ApoE4), 5 which potentiates pre-symptomatic endosomal dysfunction and defective clearance of Aβ, although how these two pathways are linked has been unclear.”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [9]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [10]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [11]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [14]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [15]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [16]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationGenes associated with endosomal trafficking have been implicated as major risk factors in AD.
“Consistent with this finding, genes associated with endosomal trafficking have been implicated as major risk factors in AD 8 .”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationApoE4 is the strongest known genetic risk factor influencing susceptibility to sporadic, late-onset AD.
“Importantly, prominent pre-symptomatic endosomopathy of the brain, evidenced by enlarged and more numerous endosomes, has been observed in the ApoE4 genotype 9,10,11 , the strongest known genetic risk factor influencing susceptibility to sporadic, late-onset AD (LOAD) 12,13 .”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [12]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [13]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
InterpretationreasoningNHE6 is a prominent effector of ApoE4 and a promising therapeutic target in Alzheimer disease.
“Thus, NHE6 is a prominent effector of ApoE4 and 15 emerges as a promising therapeutic target in Alzheimer disease.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationThe pathological E4 variant of Apolipoprotein E is present in ~50% of patients with AD, and two copies of the E4 allele increase risk of LOAD by ∼12-times compared to the E3 isoform.
“The pathological 20 E4 variant of Apolipoprotein E is present in ~50% of patients with AD, and the presence of two copies of the E4 allele increases risk of LOAD by ∼12-times as compared to E3 isoform 14 .”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim.
PremisecitationAccumulation of Aβ in the brain begins at least 20 years before symptoms appear.
“Recent studies suggest that accumulation of Aβ in the brain begins at least 20 years before symptoms appear 2 .”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim.
PremisecitationSeveral promising drugs targeting the amyloid cascade have high failure rates (99.6%) in the clinic.
“Although several promising drugs targeting the amyloid cascade have been developed, their astoundingly high failure rates (99.6%) in the clinic suggest that by the time amyloid plaques, neurofibrillary tangles and neuronal death are detected, it is unlikely that disease progression can be 10 halted and reversed 3 .”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [3]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationown dataThe work presents a novel ApoE4-regulated cellular mechanism and druggable target in Alzheimer's disease: regulation of amyloid pathology by intra-endosomal pH.
“In conclusion, this work presents, (i) a novel ApoE4 regulated cellular mechanism and druggable target in AD, namely, regulation of amyloid pathology by intra-endosomal pH;”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationNa+/H+ exchangers are estimated to have exceptionally high transport rates of ∼1,500 ions/s.
“Na + /H + exchangers are estimated to have exceptionally high transport rates of ∼1,500 ions/s 39 , so that even small perturbations in expression result in dramatic changes in ionic milieu within the limited confines of the endosomal lumen.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim.
PremisecitationPreviously, the authors showed that NHE6 regulates trafficking and BACE1-mediated processing of APP to limit production of amyloidogenic peptides.
“Previously, we showed that NHE6 regulates trafficking and BACE1-mediated processing of amyloid precursor protein APP to limit production of amyloidogenic peptides 43 .”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [43]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationNHE6 was among the most highly down regulated genes (up to 6-fold) in elderly (70 years) brain compared to adult (40 years).
“Interestingly, NHE6 was among the most highly down regulated genes (up to 6-fold) in elderly (70 years) brain, compared to adult (40 years) 42 .”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
InterpretationreasoningLoss of NHE6 function contributes to endosomal pathology observed in pre-symptomatic AD brains both by accelerating Aβ production and by inhibiting Aβ clearance, promoting development of amyloid plaques and culminating in neurodegeneration and dementia.
“Taken together, we propose that loss of NHE6 function contributes to the endosomal 15 pathology observed in pre-symptomatic AD brains both by accelerating Aβ production and by inhibiting Aβ clearance, promoting the development of amyloid plaques and culminating in neurodegeneration and dementia.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
It may state two separate claims as one.
PremisecitationAmphipathic drugs such as bepridil and amiodarone partition into acidic compartments, alkalinize endosomes, and correct Aβ pathology in cell culture and animal models.
“Amphipathic drugs such as bepridil and amiodarone partition into acidic compartments, alkalinize endosomes, and correct Aβ pathology in cell culture and animal models 47 .”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [47]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationown dataOur data demonstrate a hitherto unrecognized ability of HDAC inhibitors to specifically enhance endosomal pH that could potentially correct human pathologies resulting from aberrant endosomal hyperacidification.
“Importantly, our 30 data demonstrate a hitherto unrecognized ability of HDAC inhibitors to specifically enhance endosomal pH that could potentially correct human pathologies resulting from aberrant endosomal hyperacidification.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationGenetic studies have linked eNHE to neurodevelopmental and neurodegenerative disorders including Christianson syndrome, Parkinson's disease, multiple sclerosis and AD, although underlying mechanisms remain to be determined.
“Genetic studies have linked eNHE to a host of neurodevelopmental and neurodegenerative disorders, including Christianson 15 syndrome (CS) with symptoms of autism, intellectual disability and epilepsy, Parkinsons disease, multiple sclerosis and AD, although underlying mechanisms remain to be determined 27 .”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [27]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
It may state two separate claims as one.
Interpretationown dataThe pathogenic deficiency of ApoE4 astrocytes to clear Aβ is mediated by decreased expression of NHE6, which results in endosomal over-acidification and reduced surface levels of LRP1.
“Using ApoE-isoform-expressing isogenic astrocytes that produce, lipidate, package, and secrete ApoE in a brainrelevant physiological fashion, we showed that the well-documented pathogenic deficiency of ApoE4 astrocytes to clear Aβ is mediated by decreased expression of NHE6, which results in endosomal over-acidification and reduced surface levels of the 10 Aβ receptor LRP1.”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
InterpretationcitationLoss of NHE6 may contribute to other ApoE4 defects, including defective synaptosome uptake and synapse pruning.
“Furthermore, since LRP1 is a receptor for multiple ligands, loss of NHE6 may contribute to other ApoE4 defects, including defective synaptosome uptake and synapse pruning 12,23 .”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [12]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [23]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationDown regulation of NHE6 gene expression has been reported in autism brains.
“Similar to our observations in AD, down regulation of NHE6 gene expression has been reported in autism brains 48 .”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [48]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationMore recent network analysis of the metastable subproteome associated with AD converged on NHE6 as a major hub gene regulating protein trafficking and clearance mechanisms.
“More recent network analysis of the metastable subproteome associated with AD also converged on NHE6 as a major hub gene regulating protein trafficking and clearance mechanisms 40 .”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationEndosomal Na+/H+ exchangers have an evolutionarily conserved role as a leak pathway for protons in compartmental pH homeostasis, critical for cargo trafficking and vesicular transport.
“The discovery of endosomal Na + /H + exchangers (eNHE) first in yeast, and soon after in plants, metazoans, and mammalian systems, established their evolutionarily conserved role as a leak pathway for protons in compartmental pH homeostasis, critical 10 for cargo trafficking and vesicular transport 27,37,38 .”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [27]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [37]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [38]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenEach experiment was repeated three times independently.
“Each experiment was repeated three times independently.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationAbnormalities in histone acetylation have been linked to several neurodegenerative diseases including AD, and HDAC inhibitors appear to show a neuroprotective effect, improving memory and cognition in mouse models.
“Abnormalities in histone acetylation have been linked to several neurodegenerative diseases including AD, and HDAC inhibitors appear to show a 20 neuroprotective effect, improving memory and cognition in mouse models 44,45 .”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [44]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [45]
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenAll procedures were carried out in accordance with the Institutional Animal Care and Use Committee of the University of California, San Francisco and the Johns Hopkins University School of Medicine, Baltimore.
“All procedures were carried out in accordance with The Institutional Animal Care and Use Committee of the University of California, San Francisco and the Johns Hopkins University School of Medicine, Baltimore.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Study design and conductown dataInternalized Aβ is sorted to the lysosomal degradation pathway, as evidenced by high colocalization with late endosomal-lysosomal markers and low colocalization with the recycling compartment marker transferrin.
“Internalized Aβ is sorted to 20 the lysosomal degradation pathway as evidenced by high colocalization with late endosomal-lysosomal markers and low colocalization with the recycling compartment marker transferrin (TFN) (Fig. S1A-D).”
Quote in the paperSubstantial claim- Rests on an assumption: ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
The paper relies on this without support.
ApoE-isoform-expressing isogenic astrocytes produce, lipidate, package, and secrete ApoE in a brain-relevant physiological fashion, making them a valid model of human ApoE4 brain astrocytes.
“Using ApoE-isoform-expressing isogenic astrocytes that produce, lipidate, package, and secrete ApoE in a brainrelevant physiological fashion”
The paper relies on this without support.
Elevated brain Aβ in NHE6 KO mice reflects a role for NHE6 in amyloid pathology relevant to AD.
“Consistent with a role in amyloid pathology, in vivo Aβ levels were found to be significantly higher in the brains of NHE6 KO mice.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
ApoE4 aggregates with LRP-1 affecting Aβ degradation.
“and with LRP-1 affecting A degradation (Prasad and Rao, 2018).”
From ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes (2019) · cites this paper as Prasad and Rao, 2018
The Introduction and the section on LRP1 surface expression report that ApoE4 astrocytes have less surface LRP1 and impaired Aβ uptake and clearance. They do not report that ApoE4 aggregates with LRP1 or establish an effect specifically on Aβ degradation; the mechanism described is altered LRP1 trafficking. (LLM, conf=0.84)
Experimental — accuracy not yet measuredApoE4 astrocytes contain significantly lower levels of all three receptors (LDLR, LRP1, ApoER2).
“Data showed that ApoE4 astrocytes contain significantly lower levels of all three receptors (Figure 5), although conflicting data regarding some of them have been obtained in primary and hiPSC-derived ApoE4 astrocytes [15,24,73].”
From ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis (2022) · cites this paper as [73]
The section “Surface expression of LRP1 receptor is severely reduced in ApoE4 astrocytes” reports about 50% lower surface LRP1 in ApoE4 than ApoE3 astrocytes, but no difference in total LRP1 protein. Our copy does not establish significantly lower LDLR or ApoER2 levels, so it does not support the claim about all three receptors. (LLM, conf=0.89)
Experimental — accuracy not yet measuredLower levels of ApoE receptors in the astrocytic membrane may lead to the reduced ability of ApoE4 astrocytes to clear Aβ.
“studies suggest that lower levels of ApoE receptors in the astrocytic membrane may lead to the reduced ability of ApoE4 astrocytes to clear Aβ [16,73].”
From ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis (2022) · cites this paper as [73]
ApoE4 is able to reduce recycling of the three receptors to the cell membrane, likely because of aberrant endosomal acidification that traps receptors within intracellular compartments and leads to their degradation.
“several studies showed that ApoE4 is able to reduce their recycling to the cell membrane, likely because of the aberrant endosomal acidification that traps receptors within the intracellular compartments and leads to their degradation [73,74,75].”
From ApoE3 vs. ApoE4 Astrocytes: A Detailed Analysis Provides New Insights into Differences in Cholesterol Homeostasis (2022) · cites this paper as [73]
In ApoE4-expressing astrocytes, overexpression of NHE6 increases LRP1 on the surface, which correlated with an increase in Aβ uptake.
“In ApoE4-expressing astrocytes, others have shown that overexpression of NHE6 increases LRP1 on the surface, which correlated with an increase in Aβ uptake (Prasad and Rao, 2018).”
From NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load (2021) · cites this paper as Prasad and Rao, 2018
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.
Reported error bars conflict with the stated convention
MinorThe methods say all data are presented as mean ± SD, whereas the figure description explicitly says one measurement is plotted as mean ± standard error.
“All data are presented as mean ± SD.”
“Representative images are shown (left) and mean fluorescence ± s.e. was plotted (right).”
Fig. 4C is assigned to two different results
MinorFig. 4C is cited for both NHE6 transcript expression in astrocytes and Aβ levels in NHE6-knockout mouse brains.
“Although NHE6 transcript was similar in ApoE KO mouse astrocytes and ApoE KO astrocytes with knock-in of human ApoE3, it was ∼56% reduced in ApoE4 knock-in cells (Fig. 4C).”
“Consistent with this hypothesis, amyloid Aβ levels were found to be elevated in mouse brains from NHE6 KO (Fig. 4C)”
LRP1 surface-expression result points to an Aβ uptake figure
MinorThe text cites Fig. 1B for surface biotinylation of LRP1, but the description of Fig. 1B identifies it as an Aβ uptake measurement.
“First, surface biotinylation revealed that plasma membrane expression of LRP1 receptor in ApoE4 astrocytes was lower by ∼50% (Fig. 1B).”
“B. Representative micrographs (left) and quantification (right) of ApoE3 and ApoE4 5 astrocytes subjected to 24h of Aβ uptake.”
Citations
Cites
Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy
Liu, C.-C., Kanekiyo, T., Xu, H., & Bu, G. (2013) · Nature Reviews Neurology · doi:10.1038/nrneurol.2012.263 · Cited by 3,459
Villemagne, V. L., Burnham, S., Bourgeat, P., Brown, B., Ellis, K. A., Salvado, O., Szoeke, C., Macaulay, S. L., Martins, R., Maruff, P., et al. (2013) · The Lancet Neurology · doi:10.1016/s1474-4422(13)70044-9 · Cited by 2,279
(2015) · HAL · Cited by 2,238
Sensors and regulators of intracellular pH
Casey, J. R., Grinstein, S., & Orlowski, J. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2820 · Cited by 2,218
Decreased Clearance of CNS β-Amyloid in Alzheimer’s Disease
Mawuenyega, K. G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J. C., Yarasheski, K. E., & Bateman, R. J. (2010) · Science · doi:10.1126/science.1197623 · Cited by 2,078
Alzheimer’s disease drug-development pipeline: Few candidates, frequent failures
Cummings, J. L., Morstorf, T., & Zhong, K. (2014) · Alzheimer's Research & Therapy · doi:10.1186/alzrt269 · Cited by 1,744
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
Human ApoE isoforms differentially regulate brain amyloid-β peptide clearance
Castellano, J. M., Kim, J., Stewart, F. R., Jiang, H., DeMattos, R. B., Patterson, B. W., Fagan, A. M., Morris, J. C., Mawuenyega, K. G., Cruchaga, C., et al. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002156 · Cited by 1,242 · cited 1×
“Studies in humans, mouse models, and cell cultures have revealed the importance of ApoE isotype-specific differences in Aβ uptake and clearance in AD pathogenesis, although the underlying mechanism remains to be determined (22, 23, 27, 28).”
BackgroundLee, J.-H., Yu, W. H., Kumar, A., Lee, S., Mohan, P. S., Peterhoff, C. M., Wolfe, D. M., Martinez-Vicente, M., Massey, A. C., Sovak, G., et al. (2010) · Cell · doi:10.1016/j.cell.2010.05.008 · Cited by 1,212
Blalock, E. M., Geddes, J. W., Chen, K. C., Porter, N. M., Markesbery, W. R., & Landfield, P. W. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308512100 · Cited by 1,025
ApoE Promotes the Proteolytic Degradation of Aβ
Jiang, Q., Lee, C. Y. D., Mandrekar, S., Wilkinson, B., Cramer, P., Zelcer, N., Mann, K., Lamb, B., Willson, T. M., Collins, J. L., et al. (2008) · Neuron · doi:10.1016/j.neuron.2008.04.010 · Cited by 876
An epigenetic blockade of cognitive functions in the neurodegenerating brain
Gräff, J., Rei, D., Guan, J.-S., Wang, W.-Y., Seo, J., Hennig, K. M., Nieland, T. J. F., Fass, D. M., Kao, P. F., Kahn, M., et al. (2012) · Nature · doi:10.1038/nature10849 · Cited by 853
Cataldo, A. M., Peterhoff, C. M., Troncoso, J. C., Gomez-Isla, T., Hyman, B. T., & Nixon, R. A. (2000) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)64538-5 · Cited by 776
ApoE and Aβ in Alzheimer’s Disease: Accidental Encounters or Partners?
Kanekiyo, T., Xu, H., & Bu, G. (2014) · Neuron · doi:10.1016/j.neuron.2014.01.045 · Cited by 608
Verghese, P. B., Castellano, J. M., Garai, K., Wang, Y., Jiang, H., Shah, A., Bu, G., Frieden, C., & Holtzman, D. M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1220484110 · Cited by 556
Evolutionary origins of eukaryotic sodium/proton exchangers
Brett, C. L., Donowitz, M., & Rao, R. (2005) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00360.2004 · Cited by 554
Self-citationApoE and Clusterin Cooperatively Suppress Aβ Levels and Deposition
DeMattos, R. B., Cirrito, J. R., Parsadanian, M., May, P. C., O'Dell, M. A., Taylor, J. W., Harmony, J. A. K., Aronow, B. J., Bales, K. R., Paul, S. M., et al. (2004) · Neuron · doi:10.1016/s0896-6273(03)00850-x · Cited by 459
ApoE4 Accelerates Early Seeding of Amyloid Pathology
Liu, C.-C., Zhao, N., Fu, Y., Wang, N., Linares, C., Tsai, C.-W., & Bu, G. (2017) · Neuron · doi:10.1016/j.neuron.2017.11.013 · Cited by 451
Microglia Mediate the Clearance of Soluble Aβ through Fluid Phase Macropinocytosis
Mandrekar, S., Jiang, Q., Lee, C. Y. D., Koenigsknecht-Talboo, J., Holtzman, D. M., & Landreth, G. E. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.5572-08.2009 · Cited by 415
Nixon, R. A. (2017) · The FASEB Journal · doi:10.1096/fj.201700359 · Cited by 400 · cited 1×
“Dysfunction in endolysosomal pH is an emerging theme in AD with clear potential for intervention to exploit the diseasemodifying effects of endosomal pH (19).”
BackgroundApolipoprotein E in Alzheimer's Disease: An Update
Yu, J.-T., Tan, L., & Hardy, J. (2014) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-071013-014300 · Cited by 394
Cataldo, A. M., Barnett, J. L., Pieroni, C., & Nixon, R. A. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-16-06142.1997 · Cited by 393
Endosome function and dysfunction in Alzheimer's disease and other neurodegenerative diseases
Nixon, R. A. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.09.018 · Cited by 380
Chen, Y., Durakoglugil, M. S., Xian, X., & Herz, J. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914984107 · Cited by 368
Cataldo, A. M., Petanceska, S., Terio, N. B., Peterhoff, C. M., Durham, R., Mercken, M., Mehta, P. D., Buxbaum, J., Haroutunian, V., & Nixon, R. A. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.02.027 · Cited by 363
Kang, D. E., Pietrzik, C. U., Baum, L., Chevallier, N., Merriam, D. E., Kounnas, M. Z., Wagner, S. L., Troncoso, J. C., Kawas, C. H., Katzman, R., et al. (2000) · Journal of Clinical Investigation · doi:10.1172/jci11013 · Cited by 354
Liang, W. S., Dunckley, T. L., Beach, T. G., Grover, A., Mastroeni, D., Walker, D. G., Caselli, R. J., Kukull, W. A., McKeel, D. W., Morris, J. C., et al. (2006) · Physiological Genomics · doi:10.1152/physiolgenomics.00208.2006 · Cited by 346
The Global Impact of Dementia 2013-2050
Prince, M. J., Guerchet, M., & Prina, M. A. (2013) · Research Portal (King's College London) · Cited by 325
Genetic Control of Human Brain Transcript Expression in Alzheimer Disease
Webster, J. A., Gibbs, J. R., Clarke, J., Ray, M., Zhang, W., Holmans, P., Rohrer, K., Zhao, A., Marlowe, L., Kaleem, M., et al. (2009) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2009.03.011 · Cited by 304
Jiang, Y., Mullaney, K. A., Peterhoff, C. M., Che, S., Schmidt, S. D., Boyer‐Boiteau, A., Ginsberg, S. D., Cataldo, A. M., Mathews, P. M., & Nixon, R. A. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908953107 · Cited by 293
Apolipoprotein E4 Impairs Neuronal Insulin Signaling by Trapping Insulin Receptor in the Endosomes
Zhao, N., Liu, C.-C., Van Ingelgom, A. J., Martens, Y. A., Linares, C., Knight, J. A., Painter, M. M., Sullivan, P. M., & Bu, G. (2017) · Neuron · doi:10.1016/j.neuron.2017.09.003 · Cited by 289 · cited 2×
“Recent observations also point to a role for ApoE4 in binding and trapping insulin receptor within intracellular compartments (55), which could result from acid pH-mediated ApoE4 aggregation within the endosomes (56).”
BackgroundA two-domain elevator mechanism for sodium/proton antiport
Lee, C., Kang, H. J., von Ballmoos, C., Newstead, S. L., Uzdavinys, P., Dotson, D., Iwata, S., Beckstein, O., Cameron, A. D., & Drew, D. (2013) · Nature · doi:10.1038/nature12484 · Cited by 252
Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes
Chung, W.-S., Verghese, P. B., Chakraborty, C., Joung, J., Hyman, B. T., Ulrich, J. D., Holtzman, D. M., & Barres, B. A. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1609896113 · Cited by 242
Targeting HDACs: A Promising Therapy for Alzheimer's Disease
Xu, K., Dai, X., Huang, H., & Jiang, Z.-F. (2011) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2011/143269 · Cited by 218
Beyond endocytosis: LRP function in cell migration, proliferation and vascular permeability
Lillis, A. P., MIKHAILENKO, I. A., & Strickland, D. K. (2005) · Journal of Thrombosis and Haemostasis · doi:10.1111/j.1538-7836.2005.01371.x · Cited by 210
Endosomal traffic jams represent a pathogenic hub and therapeutic target in Alzheimer’s disease
Small, S. A., Simoes-Spassov, S., Mayeux, R., & Petsko, G. A. (2017) · Trends in Neurosciences · doi:10.1016/j.tins.2017.08.003 · Cited by 168
Traditional and emerging roles for the SLC9 na+/H+ exchangers
Fuster, D. G., & Alexander, R. T. (2014) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-013-1408-8 · Cited by 159
Ouyang, Q., Lizarraga, S. B., Schmidt, M., Yang, U., Gong, J., Ellisor, D., Kauer, J. A., & Morrow, E. M. (2013) · Neuron · doi:10.1016/j.neuron.2013.07.043 · Cited by 144
ApoE4 and Aβ Oligomers Reduce BDNF Expression via HDAC Nuclear Translocation
Sen, A., Nelson, T. J., & Alkon, D. L. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.0260-15.2015 · Cited by 133
Garbern, J. Y., Neumann, M., Trojanowski, J. Q., Lee, V. M. ‐., Feldman, G. L., Norris, J. W., Friez, M. J., Schwartz, C. E., Stevenson, R. E., & Sima, A. A. F. (2010) · Brain · doi:10.1093/brain/awq071 · Cited by 117
Oligomer-specific Aβ toxicity in cell models is mediated by selective uptake
Chafekar, S. M., Baas, F., & Scheper, W. (2008) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2008.06.003 · Cited by 114
A leak pathway for luminal protons in endosomes drives oncogenic signalling in glioblastoma
Kondapalli, K. C., Llongueras, J. P., Capilla‐González, V., Prasad, H., Hack, A., Smith, C. L., Guerrero‐Cazares, H., Quiñones‐Hinojosa, A., & Rao, R. (2015) · Nature Communications · doi:10.1038/ncomms7289 · Cited by 109
Self-citationStrømme, P., Dobrenis, K., Sillitoe, R. V., Gulinello, M. E., Ali, N. F., Davidson, C. D., Micsenyi, M. C., Stephney, G. W., Ellevog, L., Klungland, A., et al. (2011) · Brain · doi:10.1093/brain/awr250 · Cited by 100
Liu, D.-S., Pan, X.-D., Zhang, J., Shen, H., Collins, N. C., Cole, A. M., Koster, K. P., Ben Aissa, M., Dai, X.-M., Zhou, M., et al. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0002-2 · Cited by 99
An inside job: how endosomal Na+/H+ exchangers link to autism and neurological disease
Kondapalli, K. C., Prasad, H., & Rao, R. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00172 · Cited by 97
Self-citationFunctional evaluation of autism-associated mutations in NHE9
Kondapalli, K. C., Hack, A., Schushan, M., Landau, M., Ben‐Tal, N., & Rao, R. (2013) · Nature Communications · doi:10.1038/ncomms3510 · Cited by 96
Self-citationGenetic and phenotypic diversity of NHE 6 mutations in C hristianson syndrome
Pescosolido, M. F., Stein, D. M., Schmidt, M., Achkar, C. M. E., Sabbagh, M. F., Rogg, J. M., Tantravahi, U., McLean, R. L., Liu, J. S.-H., Poduri, A., et al. (2014) · Annals of Neurology · doi:10.1002/ana.24225 · Cited by 96
Mak, A. C. Y., Pullinger, C. R., Tang, L. F., Wong, J. S., Deo, R. C., Schwarz, J.-M., Gugliucci, A., Movsesyan, I., Ishida, B. Y., Chu, C., et al. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2014.2011 · Cited by 94
Neuropathology of preclinical and clinical lateonset Alzheimer's disease
Troncoso, J. C., Cataldo, A. M., Nixon, R. A., Barnett, J. L., Lee, M. K., Checler, F., Fowler, D. R., Smialek, J. E., Crain, B., Martin, L. J., et al. (1998) · Annals of Neurology · doi:10.1002/ana.410430519 · Cited by 93
Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease
Kundra, R., Ciryam, P., Morimoto, R. I., Dobson, C. M., & Vendruscolo, M. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1618417114 · Cited by 92
Nazer, B., Hong, S., & Selkoe, D. J. (2008) · Neurobiology of Disease · doi:10.1016/j.nbd.2007.12.005 · Cited by 90
Endocytic disturbances distinguish among subtypes of alzheimer's disease and related disorders
Cataldo, A., Rebeck, G. W., Ghetti, B., Hulette, C., Lippa, C., Van Broeckhoven, C., Van Duijn, C., Cras, P., Bogdanovic, N., Bird, T., et al. (2001) · Annals of Neurology · doi:10.1002/ana.1254 · Cited by 90
Xu, P., Li, Y., Qin, X., Scherzer, C. R., Xu, H., Schmechel, D. E., Hulette, C. M., Ervin, J. F., Gullans, S. R., Haines, J. L., et al. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.07.004 · Cited by 77
Prasad, H., & Rao, R. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.602219 · Cited by 76
Self-citationAlam†, M. S., Getz, M., & Haldar, K. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aad9407 · Cited by 68
Muro, S., Mateescu, M., Gajewski, C., Robinson, M. E. A., Muzykantov, V. R., & Koval, M. H. (2005) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00311.2005 · Cited by 67
Genes for endosomal NHE6 and NHE9 are misregulated in autism brains
Schwede, M., Garbett, K. A., Mirnics, K., Geschwind, D. H., & Morrow, E. M. (2013) · Molecular Psychiatry · doi:10.1038/mp.2013.28 · Cited by 61
Mitterreiter, S., Page, R. M., Kamp, F., Hopson, J., Winkler, E., Ha, H., Hamid, R., Herms, J. W., Mayer, T. U., Nelson, D. J., et al. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.1199-10.2010 · Cited by 55
Hu, H., Wrogemann, K., Kalscheuer, V. M., Tzschach, A., Richard, H., Haas, S. A., Menzel, C., Bienek, M., Froyen, G., Raynaud, M., et al. (2009) · The HUGO Journal · doi:10.1007/s11568-010-9142-1 · Cited by 52
Li, Y., Cheng, D., Cheng, R., Zhu, X., Wan, T., Liu, J., & Zhang, R. (2014) · PLoS ONE · doi:10.1371/journal.pone.0099939 · Cited by 51
Hu, H., Wrogemann, K., Kalscheuer, V., Tzschach, A., Richard, H., Haas, S. A., Menzel, C., Bienek, M., Froyen, G., Raynaud, M., et al. (2009) · The HUGO Journal · doi:10.1007/s11568-010-9137-y · Cited by 49
Xu, P., Li, Y., Qin, X., Kroner, C. C., Green-Odlum, A., Xu, H., Wang, T.-Y., Schmechel, D. E., Hulette, C. M., Ervin, J. F., et al. (2007) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2007.06.009 · Cited by 48
Zanni, G., Barresi, S., Cohen, R., Specchio, N., Basel‐Vanagaite, L., Valente, E. M., Shuper, A., Vigevano, F., & Bertini, E. (2014) · Epilepsy Research · doi:10.1016/j.eplepsyres.2014.02.009 · Cited by 43
Sinajon, P., Verbaan, D., & So, J. (2016) · Human Genetics · doi:10.1007/s00439-016-1675-5 · Cited by 38
The Interplay Between Apolipoprotein E4 and the Autophagic–Endocytic–Lysosomal Axis
Schmukler, E., Michaelson, D. M., & Pinkas-Kramarski, R. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-0892-4 · Cited by 35
Histone deacetylase–mediated regulation of endolysosomal pH
Prasad, H., & Rao, R. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.002025 · Cited by 35
Self-citationKittur, S., Hoh, J., Endo, H., Tourtellotte, W., Weeks, B., Markesbery, W., & Adler, W. H. (1994) · Journal of Geriatric Psychiatry and Neurology · doi:10.1177/089198879400700305 · Cited by 33
Qiao, F., Gao, X., Li, Y., Cai, H.-Y., & Qi, J. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-140375 · Cited by 29
Xu, M., Ouyang, Q., Gong, J., Pescosolido, M. F., Pruett, B. S., Mishra, S., Schmidt, M., Jones, R. N., Uzun, E. D. G., Lizarraga, S. B., et al. (2017) · eNeuro · doi:10.1523/eneuro.0388-17.2017 · Cited by 29
Garai, K., Baban, B. A., & Frieden, C. (2011) · Biochemistry · doi:10.1021/bi2006702 · Cited by 27
Naumova, O. Y., Palejev, D., Vlasova, N. V., Lee, M., Rychkov, S. Y., Babich, O. N., Vaccarino, F. M., & Grigorenko, E. L. (2012) · Development and Psychopathology · doi:10.1017/s0954579412000818 · Cited by 25
Applying knowledge of autism to brain cancer management: what do we know?
Prasad, H., & Rao, R. (2015) · Future Oncology · doi:10.2217/fon.15.93 · Cited by 11
Self-citationMayburd, A. L., & Baranova, A. V. (2013) · BMC Systems Biology · doi:10.1186/1752-0509-7-121 · Cited by 10
Functional Evaluation of Autism Associated Mutations in Slc9A9 (NHE9)
Kondapalli, K. C., Hack, A., Schushan, M., Ben-Tal, N., & Rao, R. (2013) · Biophysical Journal · doi:10.1016/j.bpj.2012.11.161
Self-citationA two-domain elevator mechanism for sodium/proton antiport
Lee, C., Kang, H. J., von Ballmoos, C., Newstead, S., Uzdavinys, P., Dotson, D. L., Iwata, S., Beckstein, O., Cameron, A. D., & Drew, D. (2014) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2014.05.250
Flagged first, then by citations
Cited by
Sorted by citations
Amyloid-β-independent regulators of tau pathology in Alzheimer disease
van der Kant, R., Goldstein, L. S. B., & Ossenkoppele, R. (2020) · Nature reviews. Neuroscience · doi:10.1038/s41583-019-0240-3 · Cited by 580
Astrocytic and microglial cells as the modulators of neuroinflammation in Alzheimer’s disease
Singh, D. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02565-0 · Cited by 569
The role of astroglia in Alzheimer's disease: pathophysiology and clinical implications
Arranz, A. M., & De Strooper, B. (2019) · The Lancet Neurology · doi:10.1016/s1474-4422(18)30490-3 · Cited by 334
APOE and Alzheimer’s Disease: From Lipid Transport to Physiopathology and Therapeutics
Husain, M. A., Laurent, B., & Plourde, M. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.630502 · Cited by 353
Jeremic, D., Jiménez-Díaz, L., & Navarro-López, J. D. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101496 · Cited by 306
Fernandez, C. G., Hamby, M. E., McReynolds, M. L., & Ray, W. J. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00014 · Cited by 277
Endo-lysosomal dysregulations and late-onset Alzheimer’s disease: impact of genetic risk factors
Van Acker, Z. P., Bretou, M., & Annaert, W. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0323-7 · Cited by 222
The SLC9A-C Mammalian Na + /H + Exchanger Family: Molecules, Mechanisms, and Physiology
Pedersen, S. F., & Counillon, L. (2019) · Physiological Reviews · doi:10.1152/physrev.00028.2018 · Cited by 191
Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease
Najm, R., Jones, E. A., & Huang, Y. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0324-6 · Cited by 183
Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease
Williams, T., Borchelt, D., & Chakrabarty, P. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-0358-9 · Cited by 171
ApoE4 Alters ABCA1 Membrane Trafficking in Astrocytes
Rawat, V., Wang, S., Sima, J., Bar, R., Liraz, O., Gundimeda, U., Parekh, T., Chan, J., Johansson, J. O., Tang, C., et al. (2019) · The Journal of Neuroscience · doi:10.1523/jneurosci.1400-19.2019 · Cited by 165
Alzheimer’s Disease Pathogenesis: Role of Autophagy and Mitophagy Focusing in Microglia
Eshraghi, M., Adlimoghaddam, A., Mahmoodzadeh, A., Sharifzad, F., Yasavoli-Sharahi, H., Lorzadeh, S., Albensi, B. C., & Ghavami, S. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073330 · Cited by 158
APOE alleles and diet in brain aging and Alzheimer's disease
Yassine, H. N., & Finch, C. E. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00150 · Cited by 145
Transgenic Mouse Models of Alzheimer’s Disease: An Integrative Analysis
Sanchez-Varo, R. M., Mejias‐Ortega, M., Fernandez-Valenzuela, J. J., Nuñez‐Diaz, C., Cáceres-Palomo, L., Vegas‐Gomez, L., Sánchez‐Mejías, E., Trujillo‐Estrada, L., García‐León, J. A., Moreno‐González, I., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23105404 · Cited by 134
APOE4 drives inflammation in human astrocytes via TAGLN3 repression and NF-κB activation
Arnaud, L., Benech, P., Greetham, L., Stephan, D., Jimenez, A., Jullien, N., García‐González, L., Tsvetkov, P. O., Devred, F., Sancho-Martinez, I., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111200 · Cited by 130
Cooper, J. M., Lathuiliere, A., Migliorini, M., Arai, A. L., Wani, M. M., Dujardin, S., Muratoglu, S. C., Hyman, B. T., & Strickland, D. K. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100715 · Cited by 122
Contribution of astrocytes to neuropathology of neurodegenerative diseases
Acıoğlu, Ç., Li, L., & Elkabes, S. (2021) · Brain Research · doi:10.1016/j.brainres.2021.147291 · Cited by 119
Emerging links between endosomal pH and cancer
Ko, M., Quiñones‐Hinojosa, A., & Rao, R. (2020) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09870-1 · Cited by 118
Self-citationThe therapeutic importance of acid-base balance
Quade, B. N., Parker, M. D., & Occhipinti, R. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.114278 · Cited by 106
The Glymphatic System: A Novel Therapeutic Target for Stroke Treatment
Lv, T., Zhao, B., Hu, Q., & Zhang, X. (2021) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2021.689098 · Cited by 106
APOE alters glucose flux through central carbon pathways in astrocytes
Williams, H. C., Farmer, B. C., Piron, M. A., Walsh, A. E., Bruntz, R. C., Gentry, M. S., Sun, R. C., & Johnson, L. A. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104742 · Cited by 105
de Leeuw, S. M., Kirschner, A. W. T., Lindner, K., Rust, R., Budny, V., Wolski, W. E., Gavin, A.-C., Nitsch, R. M., & Tackenberg, C. (2022) · Stem Cell Reports · doi:10.1016/j.stemcr.2021.11.007 · Cited by 105
The cell biology of APOE in the brain
Windham, I. A., & Cohen, S. (2024) · Trends in Cell Biology · doi:10.1016/j.tcb.2023.09.004 · Cited by 103
Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer’s disease
Xian, X., Pohlkamp, T., Durakoglugil, M. S., Wong, C. H., Beck, J. K., Lane-Donovan, C., Plattner, F., & Herz, J. (2018) · eLife · doi:10.7554/elife.40048 · Cited by 98
Precision Nutrition for Alzheimer’s Prevention in ApoE4 Carriers
Norwitz, N. G., Saif, N., Ariza, I. E., & Isaacson, R. (2021) · Nutrients · doi:10.3390/nu13041362 · Cited by 91
Sharma, S., & Mandal, P. K. (2022) · ACM Computing Surveys · doi:10.1145/3492865 · Cited by 91
Su, Q., Li, T., He, P.-F., Lu, X.-C., Yu, Q., Gao, Q.-C., Wang, Z.-J., Wu, M.-N., Yang, D., & Qi, J.-S. (2021) · Alzheimer's Research & Therapy · doi:10.1186/s13195-020-00746-8 · Cited by 75
Astroglial activation: Current concepts and future directions
Edison, P. (2024) · Alzheimer s & Dementia · doi:10.1002/alz.13678 · Cited by 67
Effects of APOE4 allelic dosage on lipidomic signatures in the entorhinal cortex of aged mice
Miranda, A. M., Ashok, A., Chan, R. B., Zhou, B., Xu, Y., McIntire, L. B., Area-Gomez, E., Di Paolo, G., Duff, K. E., Oliveira, T. G., et al. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-01881-6 · Cited by 60
“Also, we previously reported increased expression of several V-type ATPase subunits [33], possibly in response to altered lysosomal pH and membrane composition [68, 69].”
BackgroundA role of low-density lipoprotein receptor-related protein 4 (LRP4) in astrocytic Aβ clearance
Zhang, H., Chen, W., Tan, Z., Zhang, L., Dong, Z., Cui, W., Zhao, K., Wang, H., Jing, H., Cao, R., et al. (2020) · The Journal of Neuroscience · doi:10.1523/jneurosci.0250-20.2020 · Cited by 58
Larramona-Arcas, R., González-Arias, C., Perea, G., Gutiérrez, A., Vitorica, J., García-Barrera, T., Gómez-Ariza, J. L., Pascua-Maestro, R., Ganfornina, M. D., Kara, E., et al. (2020) · Molecular Neurodegeneration · doi:10.1186/s13024-020-00382-8 · Cited by 56
Rudajev, V., & Novotný, J. (2023) · Cell & Bioscience · doi:10.1186/s13578-023-01127-y · Cited by 51
Astrocyte in Neurological Disease: Pathogenesis and Therapy
Huang, M., Long, A., Hao, L., Shi, Z., & Zhang, M. (2025) · MedComm · doi:10.1002/mco2.70299 · Cited by 50
NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load
Pohlkamp, T., Xian, X., Wong, C. H., Durakoglugil, M. S., Werthmann, G. C., Saido, T. C., Evers, B. M., White, C. L., Connor, J., Hammer, R. E., et al. (2021) · eLife · doi:10.7554/elife.72034 · Cited by 46
Cholesterol Dysmetabolism in Alzheimer’s Disease: A Starring Role for Astrocytes?
Staurenghi, E., Giannelli, S., Testa, G., Sottero, B., Leonarduzzi, G., & Gamba, P. (2021) · Antioxidants · doi:10.3390/antiox10121890 · Cited by 44
A multi‐hit hypothesis for an APOE4 ‐dependent pathophysiological state
Steele, O. G., Stuart, A. C., Minkley, L., Shaw, K., Bonnar, O., Anderle, S., Penn, A. C., Rusted, J., Serpell, L., Hall, C., et al. (2022) · European Journal of Neuroscience · doi:10.1111/ejn.15685 · Cited by 44
The multifaceted role of WNT signaling in Alzheimer’s disease onset and age-related progression.
Kostes, W. W., & Brafman, D. A. (2023) · Cells · doi:10.3390/cells12081204 · Cited by 43
Toxic amyloid-β oligomers induced self-replication in astrocytes triggering neuronal injury
Wang, W., Hou, T., Jia, L.-F., Wu, Q., Quan, M., & Jia, J. (2019) · EBioMedicine · doi:10.1016/j.ebiom.2019.03.049 · Cited by 42
Lysosomal acidification impairment in astrocyte-mediated neuroinflammation
Zeng, J., Indajang, J., Pitt, D., & Lo, C. H. (2025) · Journal of Neuroinflammation · doi:10.1186/s12974-025-03410-w · Cited by 41
Gross, T. J., Doran, E. W., Cheema, A. K., Head, E., Lott, I. T., & Mapstone, M. E. (2019) · Developmental Neurobiology · doi:10.1002/dneu.22716 · Cited by 41
Raman, S., Brookhouser, N., & Brafman, D. A. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104788 · Cited by 41
Haghani, A., Cacciottolo, M., Doty, K. R., D’Agostino, C., Thorwald, M. A., Safi, N., Levine, M. E., Sioutas, C., Town, T., Forman, H. J., et al. (2020) · eLife · doi:10.7554/elife.54822 · Cited by 40
Phagocytic Glial Cells in Brain Homeostasis
Kono, R., Ikegaya, Y., & Koyama, R. (2021) · Cells · doi:10.3390/cells10061348 · Cited by 40
Xiao, S., Liu, Y.-J., Wang, L., Sha, Z., Che, X., Yu, Z., & Lee, S. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.875138 · Cited by 40
Therapeutic Potential of Astrocyte Transplantation
Hastings, N., Kuan, W., Osborne, A., & Kotter, M. (2022) · Cell Transplantation · doi:10.1177/09636897221105499 · Cited by 39
Endosomal-Lysosomal Processing of Neurodegeneration-Associated Proteins in Astrocytes
Wong, C.-O. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21145149 · Cited by 31
Morales, L. G. F., Correa‐Basurto, J., & Rosales‐Hernández, M. C. (2021) · Antioxidants · doi:10.3390/antiox10020218 · Cited by 38
Astrocytic microRNAs and transcription factors in Alzheimer’s disease and therapeutic interventions
Nassar, A., Kodi, T., Satarker, S., Chowdari Gurram, P., Upadhya, D., SM, F., Mudgal, J., & Nampoothiri, M. (2022) · Cells · doi:10.3390/cells11244111 · Cited by 38
Lee, Y., Miller, M. R., Fernandez, M. A., Berg, E. L., Prada, A. M., Ouyang, Q., Schmidt, M., Silverman, J. L., Young‐Pearse, T. L., & Morrow, E. M. (2021) · Brain · doi:10.1093/brain/awab467 · Cited by 36
Histone deacetylase–mediated regulation of endolysosomal pH
Prasad, H., & Rao, R. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.002025 · Cited by 35
Self-citationFote, G. M., Geller, N. R., Efstathiou, N. E., Hendricks, N., Vavvas, D. G., Reidling, J. C., Thompson, L. M., & Steffan, J. S. (2022) · Journal of Cell Science · doi:10.1242/jcs.258687 · Cited by 36
Mahaman, Y. A. R., Huang, F., Salissou, M. T. M., Yacouba, M. B. M., Wang, J., Liu, R., Zhang, B., Li, H., Zhu, F., & Wang, X. (2023) · Neurotherapeutics · doi:10.1007/s13311-023-01356-6 · Cited by 34
APOE2 mitigates disease-related phenotypes in an isogenic hiPSC-based model of Alzheimer’s disease
Brookhouser, N., Raman, S., Frisch, C., Srinivasan, G., & Brafman, D. A. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01076-3 · Cited by 33
Alzheimer’s Disease-Related Epigenetic Changes: Novel Therapeutic Targets
Paniri, A., Hosseini, M. M., & Akhavan‐Niaki, H. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03626-y · Cited by 33
Preman, P., Moechars, D., Fertan, E., Wolfs, L., Serneels, L., Shah, D., Lamote, J., Poovathingal, S., Snellinx, A., Mancuso, R., et al. (2024) · EMBO Molecular Medicine · doi:10.1038/s44321-024-00162-7 · Cited by 32
Mahaman, Y. A. R., Feng, J., Huang, F., Salissou, M. T. M., Wang, J., Liu, R., Zhang, B., Li, H., Zhu, F., & Wang, X. (2022) · Nutrients · doi:10.3390/nu14204284 · Cited by 32
pH regulating mechanisms of astrocytes: A critical component in physiology and disease of the brain
Theparambil, S. M., Begum, G., & Rose, C. R. (2024) · Cell Calcium · doi:10.1016/j.ceca.2024.102882 · Cited by 31
Ye, J., Zhong, S., Wan, H., Guo, X., Yao, X., Liu, Q., Chen, L., Wang, J., & Xiao, S. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00796-2 · Cited by 31
Novel therapeutic approaches to target neurodegeneration
de la Fuente, A. G., Pelucchi, S., Mertens, J., Luca, M. D., Mauceri, D., & Marcello, E. E. (2023) · British Journal of Pharmacology · doi:10.1111/bph.16078 · Cited by 31
Clinical and neurochemical correlates of the APOE genotype in early-stage Parkinson’s disease
Zenuni, H., Bovenzi, R., Bissacco, J., Grillo, P., Simonetta, C., Mascioli, D., Pieri, M., Bernardini, S., Sancesario, G. M., Stefani, A., et al. (2023) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2023.07.011 · Cited by 30
Genetic targeting of astrocytes to combat neurodegenerative disease
Kirschen, G., Kéry, R., & Chen, A. F. (2019) · Neural Regeneration Research · doi:10.4103/1673-5374.265541 · Cited by 29
Karaahmet, B., Le, L., Mendes, M. S., Majewska, A. K., & O’Banion, M. K. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02532-9 · Cited by 29
Poët, M., Vigier, N., Bouret, Y., Jarretou, G., Gautier, R., Bendahhou, S., Balter, V., Montanes, M., Thibon, F., & Counillon, L. (2023) · iScience · doi:10.1016/j.isci.2023.106887 · Cited by 29
Tan, N. K., Chan, H., Lu, Z., Zreiqat, H., Lakhwani, G., Lesani, P., & New, E. J. (2024) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.4c10836 · Cited by 28
Iron Responsive Element-Mediated Responses to Iron Dyshomeostasis in Alzheimer’s Disease
Hin, N., Newman, M., Pederson, S., & Lardelli, M. (2021) · Journal of Alzheimer s Disease · doi:10.3233/jad-210200 · Cited by 28
Multivariate effects of pH, salt, and Zn2+ ions on Aβ40 fibrillation
Wang, H., Wu, J., Sternke‐Hoffmann, R., Zheng, W., Mörman, C., & Luo, J. (2022) · Communications Chemistry · doi:10.1038/s42004-022-00786-1 · Cited by 28
Glycoengineering artificial receptors for microglia to phagocytose Aβ aggregates
Yu, D., Liu, C., Zhang, H., Ren, J., & Qu, X. (2021) · Chemical Science · doi:10.1039/d0sc07067j · Cited by 28
Luo, W., Chen, C., Guo, X., Guo, X., Zheng, J., Liu, J., Fan, X., Luo, M., Yu, Z., Li, H., et al. (2024) · Advanced Functional Materials · doi:10.1002/adfm.202409522 · Cited by 27
Gao, A. Y. L., Filippis, E. L.-D., Orlowski, J., & McKinney, R. A. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.892196 · Cited by 26
Endosomal Acid-Base Homeostasis in Neurodegenerative Diseases
Prasad, H., & Rao, R. (2020) · Reviews of physiology, biochemistry and pharmacology · doi:10.1007/112_2020_25 · Cited by 25
Self-citationApoE4 expression disrupts tau uptake, trafficking, and clearance in astrocytes
Eisenbaum, M., Pearson, A., Ortiz, C., Mullan, M., Crawford, F., Ojo, J., & Bachmeier, C. (2024) · Glia · doi:10.1002/glia.24469 · Cited by 25
FLIM-Based Intracellular and Extracellular pH Measurements Using Genetically Encoded pH Sensor
Goryashchenko, A. S., Pakhomov, A. A., Ryabova, A. V., Romanishkin, I. D., Maksimov, E. G., Orsa, A. N., Serova, O. V., Mozhaev, A. A., Maksimova, M. А., Martynov, V. I., et al. (2021) · Biosensors · doi:10.3390/bios11090340 · Cited by 24
Staurenghi, E., Leoni, V., Lo Iacono, M., Sottero, B., Testa, G., Giannelli, S., Leonarduzzi, G., & Gamba, P. (2022) · Antioxidants · doi:10.3390/antiox11112168 · Cited by 24
An Alternative View of Familial Alzheimer’s Disease Genetics
Lardelli, M. T. (2023) · Journal of Alzheimer s Disease · doi:10.3233/jad-230313 · Cited by 24
Bhattacharjee, A., Ghosh, S., Chatterji, A., & Chakraborty, K. (2020) · Metallomics · doi:10.1039/d0mt00168f · Cited by 23
APOE4 is a Risk Factor and Potential Therapeutic Target for Alzheimer's Disease
Ayyubova, G. (2023) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527322666230303114425 · Cited by 23
Wasilewski, D., Villalba‐Moreno, N. D., Stange, I., Glatzel, M., Falla, D. S., & Krasemann, S. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2021.739411 · Cited by 23
Lysosomal proteomics reveals mechanisms of neuronal APOE4-associated lysosomal dysfunction
Krogsaeter, E., McKetney, J., Valiente‐Banuet, L., Marquez, A., Willis, A., Cakir, Z., Stevenson, E. J., Jang, G. Μ., Rao, A. T., Li, E., et al. (2025) · Autophagy · doi:10.1080/15548627.2025.2576613 · Cited by 22
Xia, M.-C., Cai, L., Yang, Y., Zhang, S., & Zhang, X. (2019) · Analytical Chemistry · doi:10.1021/acs.analchem.9b01864 · Cited by 22
Cell type-specific functions of Alzheimer's disease endocytic risk genes
Maninger, J.-K., Nowak, K., Goberdhan, S., O'Donoghue, R., & Connor-Robson, N. (2024) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2022.0378 · Cited by 22
Ilie, A., Boucher, A., Park, J., Berghuis, A. M., McKinney, R. A., & Orlowski, J. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.012614 · Cited by 24
Application of Novel Drug‐Delivery Strategies in Neurological Disorders
Li, C., Yao, S., Li, Z., & Gao, Y. (2025) · Advanced Materials · doi:10.1002/adma.202503646 · Cited by 21
Dong, H. Y., Zhao, L., Zhou, Y., Wei, X., Xu, C., Zhang, Y., & Xu, M. (2021) · Analytical Chemistry · doi:10.1021/acs.analchem.1c02436 · Cited by 21
Cereghetti, G., Kissling, V. M., Koch, L. M., Arm, A., Schmidt, C. C., Thüringer, Y., Zamboni, N., Afanasyev, P., Linsenmeier, M., Eichmann, C., et al. (2024) · Developmental Cell · doi:10.1016/j.devcel.2024.04.018 · Cited by 21
Complex Neurological Phenotype in Female Carriers of NHE6 Mutations
Pescosolido, M. F., Kavanaugh, B. C., Pochet, N. L. M. M., Schmidt, M., Jerskey, B. A., Rogg, J. M., Jager, P. L. D., Young‐Pearse, T. L., Liu, J. S.-H., & Morrow, E. M. (2019) · Complex Psychiatry · doi:10.1159/000496341 · Cited by 21
LeVine, S. M. (2024) · Cells · doi:10.3390/cells13080689 · Cited by 20
Exploring the potential role of rab5 protein in endo-lysosomal impairment in Alzheimer’s disease
Behl, T., Kaur, D., Sehgal, A., Singh, S., Makeen, H. A., Albratty, M., Abdellatif, A. A. H., Dachani, S. R., & BUNGAU, S. G. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.112773 · Cited by 20
Chen, G., Andrade‐Talavera, Y., Zhong, X., Hassan, S., Biverstål, H., Poska, H., Abelein, A., Leppert, A., Kronqvist, N., Rising, A., et al. (2022) · RSC Chemical Biology · doi:10.1039/d2cb00187j · Cited by 20
Cholesterol Metabolism in CNS Diseases: The Potential of SREBP2 and LXR as Therapeutic Targets
Wang, N.-Q., Sun, P.-X., Shen, Q.-Q., & Deng, M.-Y. (2025) · Molecular Neurobiology · doi:10.1007/s12035-024-04672-w · Cited by 19
Proust, A. M., Barat, C., Lebœuf, M., Drouin, J., Gagnon, M., Vanasse, F., & Tremblay, M. J. (2020) · Glia · doi:10.1002/glia.23833 · Cited by 19
Nohesara, S., Abdolmaleky, H. M., & Thiagalingam, S. (2024) · Biomedicines · doi:10.3390/biomedicines12020457 · Cited by 19
Graphs of dynamic H-bond networks: from model proteins to protein complexes in cell signaling
Lazaratos, M., Karathanou, K., & Bondar, A. (2020) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2020.06.006 · Cited by 19
Lee, U., Choi, C., Ryu, S. H., Park, D., Lee, S.-E., Kim, K., Kim, Y., & Chang, S. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2011371118 · Cited by 18
Eisenbaum, M., Pearson, A., Ortiz, C., Koprivica, M., Cembran, A., MULLAN, M. J., Crawford, F., Ojo, J. O., & Bachmeier, C. J. (2024) · Experimental Neurology · doi:10.1016/j.expneurol.2024.114702 · Cited by 18
Defective Lysosomal Lipid Catabolism as a Common Pathogenic Mechanism for Dementia
Lee, J. Y., Marian, O. C., & Don, A. S. (2021) · NeuroMolecular Medicine · doi:10.1007/s12017-021-08644-4 · Cited by 18
Xicota, L., Lagarde, J., Eysert, F., Grenier-Boley, B., Rivals, I., Botté, A., Forlani, S., Landron, S., Gautier, C., Gabriel, C., et al. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02355-z · Cited by 15
Quantitative Chemical Imaging of Organelles
Tinker, J., Anees, P., & Krishnan, Y. (2024) · Accounts of Chemical Research · doi:10.1021/acs.accounts.4c00191 · Cited by 17
Gonçalves, M., Costa, M., Paiva‐Martins, F., & Silva, P. (2024) · Molecules · doi:10.3390/molecules29204841 · Cited by 17
Li, S., Li, M., Li, G., Li, L., Yang, X., Zuo, Z., Zhang, L., Hu, X., & He, X. (2025) · Aging Cell · doi:10.1111/acel.14496 · Cited by 17
Tomašovičová, N., Hu, P., Zeng, C.-L., Majorošová, J., Zakuťanská, K., & Kopčanský, P. (2018) · Nanomaterials · doi:10.3390/nano9010037 · Cited by 17
Metadata
- Authors
- Prasad, H., & Rao, R.
- Affiliations
- Johns Hopkins University (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2018-06-26
- Volume
- 115
- Issue
- 28
- Pages
- E6640-E6649
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC6048470
- OpenAlex
- W2810838937
- Semantic Scholar
- 6df1477984f5b1d0b945833f66e04a624dbbb0a5
- Cited by
- 207
- References
- 73
- Citations by year
- 2026: 19 · 2025: 26 · 2024: 30 · 2023: 25 · 2022: 34 · 2021: 32 · 2020: 23 · 2019: 14 · 2018: 4
- FWCI
- 7.14
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | National Institutes of Health (DK054214)
- Johns Hopkins Medicine Discovery Fund (N/A)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Clinical Neurology › Cerebrospinal fluid and hydrocephalus
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, APOE ε4, amyloid-beta clearance, astrocytes, endosomal acidification, endosomal pH, NHE6, Na+/H+ exchanger, epigenetic regulators, amyloidosis
- MeSH terms
- Alzheimer Disease, Animals, Astrocytes, Ataxia, Epilepsy, Histone Deacetylases, Humans, Hydrogen-Ion Concentration, Intellectual Disability, Microcephaly, Receptors, LDL, Endosomes, Ocular Motility Disorders, Amyloid beta-Peptides, Sodium-Hydrogen Exchangers, Mice, Knockout, Tumor Suppressor Proteins, Low Density Lipoprotein Receptor-Related Protein-1, Genetic Diseases, X-Linked, Epigenesis, Genetic, Mice, Apolipoprotein E4, Histone Deacetylase Inhibitors
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.
A language model drew the claims from the paper on 2026-11-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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
