The DOI matches its Crossref record; 114 of the 114 references it cites were found in a registry or an index; 4 of the 67 sources its claims cite were checked for support.
NHE6 depletion corrects ApoE4-mediated synaptic impairments and reduces amyloid plaque load
Open accessPublished version of a preprint
Abstract
Apolipoprotein E4 (ApoE4) is the most important and prevalent risk factor for late-onset Alzheimer’s disease (AD). The isoelectric point of ApoE4 matches the pH of the early endosome (EE), causing its delayed dissociation from ApoE receptors and hence impaired endolysosomal trafficking, disruption of synaptic homeostasis, and reduced amyloid clearance. We have shown that enhancing endosomal acidification by inhibiting the EE-specific sodium-hydrogen exchanger 6 (NHE6) restores vesicular trafficking and normalizes synaptic homeostasis. Remarkably and unexpectedly, loss of NHE6 (encoded by the gene Slc9a6 ) in mice effectively suppressed amyloid deposition even in the absence of ApoE4, suggesting that accelerated acidification of EEs caused by the absence of NHE6 occludes the effect of ApoE on amyloid plaque formation. NHE6 suppression or inhibition may thus be a universal, ApoE-independent approach to prevent amyloid buildup in the brain. These findings suggest a novel therapeutic approach for the prevention of AD by which partial NHE6 inhibition reverses the ApoE4-induced endolysosomal trafficking defect and reduces plaque load.
Overview
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Written from the paper’s full text.
TL;DR
NHE6 depletion acidifies early endosomes, restores ApoE4-impaired receptor trafficking and Reelin-enhanced synaptic plasticity, and reduces amyloid plaque load in App knockin mice even in the absence of ApoE4. These findings suggest partial NHE6 inhibition as a potential ApoE-independent approach to prevent amyloid buildup in Alzheimer’s disease.
Key findings
- Genetic loss of NHE6 restored surface expression of Apoer2, GluN2B, GluA1, and GluA2/3 in ApoE4-treated primary neurons, and conditional NHE6 knockout abolished Reelin resistance in ApoeAPOE4 hippocampal slices, restoring Reelin-enhanced LTP to levels comparable to ApoeAPOE3; NHE6 knockout efficiency in brain regions was 65–82%.
- NHE6 deficiency reduced plaque load by approximately 80% in 12-month-old AppNL-F mice versus littermate controls, and insoluble Aβ (GuHCl and 70% FA fractions) was reduced by approximately 71% in 1.5-year-old AppNL-F;Slc9a6- mice; the ~50% reduction in soluble Aβ (TBS fraction) was not statistically significant.
- Conditional NHE6 ablation at 2 months in AppNL-F;ApoeAPOE4 mice reduced plaque load comparably to germline depletion and abolished or delayed the age-dependent increase in plaque load, with no significant differences in cortical thickness, hippocampal area, or CA1 thickness in the conditional model.
- NHE inhibition or NHE6 knockdown did not alter β-CTF generation in AppSwe primary neurons, while NHE6 deficiency increased Iba1 and GFAP immunoreactivity; plaque-associated microglia/astrocyte proportions and 6E10 intensity within microglia did not differ between genotypes.
Methods
- Generated germline Slc9a6- and tamoxifen-inducible Slc9a6fl;CAG-CreERT2 mice, crossed to ApoeAPOE3, ApoeAPOE4, AppNL-F, and AppSwe (Tg2576) lines; tamoxifen was injected at 2 months or 6–8 weeks depending on experiment.
- Used primary cortical neurons, mouse embryonic fibroblasts, surface biotinylation, immunoblotting, Vamp3-pHluorin2 pH measurements, Aβ ELISA, histology (Thioflavin S, 4G8/6E10, GFAP/Iba1, H&E), and hippocampal field recordings with Reelin and theta burst stimulation.
- Statistical analysis used two-tailed Student’s t-test, one-way ANOVA with Dunnett’s or Tukey’s post hoc, or two-way ANOVA with Sidak’s post hoc; significance set at p < 0.05.
Limitations
- Stated: the discrepancy with Prasad and Rao, 2015, remains unresolved; whether plaque reduction is due to increased microglial/astrocytic phagocytosis or improved glial degradation/export of Aβ remains to be determined; AppNL-F and AppNL-F;ApoeAPOE4 mice do not show cognitive impairments in spatial learning tests like Morris water maze (Saito et al., 2014; own unpublished observations); the impact of NHE6 loss in microglia and astrocytes is still unknown.
- Evident: NHE6 depletion causes progressive cerebellar Purkinje cell loss in both germline and conditional models, and NHE6 is ubiquitously expressed, so therapeutic safety and cell-type-specific effects are not established; the study reports mouse data only, with no human validation.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
4 of 67 cited sources checked · 1 supported · 0 flagged · accuracy not yet measured
- Premisecitation
The ability of Reelin to protect the synapse from Aβ toxicity is impaired by ApoE4.
“the ability of Reelin to protect the synapse from Aβ toxicity is impaired by ApoE4 (Durakoglugil et al., 2009).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites Durakoglugil et al., 2009 source
The Results report that Reelin protects neurons from Aβ-induced synaptic suppression. The Discussion notes greater sensitivity to Aβ in ApoE4 knock-in mice, but says only that ApoE isoforms might differentially modulate the relevant receptor functions; it does not establish that ApoE4 impairs Reelin’s protection. (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Findingown data
NHE6/Slc9a6 depletion in AppNL-F;ApoeAPOE4 mice showed a comparable reduction in plaque load.
“NHE6/Slc9a6 depletion in AppNL-F;ApoeAPOE4 mice showed a comparable reduction in plaque load (Figure 7 and Figure 7—figure supplement 3).”
Quote in the paperSubstantial claim - Findingown data
The total amount of plaques labeled by 6E10 was reduced in Slc9a6- compared to control mice.
“Whereas the total amount of plaques labeled by 6E10 was reduced in Slc9a6- as compared to control mice (Figure 9C)”
Quote in the paperSubstantial claim - Findingown data
No significant differences were found in input-output curves between the compared genotypes.
“No significant differences were found (Figure 5I and J).”
Quote in the paperNot a substantial claim - Findingown data
In AppNL-F;ApoeAPOE4 mice, conditional Slc9a6 knockout caused a reduction in plaque load compared to Slc9a6fl control littermates.
“In AppNL-F;ApoeAPOE4 mice conditional Slc9a6 knockout caused a reduction in plaque load compared to the Slc9a6fl control littermates.”
Quote in the paperSubstantial claim
- Findingreasoning
Loss of NHE6 in mice effectively suppressed amyloid deposition even in the absence of ApoE4.
“Remarkably and unexpectedly, loss of NHE6 (encoded by the gene Slc9a6) in mice effectively suppressed amyloid deposition even in the absence of ApoE4, suggesting that accelerated acidification of EEs caused by the absence of NHE6 occludes the effect of ApoE on amyloid plaque formation.”
Quote in the paperSubstantial claim - Findingown data
There was no difference between genotypes in the amount of microglia co-labeled with 6E10.
“there was no difference between genotypes in the amount of microglia co-labeled with 6E10 (Figure 9E)”
Quote in the paperNot a substantial claim - Findingown data
Genetic loss of NHE6 equally restored the ApoE4-impaired surface expression of AMPA and NMDA receptor subunits.
“In addition, genetic loss of NHE6 equally restored the ApoE4-impaired surface expression of AMPA and NMDA receptor subunits (Figure 4D–F).”
Quote in the paperSubstantial claim - Findingown data
There was a non-significant trend toward increased immunoreactivity for both Iba1 and GFAP in the hippocampus of the Slc9a6- group.
“There was a non-significant trend toward increased immunoreactivity for both markers in the hippocampus of the Slc9a6- group.”
Quote in the paperNot a substantial claim - Findingown data
The amount of insoluble Aβ in GuHCl and 70% FA fractions was reduced in NHE6-depleted mice by approximately 71% compared to control littermates.
“The amount of insoluble Aβ (GuHCl and 70% FA fractions) was reduced in NHE6-depleted mice by approximately 71%, when compared to their control littermates (Figure 7—figure supplement 3C-E).”
Quote in the paperSubstantial claim - Findingown data
There was no difference between genotypes in the intensity of immunoreactivity for 6E10 within microglia.
“or the intensity of immunoreactivity for 6E10 within microglia (Figure 9F).”
Quote in the paperNot a substantial claim - Findingown data
The age-dependent increase in plaque load in ApoeAPOE4;AppNL-F mice was abolished or delayed when Slc9a6 was depleted after 2 months of age.
“The age-dependent increase in plaque load in ApoeAPOE4;AppNL-F mice was abolished or delayed when Slc9a6 was depleted after 2 months of age (Figure 8).”
Quote in the paperSubstantial claim - Findingown data
Slc9a6 deficiency on the background of human ApoE4 reduced plaque deposition, as shown by Thioflavin S staining and 4G8 immunoreactivity.
“Slc9a6 deficiency on the background of human ApoE4 reduced plaque deposition, as shown by Thioflavin S staining (Figure 7—figure supplement 3F, G) and 4G8 immunoreactivity (Figure 7C and D).”
Quote in the paperSubstantial claim - Findingreasoning
Loss of NHE6/Slc9a6 effectively reduced Aβ accumulation even in the absence of ApoE4.
“Remarkably and unexpectedly, loss of NHE6/Slc9a6 effectively reduced Aβ accumulation even in the absence of ApoE4”
Quote in the paperSubstantial claim - Findingnone given
The effect of germline Slc9a6 deficiency and conditional Slc9a6 deficiency induced at 2 months had a comparable effect on plaque reduction in AppNL-F and AppNL-F;ApoeAPOE4 mice.
“The effect of germline Slc9a6 deficiency and conditional Slc9a6 deficiency induced at 2 months had a comparable effect on plaque reduction in AppNL-F and AppNL-F;ApoeAPOE4 mice.”
Quote in the paperSubstantial claim - Findingown data
NHE6 deficiency leads to cerebellar Purkinje cell loss in germline and conditional knockout mice.
“NHE6 deficiency leads to cerebellar Purkinje cell loss in germline (Slc9a6-, C) and conditional (Slc9a6fl;CAG-CreERT2, D–F) knockout mice.”
Quote in the paperNot a substantial claim - Findingown data
Long-term loss of NHE6 induced after Purkinje cell maturation at 2 months led to massive Purkinje cell loss when mice were examined 1 year after NHE6 ablation.
“Long-term loss of NHE6, induced after Purkinje cell maturation at 2 months of age, also led to massive Purkinje cells loss when mice were examined 1 year after NHE6 ablation (E, lower panel).”
Quote in the paperNot a substantial claim - Findingown data
NHE6 depletion counteracts the ApoE4-induced reduction of receptor surface expression.
“NHE6 depletion counteracts the ApoE4-induced reduction of receptor surface expression.”
Quote in the paperSubstantial claim - Findingcitation
Hippocampal slices from ApoeAPOE4 mice were completely resistant to LTP enhancement by Reelin.
“By contrast, as reported previously (Chen et al., 2010), hippocampal slices from ApoeAPOE4 mice were completely resistant to LTP enhancement by Reelin (Figure 5C and G).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Chen et al., 2010 source
- Findingown data
Conditional genetic loss of NHE6 resulted in a moderate reduction of the ability of Reelin to enhance LTP in ApoeAPOE3 mice.
“Conditional genetic loss of NHE6 resulted in a moderate reduction of the ability of Reelin to enhance LTP in ApoeAPOE3 mice (comparing Figure 5A and E to B and F).”
Quote in the paperNot a substantial claim - Findingown data
Iba1 and GFAP immunoreactivity is increased in the white matter and to a lesser extent in the cortex of AppNL-F;Slc9a6- and AppNL-F;ApoeAPOE4;Slc9a6fl;CAG-CreERT2 mice compared to littermate controls.
“We found that Iba1 and GFAP immunoreactivity is increased in the white matter and to a lesser extent in the cortex of AppNL-F;Slc9a6- (Figure 9—figure supplement 1A, C, D, C, and D) and AppNL-F;ApoeAPOE4;Slc9a6fl;CAG-CreERT2 (Figure 9—figure supplement 1B, E, F) mice compared to their littermate controls.”
Quote in the paperNot a substantial claim - Findingown data
NHE6 deficiency significantly reduced the number of vesicles with pH 6.4 and above in Slc9a6- fibroblasts compared to control.
“We found a significantly reduced number of vesicles with pH 6.4 and above in Slc9a6- fibroblasts when compared to control (Figure 2D–F).”
Quote in the paperNot a substantial claim - Findingown data
The approximately 50% reduction in soluble Aβ in the TBS fraction was statistically not significant in Slc9a6- lysates.
“The ~50% reduction in soluble Aβ was statistically not significant in Slc9a6- lysates (TBS fraction).”
Quote in the paperNot a substantial claim - Findingown data
Apoer2 recycling was completely restored in Slc9a6- neurons treated with ApoE4.
“Apoer2 recycling was completely restored in Slc9a6- neurons treated with ApoE4 (Figure 4C).”
Quote in the paperSubstantial claim - Findingown data
NHE6 inhibition or knockdown did not alter BACE1 activity, as judged by unchanged Aβ generation.
“We found that NHE6 inhibition or knockdown did not alter BACE1 activity, as judged by unchanged Aβ generation.”
Quote in the paperSubstantial claim - Findingown data
NHE6 knockdown using lentiviral shRNA had no effect on the amount of β-CTF.
“NHE6 knockdown using lentiviral shRNA also had no effect on the amount of β-CTF (Figure 6B).”
Quote in the paperSubstantial claim - Findingown data
The intensity of GFAP and Iba1 in plaque areas was comparable between the groups.
“Surprisingly, the intensity of GFAP and Iba1 in plaque areas was comparable between the groups.”
Quote in the paperNot a substantial claim - Findingown data
The onset of plaque deposition in human ApoeAPOE4 mice was delayed by approximately 3 months.
“However, the onset of plaque deposition in human ApoeAPOE4 mice was delayed by ∼3 months.”
Quote in the paperNot a substantial claim - Findingown data
The amount of microglia and astrocytes surrounding plaques did not differ between genotypes.
“the amount of microglia and astrocytes surrounding plaques did not differ between genotypes (Figure 9D and G).”
Quote in the paperSubstantial claim - Findingcitation
The germline Slc9a6- model reproduces reduced cortex thickness and hippocampus volume.
“Xu et al., 2017, reported reduced cortex thickness and hippocampus volume in Slc9a6- mice, which we were able to reproduce in our germline Slc9a6- model (Figure 7—figure supplement 1).”
Quote in the paperSubstantial claim - Findingown data
NHE6/Slc9a6 ablation induced at 2 months showed a comparable reduction of plaque load as germline NHE6/Slc9a6 depletion.
“Importantly, NHE6/Slc9a6 ablation induced at 2 months showed a comparable reduction of plaque load as germline NHE6/Slc9a6 depletion.”
Quote in the paperSubstantial claim - Findingown data
An increase in reactive microglia and astrocytes resulting from NHE6/Slc9a6 depletion correlated with reduced plaque deposition in AppNL-F mice, irrespective of murine ApoE or human ApoE4.
“We observed an increase in reactive microglia and astrocytes resulting from NHE6/Slc9a6 depletion, which correlated with reduced plaque deposition in AppNL-F mice, irrespective of the presence of either murine ApoE or human ApoE4.”
Quote in the paperSubstantial claim - Findingown data
Slc9a6- and Slc9a6fl;CAG-CreERT2 mice show a comparable increase in immunoreactivity against Iba1 and GFAP.
“Slc9a6- and Slc9a6fl;CAG-CreERT2 show a comparable increase in immunoreactivity against Iba1 and GFAP.”
Quote in the paperSubstantial claim - Findingown data
There was an approximate 80% reduction of plaques in Slc9a6- mice compared to littermate controls.
“We found an approximate 80% reduction of plaques in Slc9a6- mice when compared to littermate controls (Figure 7B).”
Quote in the paperSubstantial claim - Findingown data
No reduction in brain size was detected in Slc9a6fl;CAG-CreERT2 mice compared to Slc9a6fl;AppNL-F;ApoeAPOE4 littermate controls.
“we specifically did not detect any reduction in brain size compared to Slc9a6fl;AppNL-F;ApoeAPOE4 littermate controls.”
Quote in the paperSubstantial claim - Interpretationreasoning
NHE6/Slc9a6 suppression or inhibition may be a universal approach to prevent amyloid buildup in the brain, irrespective of ApoE genotype.
“NHE6/Slc9a6 suppression or inhibition may thus be a universal approach to prevent amyloid buildup in the brain, irrespective of ApoE genotype.”
Quote in the paperSubstantial claim - Interpretationown data
Accelerated acidification of early endosomes caused by absence of NHE6 occludes the effect of ApoE on amyloid plaque formation.
“Remarkably and unexpectedly, loss of NHE6 (encoded by the gene Slc9a6) in mice effectively suppressed amyloid deposition even in the absence of ApoE4, suggesting that accelerated acidification of EEs caused by the absence of NHE6 occludes the effect of ApoE on amyloid plaque formation.”
Quote in the paperSubstantial claim - Interpretationown data
Neurodegeneration induced by NHE6/Slc9a6 deficiency is unlikely to be the trigger for the glial activation observed in cKO mice.
“our data on glial activation and cerebral volume in cKO mice, where NHE6/Slc9a6 was disrupted postnatally, suggest that neurodegeneration induced by NHE6/Slc9a6 deficiency is unlikely to be the trigger for the glial activation we observe.”
Quote in the paperNot a substantial claim - Interpretationcitation
ApoE4 dramatically delays the fast recycling step in neurons, where ApoE, Apoer2, and glutamate receptors co-traffic through fast recycling compartments upon Reelin stimulation.
“Our data, however, suggest that ApoE4 dramatically delays this fast recycling step in neurons, where ApoE, Apoer2, and glutamate receptors co-traffic through fast recycling compartments upon Reelin stimulation (Xian et al., 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Xian et al., 2018 source
- Interpretationreasoning
Reduced plaque load is not an effect of neuronal loss.
“Moreover, this further indicates that reduced plaque load is also not an effect of neuronal loss.”
Quote in the paperSubstantial claim - Interpretationcitation
The absence of cortical and hippocampal changes after adult conditional NHE6 disruption is consistent with the undergrowth model proposed by Xu et al., 2017.
“This is consistent with the undergrowth model proposed by Xu et al., 2017, as we induced conditional disruption of NHE6/Slc9a6 in the adult after postnatal brain growth was completed.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Xu et al., 2017
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Interpretationnone given
ApoE4 impairs vesicle recycling due to isoelectric precipitation and structural unfolding at the physiological pH of the early endosome environment.
“We have proposed that ApoE4 impairs vesicle recycling due to isoelectric precipitation and structural unfolding at the physiological pH of the EE environment.”
Quote in the paperNot a substantial claim - Interpretationreasoning
NHE6 serves as a pH regulator of Reelin-controlled fast recycling endosomes containing Apoer2 and glutamate receptors.
“Our findings are consistent with a model where NHE6 serves as a pH regulator of Reelin-controlled fast recycling endosomes containing Apoer2 and glutamate receptors.”
Quote in the paperSubstantial claim - Premisecitation
The early endosomal pH that triggers ligand-receptor dissociation closely matches the isoelectric point of ApoE4.
“The early endosomal pH, which triggers ligand-receptor dissociation, closely matches the IEP of ApoE4 (Xian et al., 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Xian et al., 2018 source
- Interpretationown data
Prevention of plaque formation in the Slc9a6-deficient model was likely caused by increased microglial activation and plaque phagocytosis.
“Prevention of plaque formation in our Slc9a6-deficient model was likely caused by increased microglial activation and plaque phagocytosis (Figure 7, Figure 7—figure supplement 3, 8,9Figure 8, Figure 9, Figure 9—figure supplement 1, and Figure 9—figure supplement 2).”
Quote in the paperSubstantial claim - Premisecitation
Early endosome acidification by pharmaceutical pan-NHE inhibition or selective NHE6/Slc9a6 knockdown in neurons prevents the ApoE4-caused trafficking delay of ApoE and glutamate receptors.
“We showed that EE acidification by pharmaceutical pan-NHE inhibition or selective NHE6/Slc9a6 knockdown in neurons prevents the ApoE4-caused trafficking delay of ApoE and glutamate receptors (Xian et al., 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Xian et al., 2018 source
- Interpretationreasoning
ApoE4 net charge affects its endosomal trafficking.
“We conclude that ApoE4 net charge affects its endosomal trafficking.”
Quote in the paperSubstantial claim - Interpretationreasoning
Microglia in Slc9a6- mice may be more efficient in taking up and degrading Aβ.
“This suggests that microglia in the Slc9a6- may be more efficient in taking up and degrading Aβ.”
Quote in the paperSubstantial claim - Interpretationown data
Hyperacidification of early endosomes prevents amyloid plaque formation independently of ApoE4.
“suggesting that hyperacidification of EEs prevents amyloid plaque formation independently of ApoE4.”
Quote in the paperSubstantial claim - Premisecitation
Dysregulation of endolysosomal trafficking by ApoE4 causes an age-dependent increase in early endosome number and size.
“Dysregulation of endolysosomal trafficking by ApoE4 causes an age-dependent increase in EE number and size (Nuriel et al., 2017).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Nuriel et al., 2017 source
- Interpretationreasoning
NHE6 suppression or inhibition may be a universal, ApoE-independent approach to prevent amyloid buildup in the brain.
“NHE6 suppression or inhibition may thus be a universal, ApoE-independent approach to prevent amyloid buildup in the brain.”
Quote in the paperSubstantial claim- Rests on an assumption: Partial NHE6 inhibition can be achieved without causing Christianson syndrome-like neurodevelopmental defects or Purkinje cell loss.
- Premisecitation
The AppNL-F mouse model used in the study develops plaques at 12 months in the presence of murine ApoE.
“The AppNL-F mouse model used in our study develops plaques at 12 months (Saito et al., 2014) in the presence of murine ApoE.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Saito et al., 2014 source
- Interpretationown data
NHE6 inhibition is unlikely to increase Aβ production under near-physiological conditions.
“We conclude that NHE6 inhibition is unlikely to increase Aβ production under near-physiological conditions.”
Quote in the paperSubstantial claim - Premisecitation
NHE6 depletion acidifies early and recycling endosomes.
“NHE6 depletion acidifies early and recycling endosomes (Lucien et al., 2017; Ohgaki et al., 2010; Ouyang et al., 2013; Xinhan et al., 2011).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites Lucien et al., 2017 source
Checked before — its earlier verdict is held back until a new check runs.
- cites Ohgaki et al., 2010 source
Checked before — its earlier verdict is held back until a new check runs.
- cites Ouyang et al., 2013 source
Checked before — its earlier verdict is held back until a new check runs.
- Premisecitation
Reduction of endosomal pH and increasing the differential to the ApoE4 isoelectric point abolishes ApoE4-mediated Reelin resistance in vitro.
“Reduction of endosomal pH and increasing the differential to the ApoE4 IEP abolishes this effect in vitro (Xian et al., 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Xian et al., 2018 source
- Premisecitation
AppNL-F and AppNL-F;ApoeAPOE4 mice do not show cognitive impairments in spatial learning tests like Morris water maze.
“These mice, however, do not show cognitive impairments in spatial learning tests like Morris water maze (Saito et al., 2014) (own unpublished observations).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Saito et al., 2014 source
- Probably not a substantial claim. 36
- It may state two separate claims as one. 41
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationImproved ApoE lipidation by overexpression of ABCA1 decreased plaque deposition in a mouse model.
“In a mouse model, improved ApoE lipidation by the overexpression of ATP-binding cassette transporter family member A1 (ABCA1) decreased plaque deposition (Wahrle et al., 2005; Wahrle et al., 2008; Wahrle et al., 2004).”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites Wahrle et al., 2005 source
The Discussion (page unavailable) predicts that increasing ABCA1 might decrease amyloid deposition by increasing apoE lipidation, but explicitly says this hypothesis needs direct testing. This paper instead reports that deleting Abca1 increased amyloid deposition in PDAPP mice; it does not report an overexpression experiment or an observed decrease in plaques. (LLM, conf=0.90)
Experimental — accuracy not yet measured - cites Wahrle et al., 2008 source
- cites Wahrle et al., 2004 source
The Abstract and Discussion (page unavailable) show that ABCA1 is required for normal ApoE lipidation in mice. But this study examined ABCA1-deficient mice, not ABCA1 overexpression, and did not show decreased plaque deposition. The Discussion describes an effect on amyloid pathology as a possibility, not a measured outcome. (LLM, conf=0.87)
Experimental — accuracy not yet measured
It may state two separate claims as one.
Findingown dataUsing a humanized AppNL-F knockin mouse model, NHE6/Slc9a6 deficiency in 1-year-old animals reduces plaque deposition by approximately 80%.
“Using a humanized AppNL-F knockin mouse model, we show that NHE6/Slc9a6 deficiency in 1-year-old animals reduces plaque deposition by ∼80%.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe proportion of microglial structures containing Aβ (6E10) was comparable between Slc9a6-deficient and control AppNL-F mice, as was the intensity signal for 6E10.
“the proportion of microglial structures containing Aβ (6E10 antibody) was comparable between Slc9a6-deficient and control AppNL-F mice, as was the intensity signal for 6E10.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataConditional and germline Slc9a6 deficient AppNL-F mice have a reduced number of plaques and an increase of Iba1 and GFAP labeled glia.
“Conditional and germline Slc9a6 deficient AppNL-F mice have a reduced number of plaques in the brain and an increase of Iba1 and GFAP labeled glia.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataThe reduction in plaque deposition by Slc9a6 deficiency persists from early (12 months) to later stages (18 months) of AD, as Slc9a6-deficient AppNL-F animals aged 18 months had a reduction in insoluble Aβ by approximately 71%.
“the reduction in plaque deposition by Slc9a6 deficiency persists from early (12 months) to later stages (18 months) of AD, as Slc9a6-deficient AppNL-F animals aged 18 months had a reduction in insoluble Aβ by approximately 71%.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataSlc9a6-deficient AppNL-F mice show an increase in Iba1 and GFAP immunoreactivity but reduced Aβ immunoreactivity compared to control AppNL-F mice.
“When compared to control AppNL-F mice, Slc9a6-deficient AppNL-F mice show an increase in Iba1 (microglia) and GFAP (astrocytes) immunoreactivity, but reduced Aβ immunoreactivity.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataReelin resistance was abolished when NHE6 was genetically disrupted in ApoeAPOE4 mice: Reelin application enhanced LTP in ApoeAPOE4;Slc9a6fl;CAG-CreERT2 to a comparable extent as in ApoeAPOE3;Slc9a6fl;CAG-CreERT2 mice.
“This resistance was abolished when NHE6 was genetically disrupted in ApoeAPOE4 mice: Reelin application enhanced LTP (Figure 5D and H) in ApoeAPOE4;Slc9a6fl;CAG-CreERT2 to a comparable extent as in the ApoeAPOE3;Slc9a6fl;CAG-CreERT2 mice (Figure 5B).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataBoth germline deficiency and adult-onset deficiency of NHE6 cause massive Purkinje cell loss in the cerebellum.
“Since both germline deficiency and adult-onset deficiency of NHE6 causes massive Purkinje cell loss in the cerebellum (Figure 3C–E)”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataAppNL-F mice expressing murine ApoE developed plaques at 12 months, whereas ApoeAPOE4;AppNL-F mice showed a similar number of plaques at 15-16 months.
“AppNL-F mice expressing murine ApoE developed plaques at 12 months (Figure 7A and B), compared to ApoeAPOE4;AppNL-F which showed a similar number of plaques at 15–16 months (Figures 7C–D–8, and Figure 7—figure supplement 3F-G).”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataNone of brain size, cortical thickness, hippocampal area, and CA1 thickness differed significantly between Slc9a6fl;CAG-CreERT2 and controls in the AppNL-F;ApoeAPOE4 model.
“none of the analyzed parameters differed significantly between Slc9a6fl;CAG-CreERT2 and controls (Figure 7E–I)”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataTamoxifen-induced Slc9a6fl;CAG-CreERT2 mice do not present with a reduction in cortical or hippocampal volume, yet have comparable immunoreactivity for markers of glial activation.
“However, the tamoxifen-induced Slc9a6fl;CAG-CreERT2 mice do not present with a reduction in cortical or hippocampal volume (Figure 7), yet have comparable immunoreactivity for markers of glial activation.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataInhibition of γ-secretase in ApoE4-treated AppSwe neurons strongly enhanced β-CTF accumulation, but additional treatment with EMD87580 did not alter the amount of β-CTF in cell lysates.
“Inhibition of γ-secretase in ApoE4-treated AppSwe neurons strongly enhanced β-CTF accumulation, however, additional treatment with EMD87580 did not alter the amount of β-CTF in the cell lysates (Figure 6A).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataIn the time range analyzed, plaque load increased by age in control mice, but not in Slc9a6fl;CAG-CreERT2 mice.
“In the time range analyzed, plaque load increased by age in control, but not in Slc9a6fl;CAG-CreERT2 mice.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
FindingcitationNHE6 ablation led to glial activation and decreased plaque load in ApoeAPOE4 and AppNL-F double knockin mice.
“By contrast, NHE6 ablation led to glial activation and decreased plaque load in ApoeAPOE4 (Sullivan et al., 1997) and AppNL-F (Saito et al., 2014) double knockin mice.”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationEach ApoE4 allele reduces the age of Alzheimer's disease onset by approximately 3-5 years compared to ApoE3 homozygotes.
“Each ApoE4 allele reduces the age of Alzheimer’s disease (AD) onset by approximately 3–5 years compared to ApoE3 homozygotes, which comprise ~80% of the human population (Roses, 1994; Sando et al., 2008).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationApoE2 is protective against Alzheimer's disease.
“By contrast and by comparison, ApoE2 is protective against AD (Corder et al., 1994; Panza et al., 2000; West et al., 1994).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationApoE3 homozygotes comprise approximately 80% of the human population.
“Each ApoE4 allele reduces the age of Alzheimer’s disease (AD) onset by approximately 3–5 years compared to ApoE3 homozygotes, which comprise ~80% of the human population (Roses, 1994; Sando et al., 2008).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationPositively charged arginines raise the net charge and thus the isoelectric point of ApoE.
“The positively charged arginines raise the net charge and thus the isoelectric point (IEP) of the protein (Eto et al., 1985; Warnick et al., 1979).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationThe isoelectric point of ApoE2 is 5.9, ApoE3 is 6.1, and ApoE4 is approximately 6.4.
“The IEP of ApoE2 is the lowest (5.9), ApoE3 has an intermediate IEP of 6.1, and the IEP of ApoE4 is ~6.4 (Ordovas et al., 1987).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ordovas et al., 1987 source
It may state two separate claims as one.
InterpretationreasoningAccelerated acidification of early endosomes abolishes the ApoE4-induced Reelin resistance and restores normal synaptic plasticity in ApoE4-targeted replacement mice.
“Accelerated acidification of EEs abolishes the ApoE4-induced Reelin resistance and restores normal synaptic plasticity in ApoE4-targeted replacement mice.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationIn the brains of AD patients and APP-overexpressing mice, plaques are surrounded by reactive microglia and astrocytes.
“In the brains of AD patients and APP-overexpressing mice, plaques are surrounded by reactive microglia and astrocytes (Meyer-Luehmann et al., 2008; Serrano-Pozo et al., 2013)”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisenone givenBACE1 cleaves APP to create β-CTF and sAPPβ, and β-CTF is further cleaved by γ-secretase to release Aβ peptide.
“The β-site amyloid precursor protein cleaving enzyme 1 (BACE1) cleaves APP in its extracellular juxtamembrane domain to create a membrane-anchored C-terminal fragment (β-CTF) and a soluble extracellular APP domain (sAPPβ). β-CTF is further cleaved by the γ-secretase complex, which leads to the release of the Aβ peptide.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
PremisecitationEndocytic subcompartments become progressively more acidic, and their pH is regulated by vATPase proton pumps and NHE proton leakage channels.
“Endocytic subcompartments become progressively more acidic, and the pH of these compartments is regulated by the opposing functions of vesicular ATP-dependent proton pumps (vATPase) and proton leakage channels (Na+/H+ exchangers, NHEs).”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisenone givenApoE3 has a cysteine at amino acid position 112 and an arginine at position 158; ApoE4 has two arginines; ApoE2 has two cysteines at these positions.
“The most common isoform, ApoE3, has a charge neutral cysteine at amino acid position 112 and an arginine at position 158. The second most common isoform, ApoE4, has two arginines, while the less frequent ApoE2 has two cysteines at these respective positions.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Premisenone givenThe number of positively charged arginine residues differs between the three human ApoE isoforms due to two single nucleotide polymorphisms in the ApoE gene.
“The number of positively charged arginine residues differs between the three human isoforms due to two single nucleotide polymorphisms in the ApoE gene.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataBoth the endosomal trafficking defect induced by ApoE4 in neurons and increased plaque deposition irrespective of ApoE genotype can be corrected by inhibition or genetic deletion of NHE6/Slc9a6.
“In conclusion, we have shown that both the endosomal trafficking defect induced by ApoE4 in neurons and increased plaque deposition irrespective of ApoE genotype can be corrected by inhibition or genetic deletion of NHE6/Slc9a6, a key regulator of early endosomal pH.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationIn AppNL-F mice, plaques can be identified as early as 9 months of age.
“In AppNL-F mice, plaques can be identified as early as 9 months of age.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Saito et al., 2014 source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationNHE6 is ubiquitously expressed in all cells of the body, but in the CNS it is highly expressed in neurons and to a lesser extent in glial cells.
“NHE6 is ubiquitously expressed in all cells of the body, however, in the CNS it is highly expressed in neurons where abundant synaptic vesicles and neurotransmitter receptors recycle in synapses (Lee et al., 2020; Lee et al., 2021) and to a lesser extent in glial cells (Zhang et al., 2014).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Premisenone givenNHE6 deficiency in humans causes neurodevelopmental defects resulting in Christianson syndrome, characterized by cognitive dysfunction, autism, ataxia, and epilepsy.
“NHE6 deficiency in humans causes neurodevelopmental defects, which result in Christianson syndrome, an X-linked genetic disorder characterized by cognitive dysfunction, autism, ataxia, and epilepsy.”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Interpretationown dataNHE6 has a temporally distinct function in the adult brain: the cerebrum requires NHE6 for development but not for postnatal neuronal survival, whereas Purkinje cells in the cerebellum do.
“Our study supports a temporally distinct function of NHE6 in the adult brain where the cerebrum requires NHE6 for development, but not for postnatal neuronal survival, whereas Purkinje cells in the cerebellum do.”
Quote in the paperSubstantial claimProbably not a substantial claim.
PremisecitationBACE1 activity is preferentially active in acidic environments.
“It has further been reported that BACE1 activity is preferentially active in acidic environments (Shimizu et al., 2008).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Shimizu et al., 2008 source
Probably not a substantial claim.
PremisecitationAPP and its secretases co-localize in endosomal compartments where cleavage can occur.
“APP and its secretases co-localize in endosomal compartments where cleavage can occur (Wang et al., 2018).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Wang et al., 2018 source
It may state two separate claims as one.
Interpretationown dataCombined data suggest that endosomal acidification has considerable potential as a novel therapeutic approach for AD prevention and possibly also for prevention of disease progression.
“Taken together, our combined data suggest that endosomal acidification has considerable potential as a novel therapeutic approach for AD prevention and possibly also for the prevention of disease progression.”
Quote in the paperSubstantial claimProbably not a substantial claim.
PremisecitationThe pH of early endosomes and recycling endosomes is approximately 6.4-6.5.
“The pH of EEs and recycling endosomes is ∼6.4–6.5 (Casey et al., 2010).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Casey et al., 2010 source
It may state two separate claims as one.
PremisecitationpH-dependent release of ApoE from its receptor in the early endosome is important for endosomal maturation, cargo delivery, and rapid recycling of endosomal content to the cell surface.
“The pH-dependent release of ApoE from its receptor in the EE is important for endosomal maturation and cargo delivery (Yamamoto et al., 2008) for the ability of endosomal content to rapidly recycle to the cell surface (Heeren et al., 1999; Nixon, 2017).”
Quote in the paperSubstantial claim0 of 3 sources checkedIt may state two separate claims as one.
Interpretationown dataPurkinje cell degeneration manifests postnatally and is not developmentally determined by the absence of NHE6.
“Therefore, Purkinje cell degeneration manifests itself postnatally and is not developmentally determined by the absence of NHE6.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductown dataTamoxifen-induced recombination led to broad expression of tdTomato in the hippocampus.
“Tamoxifen-induced recombination led to a broad expression of tdTomato in the hippocampus (Figure 2G).”
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.
Premisenone givenThe pathological hallmarks of Alzheimer's disease are extracellular aggregates of amyloid β peptide and intracellular tangles of hyperphosphorylated tau protein.
“The pathological hallmarks of AD are extracellular aggregates of the amyloid β (Aβ) peptide and intracellular tangles of hyperphosphorylated tau protein.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
InterpretationcitationThe delay of plaque deposition caused by human ApoE4 as opposed to murine ApoE is consistent with earlier findings by the Holtzman group.
“This delay of plaque deposition caused by the presence of human ApoE4 as opposed to murine ApoE is consistent with earlier findings by the Holtzman group (Liao et al., 2015).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Liao et al., 2015 source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationBeneficial or detrimental roles of reactive microglia and astrocytes in the degradation of Aβ have been reported, depending on the activation state of these cells.
“Beneficial or detrimental roles of reactive microglia and astrocytes in the degradation of Aβ have been reported, depending on the activation state of these cells (Meyer-Luehmann et al., 2008; Ziegler-Waldkirch and Meyer-Luehmann, 2018).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationApoE is an arginine-rich protein and a major component of very-low-density lipoproteins.
“ApoE is an arginine-rich protein and a major component of very-low-density lipoproteins (Shore and Shore, 1973).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Shore and Shore, 1973 source
Probably not a substantial claim. It may state two separate claims as one.
PremisecitationEarly endocytic vesicles are slightly acidic at pH ~6.4, facilitating ligand/receptor dissociation, while lysosomes are highly acidic at pH 4-5, required for digestion of endocytosed biomolecules.
“Early endocytic vesicles are slightly acidic (pH, ~6.4), which facilitates ligand/receptor dissociation. Lysosomes are highly acidic (pH 4–5), which is required for the digestion of endocytosed biomolecules (Figure 1A; Casey et al., 2010; Naslavsky and Caplan, 2018).”
Quote in the paperSubstantial claim0 of 2 sources checkedIt may state two separate claims as one.
Interpretationown dataPartial NHE6 inhibition reverses the ApoE4-induced endolysosomal trafficking defect and reduces plaque load, suggesting a novel therapeutic approach for prevention of Alzheimer's disease.
“These findings suggest a novel therapeutic approach for the prevention of AD by which partial NHE6 inhibition reverses the ApoE4-induced endolysosomal trafficking defect and reduces plaque load.”
Quote in the paperSubstantial claim- Rests on an assumption: Partial NHE6 inhibition can be achieved without causing Christianson syndrome-like neurodevelopmental defects or Purkinje cell loss.
It may state two separate claims as one.
Interpretationown dataPlaque deposition is modulated by the presence of NHE6 postnatally and is not affected by NHE6 activity during development.
“We conclude that plaque deposition is modulated by the presence of NHE6 postnatally and is not affected by NHE6 activity during development.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationPlaque deposition increases by less than twofold between 9 and 12 months of age and increases tenfold between 12 and 18 months in AppNL-F mice.
“Whereas plaque deposition only increases by less than twofold between 9 and 12 months of age, it increases tenfold between 12 and 18 months (Saito et al., 2014).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Saito et al., 2014 source
It may state two separate claims as one.
Interpretationown dataSlc9a6- and Slc9a6fl;CAG-CreERT2 mice both show progressive Purkinje cell loss in the cerebellum, indicating that NHE6 requirement is cell-autonomous and not developmentally determined.
“Slc9a6- and Slc9a6fl;CAG-CreERT2 both show progressive Purkinje cell loss in the cerebellum, indicating that NHE6 requirement is cell-autonomous and not developmentally determined.”
Quote in the paperSubstantial claimProbably not a substantial claim. It may state two separate claims as one.
Premisenone givenProcessing of APP at the β- and γ-sites leads to Aβ production, and Aβ forms neurotoxic oligomers and accumulates in plaques.
“Processing of the transmembrane amyloid precursor protein (APP) at the β- and γ-sites leads to Aβ production. Aβ forms neurotoxic oligomers and accumulates in plaques.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationMouse ApoE promotes plaque deposition more potently than human ApoE4.
“Our data are consistent with previous findings by the Holtzman group (Fagan et al., 2002) that showed that mouse ApoE promotes plaque deposition more potently than human ApoE4.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Fagan et al., 2002 source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationSome Slc9a6 mutant variants causing Christianson syndrome do not significantly alter NHE6 ion exchange properties, suggesting Christianson syndrome could be caused by loss of NHE6 scaffolding functions rather than loss of endosomal pH regulation.
“However, some Slc9a6 mutant variants causing Christianson syndrome in humans do not significantly alter the ion exchange properties of NHE6 (Ilie et al., 2020; Ilie et al., 2019) suggesting that Christianson syndrome could be caused by loss of NHE6 scaffolding functions and not by loss of endosomal pH regulation.”
Quote in the paperNot a substantial claim0 of 2 sources checkedIt may state two separate claims as one.
Study design and conductown dataSlc9a6 knockout efficiency in the brains of tamoxifen-injected Slc9a6fl;CAG-CreERT2 mice was 65-82% and varied between brain regions.
“Slc9a6 KO efficiency in the brains of tamoxifen-injected Slc9a6fl;CAG-CreERT2 mice was 65–82% and varied between brain regions (Figure 3B).”
Quote in the paperSubstantial claimIt may state two separate claims as one.
PremisecitationApoE4, unlike ApoE3 and ApoE2, prevents Reelin-mediated glutamate receptor insertion at the synapse, a state called ApoE4-mediated Reelin resistance.
“We previously showed that ApoE4, in contrast to ApoE3 and ApoE2, prevents Reelin-mediated glutamate receptor insertion at the synapse, a state we refer to as ApoE4-mediated Reelin resistance (Chen et al., 2010; Durakoglugil et al., 2009; Lane-Donovan and Herz, 2017; Lane-Donovan et al., 2014; Xian et al., 2018).”
Quote in the paperSubstantial claim0 of 3 sources checkedIt may state two separate claims as one.
PremisecitationLoss of net surface charge at the isoelectric point reduces solubility and impairs dissociation of ApoE4 from its receptors, aided by ApoE4's greater propensity to form a molten globule under acidic conditions.
“Loss of net surface charge at the IEP is accompanied by reduced solubility in an aqueous environment, leading to impaired dissociation of ApoE4 from its receptors (Xian et al., 2018) and aided by a greater propensity of ApoE4 to form a molten globule configuration under acidic conditions (Morrow et al., 2002).”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim. It may state two separate claims as one.
PremisecitationApoE4 alters APP processing and Aβ degradation.
“ApoE4 alters APP processing and Aβ degradation (reviewed in Benilova et al., 2012; Haass et al., 2012; Huynh et al., 2017; Lane-Donovan and Herz, 2017; Pohlkamp et al., 2017; Yamazaki et al., 2019)”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationIn 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).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Prasad and Rao, 2018 source
Probably not a substantial claim.
Study design and conductnone givenA blind observer selected the area of plaques with circles of 20, 40, or 80 μm diameter and analyzed the intensity of 6E10 and Iba1 or GFAP using the ImageJ plugin RGB_measure.
“A blind observer selected the area of plaques with circles of 20, 40, or 80 µm diameter and analyzed the intensity of 6E10 and Iba1 or GFAP by using the ImageJ plugin RGB_measure.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationOther neurobehavioral phenotypes described for Slc9a6- mice recapitulate symptoms in Christianson syndrome patients, for example, hyposensitivity to pain.
“Other neurobehavioral phenotypes have been described for Slc9a6- mice, which also recapitulate symptoms in Christianson syndrome patients, for example, hyposensitivity to pain (Petitjean et al., 2020).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Petitjean et al., 2020 source
Checked before — its earlier verdict is held back until a new check runs.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
InterpretationcitationNHE6 depletion in microglia might conversely augment toll-like receptor response.
“suggesting that NHE6 depletion in microglia might conversely augment TLR response.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationIn phagocytic cells, deacidification of endosomes using chloroquine reduces endosomal toll-like receptor response.
“In phagocytic cells, the deacidification of endosomes using pharmacological inhibitors like chloroquine has been shown to reduce endosomal toll-like receptor (TLR) response (de Bouteiller et al., 2005; Fox, 2019; Kuznik et al., 2011; Wozniacka et al., 2006; Yang et al., 2016)”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
Study design and conductnone given6E10-positive microglia (Iba1) were quantified by a blind observer by first identifying microglia structures/cells in the green channel (Iba1), and then analyzing the proportion of 6E10-positive structures and signal intensity (red channel).
“6E10-positive microglia (Iba1) were quantified by a blind observer by first identifying microglia structures/cells in the green channel (Iba1), and then analyzing the proportion of 6E10-positive structures and signal intensity (red channel).”
Quote in the paperNot a substantial claimProbably not a substantial claim.
Study design and conductnone givenRecombination was verified with the NHE6-rec PCR, which amplifies 400 bp if recombination has occurred.
“Recombination was verified with the NHE6-rec PCR, which amplifies 400 bp if recombination has occurred.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationNeuronal NHE6 plays a direct role in both synaptic development and plasticity, potentially through BDNF/TrkB and other pathways.
“Neuronal NHE6 plays a direct role in both synaptic development and plasticity, potentially through BDNF/TrkB (Deane et al., 2013; Ouyang et al., 2013) and other pathways.”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductnone givenThe same settings were used for every image.
“The same settings were used for every image, and images were analyzed using ImageJ software.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Partial NHE6 inhibition can be achieved without causing Christianson syndrome-like neurodevelopmental defects or Purkinje cell loss.
“NHE6 suppression or inhibition may thus be a universal, ApoE-independent approach to prevent amyloid buildup in the brain.”
“These findings suggest a novel therapeutic approach for the prevention of AD by which partial NHE6 inhibition reverses the ApoE4-induced endolysosomal trafficking defect and reduces plaque load.”
The paper relies on this without support.
The reduction in brain size, cortical thickness, hippocampal area, and CA1 thickness in NHE6-deficient AppNL-F mice does not account for the reduced plaque load.
“H&E staining did not reveal any obvious anatomical structural differences between genotypes, but brain size, cortical thickness, hippocampal area, and CA1 thickness were reduced, as described previously (Xu et al., 2017; Figure 7—figure supplement 1).”
“We found an approximate 80% reduction of plaques in Slc9a6- mice when compared to littermate controls (Figure 7B).”
The paper relies on this without support.
ApoE4 is the most important genetic risk factor for Alzheimer's disease.
“ApoE4 is the most important genetic risk factor.”
The paper relies on this without support.
Only small molecule drug therapies or immunization approaches can satisfy the requirement for globally scalable Alzheimer's disease treatment.
“Only small molecule drug therapies or, alternatively, immunization approaches can satisfy this requirement.”
The paper relies on this without support.
Biologics, including monoclonal antibodies and potential viral gene therapy approaches, are unlikely to be sufficiently scalable.
“Biologics, including monoclonal antibodies and potential viral gene therapy approaches, are unlikely to be sufficiently scalable.”
The paper relies on this without support.
AppNL-F and AppNL-F;ApoeAPOE4 mice are the most physiological currently available mouse models of Alzheimer's disease that do not rely on excessive amyloid overproduction.
“In the current study we used AppNL-F and AppNL-F;ApoeAPOE4 mice as the most physiological currently available mouse models of AD that do not rely on excessive amyloid overproduction.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The noxious propensity of apoE4 is due to an increase in isoelectric point compared to apoE3, resulting in unfolding of the protein in the acidic milieu of endosomes.
“This noxious propensity of apoE4 is due to an increase in the isoelectric point, as compared to apoE3, resulting in unfolding of the protein in the acidic milieu of endosomes75–79.”
From Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel (2025) · cites this paper as [79]
The Introduction reports that ApoE4 has a higher isoelectric point than ApoE3 (about 6.4 versus 6.1). The Discussion proposes isoelectric precipitation and structural unfolding at early-endosomal pH as a mechanism for impaired recycling. The citing sentence presents that proposed mechanism as an established cause, which the source does not establish. (LLM, conf=0.84)
Experimental — accuracy not yet measured
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.
Wild-type genotyping PCR product has two reported sizes
MinorThe Figure 2 legend reports a 220 bp wild-type product, while Materials and methods reports a 250 bp wild-type product for the Slc9a6fl PCR. Both give 270 bp for the floxed product.
“The wildtype and floxed allele PCR products differ by 50 bp (270 for floxed, 220 for wildtype).”
“The Slc9a6fl PCR amplifies a 250 bp of the wildtype and 270 bp of the floxed allele”
Triple-asterisk significance threshold differs
MinorThe figure legend defines *** as p < 0.005, whereas the Statistical methods section defines the same notation as p < 0.001.
“*p < 0.05, **p < 0.01, ***p < 0.005.”
“The differences were considered to be significant at p < 0.05 (*p < 0.05, **p < 0.01, ***p < 0.001).”
Citations
Cites
Shrestha, S., & Offer, S. M. (2016) · Medical Epigenetics · doi:10.1159/000444713 · Cited by 8,951
A robust and high-throughput Cre reporting and characterization system for the whole mouse brain
Madisen, L., Zwingman, T. A., Sunkin, S. M., Oh, S. W., Zariwala, H. A., Gu, H., Ng, L. L., Palmiter, R. D., Hawrylycz, M. J., Jones, A. R., et al. (2010) · Nature Neuroscience · doi:10.1038/nn.2467 · Cited by 6,907
Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O'Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., et al. (2014) · The Journal of Neuroscience · doi:10.1523/jneurosci.1860-14.2014 · Cited by 4,875 · cited 1×
“, 2021) and to a lesser extent in glial cells (Zhang et al., 2014).”
BackgroundCorrelative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice
Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F., & Cole, G. (1996) · Science · doi:10.1126/science.274.5284.99 · Cited by 4,210
Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., Teplow, D. B., Ross, S., Amarante, P., Loeloff, R., et al. (1999) · Science · doi:10.1126/science.286.5440.735 · Cited by 3,876
The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease
Sevigny, J., Chiao, P., Bussière, T., Weinreb, P. H., Williams, L., Maier, M., Dunstan, R., Salloway, S., Chen, T., Ling, Y., et al. (2016) · Nature · doi:10.1038/nature19323 · Cited by 3,059
Alzheimer Disease Genetics Consortium (ADGC), Kunkle, B. W., The European Alzheimer’s Disease Initiative (EADI), Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (CHARGE), Genetic and Environmental Risk in AD/Defining Genetic, P. A. E. R. F. A. D. C. (., Grenier-Boley, B., Sims, R., Bis, J. C., Damotte, V., Naj, A. C., et al. (2019) · Nature Genetics · doi:10.1038/s41588-019-0358-2 · Cited by 2,946
Self-citationKnopman, D. S., Amieva, H., Petersen, R. C., Chételat, G., Holtzman, D. M., Hyman, B. T., Nixon, R. A., & Jones, D. T. (2021) · Nature Reviews Disease Primers · doi:10.1038/s41572-021-00269-y · Cited by 2,606
Hematoxylin and Eosin Staining of Tissue and Cell SectionsPreprint
Fischer, A. H., Jacobson, K. A., Rose, J., & Zeller, R. (2008) · Cold Spring Harbor Protocols · doi:10.1101/pdb.prot4986 · Cited by 2,240
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
The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes
Benilova, I., Karran, E., & De Strooper, B. (2012) · Nature Neuroscience · doi:10.1038/nn.3028 · Cited by 1,962
Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease
Corder, E. H., Saunders, A. M., Risch, N. J., Strittmatter, W. J., Schmechel, D. E., Gaskell, P. C., Rimmler, J. B., Locke, P. A., Conneally, P. M., Schmader, K. E., et al. (1994) · Nature Genetics · doi:10.1038/ng0694-180 · Cited by 1,920
Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies
Yamazaki, Y., Zhao, N., Caulfield, T. R., Liu, C.-C., & Bu, G. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-019-0228-7 · Cited by 1,425
Single App knock-in mouse models of Alzheimer’s disease
Saito, T., Matsuba, Y., Mihira, N., Takano, J., Nilsson, P., Itohara, S., Iwata, N., & Saido, T. C. (2014) · Nature Neuroscience · doi:10.1038/nn.3697 · Cited by 1,366
Self-citationHayashi, S., & McMahon, A. P. (2002) · Developmental Biology · doi:10.1006/dbio.2002.0597 · Cited by 1,351
Trommsdorff, M., Gotthardt, M., Hiesberger, T., Shelton, J., Stockinger, W., Nimpf, J., Hammer, R. E., Richardson, J. A., & Herz, J. (1999) · Cell · doi:10.1016/s0092-8674(00)80782-5 · Cited by 1,261
Self-citationLee, E.-C., Yu, D., de Velasco, J. M., Tessarollo, L., Swing, D. A., Court, D. L., Jenkins, N. A., & Copeland, N. G. (2001) · Genomics · doi:10.1006/geno.2000.6451 · Cited by 1,180
Trafficking and Proteolytic Processing of APP
Haass, C., Kaether, C., Thinakaran, G., & Sisodia, S. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006270 · Cited by 1,075
Basu, S. K., Goldstein, J. L., Anderson, G. W., & Brown, M. S. (1976) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.73.9.3178 · Cited by 1,019
Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer’s disease
Meyer-Luehmann, M., Spires-Jones, T. L., Prada, C., Garcia-Alloza, M., de Calignon, A., Rozkalne, A., Koenigsknecht-Talboo, J., Holtzman, D. M., Bacskai, B. J., & Hyman, B. T. (2008) · Nature · doi:10.1038/nature06616 · Cited by 987
Hiesberger, T., Trommsdorff, M., Howell, B. W., Goffinet, A., Mumby, M. C., Cooper, J. A., & Herz, J. (1999) · Neuron · doi:10.1016/s0896-6273(00)80861-2 · Cited by 916
Self-citationMicroglia in Alzheimer's disease
Sarlus, H., & Heneka, M. T. (2017) · Journal of Clinical Investigation · doi:10.1172/jci90606 · Cited by 911
HDL and Reverse Cholesterol Transport
Ouimet, M. I., Barrett, T. J., & Fisher, E. A. A. (2019) · Circulation Research · doi:10.1161/circresaha.119.312617 · Cited by 810
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
Reelin and ApoE receptors cooperate to enhance hippocampal synaptic plasticity and learning
Weeber, E. J., Beffert, U., Jones, C., Christian, J. M., Förster, E., Sweatt, J. D., & Herz, J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m205147200 · Cited by 623
Self-citationMechanism of endosomal TLR inhibition by antimalarial drugs and imidazoquinolines
Kužnik, A., Benčina, M., Švajger, U., Jeras, M., Rozman, B., & Jerala, R. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1000702 · Cited by 606
Arboleda-Velasquez, J. F., Lopera, F., O’Hare, M., Delgado-Tirado, S., Marino, C., Chmielewska, N., Saez-Torres, K. L., Amarnani, D., Schultz, A. P., Sperling, R. A., et al. (2019) · Nature Medicine · doi:10.1038/s41591-019-0611-3 · Cited by 598
Sullivan, P. M., Mezdour, H., Aratani, Y., Knouff, C., Najib, J., Reddick, R. L., Quarfordt, S. H., & Maeda, N. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.29.17972 · Cited by 575
Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE
Parhizkar, S., Arzberger, T., Brendel, M., Kleinberger, G., Deussing, M., Focke, C., Nuscher, B., Xiong, M., Ghasemigharagoz, A., Katzmarski, N., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-018-0296-9 · Cited by 555
Reelin Is a Secreted Glycoprotein Recognized by the CR-50 Monoclonal Antibody
D’Arcangelo, G., Nakajima, K., Miyata, T., Ogawa, M., Mikoshiba, K., & Curran, T. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-01-00023.1997 · Cited by 515
Beffert, U., Weeber, E. J., Durudas, A., Qiu, S., Masiulis, I., Sweatt, J. D., Li, W.-P., Adelmann, G., Frotscher, M., Hammer, R. E., et al. (2005) · Neuron · doi:10.1016/j.neuron.2005.07.007 · Cited by 497
Self-citationStructure of the LDL Receptor Extracellular Domain at Endosomal pH
Rudenko, G., Henry, L., Henderson, K., Ichtchenko, K., Brown, M. S., Goldstein, J. L., & Deisenhofer, J. (2002) · Science · doi:10.1126/science.1078124 · Cited by 482
Wahrle, S. E., Jiang, H., Parsadanian, M., Legleiter, J., Han, X., Fryer, J. D., Kowalewski, T., & Holtzman, D. M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m407963200 · Cited by 474
Reiman, E. M., Arboleda-Velasquez, J. F., Quiroz, Y. T., Huentelman, M. J., Beach, T. G., Caselli, R. J., Chen, Y., Su, Y., Myers, A. J., Hardy, J., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-14279-8 · Cited by 473 · cited 1×
“Each ApoE4 allele reduces the age of Alzheimer’s disease (AD) onset by approximately 3–5 years compared to ApoE3 homozygotes, which comprise ~80 % of the human population (Roses, 1994; Sando et al., 2008).”
BackgroundDavis, C. G., Goldstein, J. L., Südhof, T. C., Anderson, R. G. W., Russell, D. W., & Brown, M. S. (1987) · Nature · doi:10.1038/326760a0 · Cited by 411
Nixon, R. A. (2017) · The FASEB Journal · doi:10.1096/fj.201700359 · Cited by 400
The early endosome: a busy sorting station for proteins at the crossroads.
Jović, M., Sharma, M., Rahajeng, J., & Caplan, S. (2010) · PubMed · doi:10.14670/hh-25.99 · Cited by 380
Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease
Wahrle, S. E., Jiang, H., Parsadanian, M., Kim, J., Li, A., Knoten, A., Jain, S., Hirsch-Reinshagen, V., Wellington, C. L., Bales, K. R., et al. (2008) · Journal of Clinical Investigation · doi:10.1172/jci33622 · Cited by 370
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
Self-citationNakamura, N., Tanaka, S., Teko, Y., Mitsui, K., & Kanazawa, H. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m410041200 · Cited by 353
The enigmatic endosome—sorting the ins and outs of endocytic trafficking
Naslavsky, N., & Caplan, S. (2018) · Journal of Cell Science · doi:10.1242/jcs.216499 · Cited by 353
Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE
Parhizkar, S., Arzberger, T., Brendel, M., Kleinberger, G., Deußing, M., Focke, C., Nuscher, B., Xiong, M., Ghasemigharagoz, A., Katzmarski, N., et al. (2019) · doi:10.7892/boris.125653 · Cited by 352
Tallquist, M. D., & Soriano, P. M. (2000) · genesis · doi:10.1002/(sici)1526-968x(200002)26:2 · Cited by 342
Deletion of Abca1 Increases Aβ Deposition in the PDAPP Transgenic Mouse Model of Alzheimer Disease
Wahrle, S. E., Jiang, H., Parsadanian, M., Hartman, R. E., Bales, K. R., Paul, S. M., & Holtzman, D. M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508780200 · Cited by 325
Apo E structure determines VLDL clearance and atherosclerosis risk in mice
Knouff, C., Hinsdale, M. E., Mezdour, H., Altenburg, M. K., Watanabe, M., Quarfordt, S. H., Sullivan, P. M., & Maeda, N. (1999) · Journal of Clinical Investigation · doi:10.1172/jci6172 · Cited by 324
Reelin modulates NMDA receptor activity in cortical neurons
Chen, Y., Beffert, U., Ertunc, M., Tang, T.-S., Kavalali, E. T., Bezprozvanny, I., & Herz, J. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1951-05.2005 · Cited by 299
Self-citationFagan, A. M., Watson, M., Parsadanian, M., Bales, K. R., Paul, S. M., & Holtzman, D. M. (2002) · Neurobiology of Disease · doi:10.1006/nbdi.2002.0483 · Cited by 290
Shore, V. G., & Shore, B. (1973) · Biochemistry · doi:10.1021/bi00727a022 · Cited by 281
Sando, S. B., Melquist, S., Cannon, A., Hutton, M. L., Sletvold, O., Saltvedt, I., White, L. R., Lydersen, S., & Aasly, J. O. (2008) · BMC Neurology · doi:10.1186/1471-2377-8-9 · Cited by 261
Roses, A. D. (1994) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199409000-00002 · Cited by 252
Ordovas, J. M., Litwack-Klein, L., Wilson, P. W., Schaefer, M. M., & Schaefer, E. J. (1987) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)38690-9 · Cited by 238
Serrano-Pozo, A., Muzikansky, A., Gómez-Isla, T., Growdon, J. H., Betensky, R. A., Frosch, M. P., & Hyman, B. T. (2013) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3182933788 · Cited by 226
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
de Bouteiller, O., Merck, E., Hasan, U. A., Hubac, S., Benguigui, B., Trinchieri, G., Bates, E. E. M., & Caux, C. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m507163200 · Cited by 220
Microglial immunophenotype in dementia with Alzheimer’s pathology
CFAS, M., Minett, T., Classey, J., Matthews, F. E., Fahrenhold, M., Taga, M., Brayne, C., Ince, P. G., Nicoll, J. A. R., & Boche, D. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0601-z · Cited by 219
Huynh, T.-P. V., Davis, A. A., Ulrich, J. D., & Holtzman, D. M. (2017) · Journal of Lipid Research · doi:10.1194/jlr.r075481 · Cited by 210
Amyloid clearance defect in ApoE4 astrocytes is reversed by epigenetic correction of endosomal pH
Prasad, H., & Rao, R. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1801612115 · Cited by 207
Crystal Structure of an Active Form of BACE1, an Enzyme Responsible for Amyloid β Protein Production
Shimizu, H., Tosaki, A., Kaneko, K., Hisano, T., Sakurai, T., & Nukina, N. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.02185-07 · Cited by 205
Apolipoprotein E4 Forms a Molten Globule
Morrow, J. A., Hatters, D. M., Lu, B., Höchtl, P., Oberg, K. A., Rupp, B., & Weisgraber, K. H. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204898200 · Cited by 204
Caporaso, G., Takei, K., Gandy, S., Matteoli, M., Mundigl, O., Greengard, P., & Camilli, P. V. D. (1994) · Journal of Neuroscience · doi:10.1523/jneurosci.14-05-03122.1994 · Cited by 196
Understanding Alzheimer Disease at the Interface between Genetics and Transcriptomics
Verheijen, J., & Sleegers, K. (2018) · Trends in Genetics · doi:10.1016/j.tig.2018.02.007 · Cited by 192
Gel isoelectric focusing method for specific diagnosis of familial hyperlipoproteinemia type 3
Warnick, G. R., Mayfield, C., Albers, J. J., & Hazzard, W. R. (1979) · Clinical Chemistry · doi:10.1093/clinchem/25.2.279 · Cited by 182
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
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
Woźniacka, A. J., Lesiak, A., Narbutt, J., McCauliffe, D. P., & Sysa‐Jędrzejowska, A. (2006) · Lupus · doi:10.1191/0961203306lu2299oa · Cited by 160
More than cholesterol transporters: lipoprotein receptors in CNS function and neurodegeneration
Lane-Donovan, C., Philips, G. T., & Herz, J. (2014) · Neuron · doi:10.1016/j.neuron.2014.08.005 · Cited by 158
Self-citationApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease
Lane-Donovan, C., & Herz, J. (2017) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2016.12.001 · Cited by 157 · cited 5×
“We previously showed that ApoE4, in contrast to ApoE3 and ApoE2, prevents Reelin- mediated glutamate receptor insertion at the synapse, a state we refer to as ApoE4- mediated Reelin resistance (Chen et al., 2010; Durakoglugil et al., 2009; Lane- Donovan and Herz, 2017; Lane- Donovan et al., 2014; Xian et al., 2018).”
BackgroundInfluentialSelf-citationReelin signaling antagonizes β-amyloid at the synapse
Durakoglugil, M. S., Chen, Y., White, C. L., Kavalali, E. T., & Herz, J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0908176106 · Cited by 153
Self-citationReciprocal regulation of signaling and endocytosis: Implications for the evolving cancer cell
Schmid, S. L. (2017) · The Journal of Cell Biology · doi:10.1083/jcb.201705017 · Cited by 152
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
The endosomal-lysosomal pathway is dysregulated by APOE4 expression in vivo
Nuriel, T., Peng, K. Y., Ashok, A., Dillman, A. A., Figueroa, H. Y., Apuzzo, J., Ambat, J., Levy, E., Cookson, M. R., Mathews, P. M., et al. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00702 · Cited by 140
Guntern, R., Bouras, C., Hof, P. R., & Vallet, P. G. (1992) · Cellular and Molecular Life Sciences · doi:10.1007/bf01923594 · Cited by 137
Shi, Y., Andhey, P. S., Ising, C., Wang, K., Snipes, L. L., Boyer, K., Lawson, S., Yamada, K., Qin, W., Manis, M., et al. (2021) · Neuron · doi:10.1016/j.neuron.2021.05.034 · Cited by 135
Pensalfini, A., Kim, S., Subbanna, S., Bleiwas, C., Goulbourne, C. N., Stavrides, P. H., Jiang, Y., Lee, J., Darji, S., Pawlik, M., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.108420 · Cited by 134
Frequency of the apolipoprotein E ε2 allele is diminished in sporadic Alzheimer disease
West, H. L., William Rebeck, G., & Hyman, B. T. (1994) · Neuroscience Letters · doi:10.1016/0304-3940(94)91074-x · Cited by 125
Merrill, J. T., & Lahita, R. G. (1996) · Lupus · doi:10.1177/096120339600500103 · Cited by 118
The RAD51 Family Member, RAD51L3, Is a DNA-stimulated ATPase That Forms a Complex with XRCC2
Braybrooke, J. P., Spink, K. G., Thacker, J., & Hickson, I. D. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m002075200 · Cited by 110
Live-cell Microscopy and Fluorescence-based Measurement of Luminal pH in Intracellular Organelles
Ma, L., Ouyang, Q., Werthmann, G. C., Thompson, H. M., & Morrow, E. M. (2017) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2017.00071 · Cited by 110
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
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
Self-citationReelin protects against amyloid β toxicity in vivo
Lane-Donovan, C., Philips, G. T., Wasser, C. R., Durakoglugil, M. S., Masiulis, I., Upadhaya, A., Pohlkamp, T., Coskun, C., Kotti, T., Steller, L., et al. (2015) · Science Signaling · doi:10.1126/scisignal.aaa6674 · Cited by 96
Self-citationFunctional Roles of the Interaction of APP and Lipoprotein Receptors
Pohlkamp, T., Wasser, C. R., & Herz, J. (2017) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00054 · Cited by 92
Self-citationYanuck, S. F. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00712 · Cited by 86
THE ISOELECTRIC POINT OF INSULIN
Wintersteiner, O., & Abramson, H. A. (1933) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)76023-7 · Cited by 84
Genetic Modulation of Tau Phosphorylation in the Mouse
Brich, J., Shie, F., Howell, B. W., Li, R., Tus, K., Wakeland, E. K., Jin, L., Mumby, M. C., Churchill, G. A., Herz, J., et al. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-01-00187.2003 · Cited by 84
Self-citationLiao, F., Zhang, T. J., Jiang, H., Lefton, K. B., Robinson, G. O., Vassar, R., Sullivan, P. M., & Holtzman, D. M. (2015) · Acta Neuropathologica Communications · doi:10.1186/s40478-015-0250-y · Cited by 77
Fox, R. (1996) · Lupus · doi:10.1177/0961203396005001031 · Cited by 77
Prasad, H., & Rao, R. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.602219 · Cited by 76
Genetic variation within endolysosomal system is associated with late-onset Alzheimer’s disease
Gao, S., Casey, A., Sargeant, T. J., & Mäkinen, V. (2018) · Brain · doi:10.1093/brain/awy197 · Cited by 76
Sinclair, R. A., Burns, J. M., & Dunnill, M. S. (1981) · Journal of Clinical Pathology · doi:10.1136/jcp.34.8.859 · Cited by 73
Yang, H. Y., Kozicky, L. K., Saferali, A., Fung, S., Afacan, N. J., Cai, B., Falsafi, R., Gill, E. E., Liu, M., Kollmann, T. R., et al. (2016) · Biomaterials · doi:10.1016/j.biomaterials.2016.09.032 · Cited by 73
Ohgaki, R., Matsushita, M., Kanazawa, H., Ogihara, S., Hoekstra, D., & van IJzendoorn, S. C. D. (2010) · Molecular Biology of the Cell · doi:10.1091/mbc.e09-09-0767 · Cited by 72
Xinhan, L., Matsushita, M., Numaza, M., Taguchi, A., Mitsui, K., & Kanazawa, H. (2011) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00154.2011 · Cited by 69
Will some day PAPS fade into SLE?
Cabral, A., & Alarcón-Segovia, D. (1996) · Lupus · doi:10.1177/096120339600500102 · Cited by 66
Lucien, F., Pelletier, P.-P., Lavoie, R. R., Lacroix, J.-M., Roy, S., Parent, J.-L., Arsenault, D., Harper, K., & Dubois, C. M. (2017) · Nature Communications · doi:10.1038/ncomms15884 · Cited by 66
HOOK, V. Y. H., Toneff, T., Aaron, W. H., Yasothornsrikul, S., Bundey, R. A., & Reisine, T. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.00794.x · Cited by 57
Heeren, J., Weber, W., & Beisiegel, U. (1999) · Journal of Cell Science · doi:10.1242/jcs.112.3.349 · Cited by 55
The zebrafishmerovingianmutant reveals a role for pH regulation in hair cell toxicity and function
Stawicki, T. M., Owens, K. N., Linbo, T. H., Reinhart, K. E., Rubel, E. W., & Raible, D. W. (2014) · Disease Models & Mechanisms · doi:10.1242/dmm.016576 · Cited by 54
Deane, E. C., Ilie, A. E., Sizdahkhani, S., Das Gupta, M., Orlowski, J., & McKinney, R. A. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.2583-12.2013 · Cited by 51
Eto, M., Watanabe, K., & Ishii, K. (1985) · Clinica Chimica Acta · doi:10.1016/0009-8981(85)90269-4 · Cited by 42
Fox, R. I. (1995) · BioDrugs · doi:10.1007/bf03259287 · Cited by 41
Panza, F., Solfrizzi, V., Torres, F., Mastroianni, F., Colacicco, A. M., Basile, A. M., Capurso, C., D'Introno, A., Del Parigi, A., & Capurso, A. (2000) · Neuroscience Letters · doi:10.1016/s0304-3940(00)01447-6 · Cited by 33
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 30
Ilie, A., Gao, A. Y. L., Boucher, A., Park, J., Berghuis, A. M., Hoffer, M. J. V., Hilhorst-Hofstee, Y., McKinney, R. A., & Orlowski, J. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2018.10.002 · Cited by 26
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
Molecular studies of pH-dependent ligand interactions with the low-density lipoprotein receptor
Yamamoto, T., Chen, H.-C., Guigard, E., Kay, C. M., & Ryan, R. O. (2008) · Biochemistry · doi:10.1021/bi801117t · Cited by 23
The Role of Glial Cells and Synapse Loss in Mouse Models of Alzheimer’s Disease
Ziegler-Waldkirch, S., & Meyer-Luehmann, M. (2018) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2018.00473 · Cited by 21
Beta-secretase/BACE1 promotes APP endocytosis and processing in the endosomes and on cell membrane
Wang, M., Jing, T., Wang, X., & Yao, D. (2018) · Neuroscience Letters · doi:10.1016/j.neulet.2018.08.016 · Cited by 20
Loss of SLC9A6/NHE6 impairs nociception in a mouse model of Christianson syndrome
Petitjean, H., Fatima, T., Mouchbahani-Constance, S., Davidova, A., Ferland, C. E., Orlowski, J., & Sharif-Naeini, R. (2020) · Pain · doi:10.1097/j.pain.0000000000001961 · Cited by 19
Gao, A. Y. L., Ilie, A., Chang, P. K. ‐., Orlowski, J., & McKinney, R. A. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.104490 · Cited by 18
Zhong, L., Xu, Y., Zhuo, R., Wang, T., Wang, K., Huang, R., Wang, D., Gao, Y., Zhu, Y., Sheng, X., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10950-2 · Cited by 18
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
APPL1 gates long-term potentiation through its plekstrin homology domain
Fernández‐Monreal, M., Sánchez‐Castillo, C., & Esteban, J. A. (2016) · Journal of Cell Science · doi:10.1242/jcs.183475 · Cited by 17
Lee, U., Ryu, S. H., & Chang, S. (2021) · Molecular Brain · doi:10.1186/s13041-021-00763-0 · Cited by 12
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ApoE Cascade Hypothesis in the pathogenesis of Alzheimer’s disease and related dementias
Martens, Y. A., Zhao, N., Liu, C.-C., Kanekiyo, T., Yang, A. J., Goate, A. M., Holtzman, D. M., & Bu, G. (2022) · Neuron · doi:10.1016/j.neuron.2022.03.004 · Cited by 316
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
Apolipoprotein E in Alzheimer’s disease: molecular insights and therapeutic opportunities
Belaidi, A. A., Bush, A. I., & Ayton, S. (2025) · Molecular Neurodegeneration · doi:10.1186/s13024-025-00843-y · Cited by 91
Vance, J. M., Farrer, L. A., Huang, Y., Cruchaga, C., Hyman, B. T., Pericak‐Vance, M. A., Goate, A. M., Greicius, M. D., Griswold, A. J., Haines, J. L., et al. (2024) · Annals of Neurology · doi:10.1002/ana.26864 · Cited by 52
Self-citationA 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
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Zhou, X., Shi, Q., Zhang, X., Gu, L., Li, J., Ju, Y., Hu, M., Zhao, X., & Li, Q. (2022) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2023.110670 · Cited by 40
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Belloy, M. E., Guen, Y. L., Stewart, I., Williams, K., Herz, J., Sherva, R., Zhang, R., Merritt, V. C., Panizzon, M. S., Hauger, R. L., et al. (2024) · JAMA Neurology · doi:10.1001/jamaneurol.2024.2843 · Cited by 36
Self-citationLee, 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
Kloske, C. M., Belloy, M. E., Blue, E. E., Bowman, G. R., Carrillo, M. C., Chen, X., Chiba‐Falek, O., Davis, A. A., Paolo, G. D., Garretti, F., et al. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.13877 · Cited by 33
Self-citationPreman, 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
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Eisenbaum, M., Pearson, A., Ortiz, C., Mullan, M., Crawford, F., Ojo, J., & Bachmeier, C. (2024) · Glia · doi:10.1002/glia.24469 · Cited by 25
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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
Greda, A. K., Gomes, J. P., Schmidt-Krueger, V., Zurawska-Plaksej, E., Fritsche-Guenther, R., Rudolph, I.-M., Telugu, N. S., Cömert, C., Kirwan, J., Kunz, S., et al. (2025) · Nature Metabolism · doi:10.1038/s42255-025-01389-5 · Cited by 21
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Fernandez, M. A., Bah, F., Ma, L., Lee, Y., Schmidt, M., Welch, E., Morrow, E. M., & Young‐Pearse, T. L. (2022) · Stem Cell Reports · doi:10.1016/j.stemcr.2022.08.001 · Cited by 19
Chen, K. H., Yang, J., Liu, B., Jiang, C., Koylass, N., Zhang, Z., Sun, S., Huganir, R. L., & Qiu, Z. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.115302 · Cited by 10
Huynh, T. N. T., Fikse, E. N., Torre, A. L. D. L., Havrda, M. C., Chang, C. C. Y., & Chang, T. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252413690 · Cited by 9
Safieh, M., Liraz, O., Ovadia, M., & Michaelson, D. M. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-230514 · Cited by 8
Asiamah, E. A., Feng, B., Guo, R., Yaxing, X., Du, X., Liu, X., Zhang, J., Cui, H., & Ma, J. (2024) · Journal of Alzheimer s Disease · doi:10.3233/jad-230658 · Cited by 8
Tejwani, L., Heffner, C. M., Balak, C. D., Skuja, L. L., Tatarakis, D., Rana, A., Yu, S. B., Fitzgerald, G. A., Ha, C., de Melo, G. L., et al. (2026) · Immunity · doi:10.1016/j.immuni.2026.07.009 · Cited by 7
Yao, Z., Godje, I. S. G., Jiao, B., Shen, L., & Luo, S. (2026) · Ageing Research Reviews · doi:10.1016/j.arr.2026.103153 · Cited by 6
Jiang, F., Wang, N., & Meng, Q. (2025) · Journal of Alzheimer s Disease · doi:10.1177/13872877251360321 · Cited by 6
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Prasad, H., & Rao, R. (2025) · FEMS Yeast Research · doi:10.1093/femsyr/foaf034 · Cited by 5
Gao, A. Y. L., Inglebert, Y., Shi, R., Ilie, A., Popic, J., Mustian, J., Sonenberg, N., Orlowski, J., & McKinney, R. A. (2025) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2024.167529 · Cited by 5
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Tejwani, L., Balak, C., Skuja, L. L., Tatarakis, D., Rana, A., Fitzgerald, G. A., Ha, C., Lunkes de Melo, G., Sun, E. W., Heffner, C. M., et al. (2024) · doi:10.1101/2024.11.11.623074 · Cited by 4
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Dodd, R. B., Enomoto, M., Zhou, Y., Satoh, K., Zhang, Y., Chen, F., Acheson, B., Ghaffari, D., Sayn-Wittgenstein, E., Manning, J. J., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-75140-3 · Cited by 4
Self-citationElucidating the Functional Roles of Long Non-Coding RNAs in Alzheimer’s Disease
Huang, Z., Chen, Q., Mu, X., An, Z., & Xu, Y. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25179211 · Cited by 4
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Radhakrishna, B. K., Kaladiyil, A. P., Chakraborty, A., Gautam, V., & Muddashetty, R. S. (2025) · Life Science Alliance · doi:10.26508/lsa.202503287 · Cited by 3
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Huang, Z., Mu, X., Chen, Q., Zhong, L., Xiao, J., Zuo, C., Zhang, Y., Shi, B., Qu, Y., Tan, R., et al. (2025) · Genomics Proteomics & Bioinformatics · doi:10.1093/gpbjnl/qzaf087 · Cited by 2
Prasad, H. (2025) · European Journal of Neuroscience · doi:10.1111/ejn.70334 · Cited by 2
Herz, J. (2025) · Journal of Clinical Investigation · doi:10.1172/jci200393 · Cited by 2
Self-citationMasson, L.-C., Kanagasabai, A. S., Toscano‐Márquez, B., Tourbina-Kolomiets, J., Charron, F. M., Watt, A. J., & McKinney, R. A. (2025) · The Cerebellum · doi:10.1007/s12311-025-01850-x · Cited by 1
Cell-type-specific APOE4 cascade across the Alzheimer’s disease continuum
Shostak, D. M., Liang, Z., & Huang, Y. (2026) · Neuron · doi:10.1016/j.neuron.2026.04.024 · Cited by 1
Apoer2/Lrp8: the undercover cop of synaptic homeostasis
Werthmann, G. C., & Herz, J. (2024) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-23-02002 · Cited by 1
Self-citationApoE4 impairs astrocyte lipid droplet formation via endolysosomal dysfunction
Ralhan, I., Bae, J.-Y., Lee, N. Y., Cai, W., Chang, J., Jarad, S., Gu, H., Zhang, D., & Ioannou, M. S. (2026) · doi:10.64898/2026.09.01.748585
Applications of App and MAPT knock-in mice to understanding disease mechanisms
Saido, T. C. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-28979-8.00006-1
Self-citationResearch Progress of Neurodegenerative Diseases Targeting APOE
苏, 航. (2024) · Aging Research · doi:10.12677/ar.2024.115295
Apolipoprotein E in Embryogenesis and Development
Getz, G. S., & Reardon, C. A. (2025) · Springer eBooks · doi:10.1007/978-3-031-52641-1_8-1
Shin, J., Brady, E. S., Chen, C., Lauderdale, K., Agrawal, A., Zhang, Y., Jiang, X., Nambiar, P., Herbert, J., Mallen, D. D., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.11.11.687887
Ontrafelen van de rol van APOE in astrocyten en microglia bij de ziekte van Alzheimer
Preman, P. (2023) · Lirias (KU Leuven)
LIPID DROPLET TARGETING AND FUNCTION OF APOLIPOPROTEIN E
Windham, I. A. (2026) · Carolina Digital Repository (University of North Carolina at Chapel Hill) · doi:10.17615/yant-mg96
NHE6-driven endosome-autophagy axis confers proteasome inhibitor resistance in multiple myeloma
Chen, L., Cheng, F., Huang, Y.-H., Wang, Y., He, J., Liu, J., Wang, Z., Lin, P., Fan, Y., Bao, L., et al. (2026) · Drug Resistance Updates · doi:10.1016/j.drup.2026.101436
ALBAYRAK, İ. G. (2026) · Akademisyen Kitabevi eBooks · doi:10.37609/akya.4278
Structure of NHE6 and its lipid-mediated interactions regulating endosomal pH
Jung, S., Yeo, H. K., Li, H., Kokane, S., Reichenbach, T., Gulati, A., Albano, G., Kirschbaum, C., Ho, M. T., Landreh, M., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-75877-x
Meena, R. K., Duddu, A. S., Jolly, M. K., & Prasad, H. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.23.752284
Emerging therapeutic strategies to target APOE4 in Alzheimer's disease
Jiang, W. I., 王冰莹, & Ma, D. K. (2026) · FEBS Journal · doi:10.1111/febs.70759
Metadata
- Authors
- 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., & Herz, J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Peking University (CN)
- RIKEN Center for Brain Science (JP)
- Center for Translational Neurodegeneration Research
- Corresponding author
- Pohlkamp, Theresa
- Herz, Joachim
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2021-10-07
- Volume
- 10
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC8547963
- OpenAlex
- W3204755653
- Cited by
- 46
- References
- 114
- Citations by year
- 2026: 11 · 2025: 12 · 2024: 14 · 2023: 4 · 2022: 4 · 2021: 1
- FWCI
- 2.08
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institutes of Health (HL063762, NS093382, NS108115, AG053391)
- BrightFocus Foundation (A20135245, A2016396S)
- National Institute on Aging (1F31AG067708-01)
- Darrell K Royal Research Fund
- Harrington Discovery Institute
- Circle of Friends Pilot Synergy
- Blue Field Project to Cure FTD
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- NHE6, SLC9A6, APOE ε4, Alzheimer's disease, endolysosomal trafficking, synaptic homeostasis, amyloid plaques, amyloid clearance, apoE receptors, therapeutic target
- MeSH terms
- Animals, Female, Male, Sodium-Hydrogen Exchangers, Mice, Knockout, Low Density Lipoprotein Receptor-Related Protein-1, Mice, Apolipoprotein E4, Plaque, Amyloid
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