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Cited by 32Alzheimer's disease research and treatmentsCellular transport and secretionNeuroinflammation and Neurodegeneration Mechanisms

The DOI matches its Crossref record; 100 of the 100 references it cites were found in a registry or an index; 27 of the 62 sources its claims cite were checked for support.

The neuronal retromer can regulate both neuronal and microglial phenotypes of Alzheimer's disease

Open access
Qureshi, Yasir H., Berman, Diego E., Marsh, Samuel E., Klein, Ronald L., Patel, Vivek M., Simoes, Sabrina, Kannan, Suvarnambiga, Petsko, Gregory A., Stevens, Beth, Small, Scott A.·2022·Cell Reports
DOI 10.1016/j.celrep.2021.110262PMC PMC8830374
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Abstract

Disruption of retromer-dependent endosomal trafficking is considered pathogenic in late-onset Alzheimer's disease (AD). Here, to investigate this disruption in the intact brain, we turn to a genetic mouse model where the retromer core protein VPS35 is depleted in hippocampal neurons, and then we replete VPS35 using an optimized viral vector protocol. The VPS35 depletion-repletion studies strengthen the causal link between the neuronal retromer and AD-associated neuronal phenotypes, including the acceleration of amyloid precursor protein cleavage and the loss of synaptic glutamate receptors. Moreover, the studies show that the neuronal retromer can regulate a distinct, dystrophic, microglia morphology, phenotypic of hippocampal microglia in AD. Finally, the neuronal and, in part, the microglia responses to VPS35 depletion were found to occur independent of tau. Showing that the neuronal retromer can regulate AD-associated pathologies in two of AD's principal cell types strengthens the link, and clarifies the mechanism, between endosomal trafficking and late-onset sporadic AD.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

Neuronal VPS35 depletion in mouse hippocampal CA1 recapitulates AD-associated neuronal and microglial phenotypes, and AAV9-VPS35 repletion partially rescues them. The neuronal retromer can regulate both neuronal and microglial phenotypes, and these effects occur independently of tau.

Key findings

  • In 3-month-old VPS35 nsKO mice, VPS35 depletion increased APP C-terminal fragments (t = 9.08, p = 0.00002), reduced GluA1 (t = 4.93, p = 0.0011), and increased GFAP (t = 7.8, p = 0.00005) and IBA1 (t = 5.69, p = 0.0005).
  • AAV9-VPS35 repletion normalized APP CTFs (t = 3.88, p = 0.018) and GluA1 (t = −6.45, p = 0.003), partially normalized GFAP (t = 3.39, p = 0.028), but did not significantly change IBA1 (p = 0.11) or CD11b (p = 0.19).
  • VPS35 depletion altered microglial morphology, decreasing process spatial extension (t = 7.82, p = 2.52 × 10−12) and branching (t = 6.15, p = 1.11 × 10−8; t = 7.73, p = 3.9 × 10−12), with fragmentation, beading, and spheroid formation partially normalized by AAV9-VPS35.
  • In VPS35 nsKO × Tau KO mice, neuronal and glial responses to VPS35 depletion still occurred, indicating they are independent of tau.

Methods

  • VPS35fl/fl mice were crossed with Camk2α-Cre mice to generate neuronal-selective VPS35 knockout (VPS35 nsKO) mice; dorsal CA1 was micro-dissected from 3-month-old and 6-month-old mice, with WT littermates as controls.
  • AAV9-VPS35-HA or AAV9-GFP was delivered stereotactically to CA1 of 3-month-old VPS35 nsKO mice, which were aged to 6 months; AAV9-VPS35 was optimized in neuronal cultures and WT C57BL/6J mice, with co-immunoprecipitation confirming binding to VPS29 and VPS26.
  • Analyses included immunoblotting, fluorescent immunohistochemistry, Sholl analysis of microglia, and statistics using t-tests, Pearson correlation, and multiple regression.

Limitations

  • The paper states that the main limitation is that conclusions are shown only in a mouse model of late-onset AD, and mechanistic conclusions about AD are best achieved in AD patients.
  • The authors note an outstanding issue in the AAV9-GFP condition: apparent antibody cross-reactivity to GFP because of immunoblot overlap of GFP and mature-CTSD bands.
  • The authors also note that increased microglial branching near the cell body after AAV9-VPS35 was also seen with AAV9-GFP and is likely a viral vector effect.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.celrep.2021.110262

Cites

100 of 100 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

27 of 62 cited sources checked · 9 supported · 1 flagged · accuracy not yet measured

  • Findingcitation

    SORL1 protein is differentially expressed in neurons in wild-type mice.

    “an immunofluorescence map of SORL1 protein expression in WT mice confirms previous cell culture observations (Thonberg et al., 2017), showing that SORL1 protein is differentially expressed in neurons (Figures 5A and 5B).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Thonberg et al., 2017 source

      The Results (Neuropathology and immunohistochemistry; page unavailable) report reduced SORL1 staining in pyramidal neurons from affected family members compared with human controls and sporadic Alzheimer disease cases. That supports a difference in neuronal SORL1 staining, but the cited observations are from post-mortem human brain tissue, not cell culture or wild-type mice. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    Disruption of retromer-dependent endosomal trafficking is pathogenic in late-onset Alzheimer's disease.

    “Disruption of retromer-dependent endosomal trafficking is considered pathogenic in late-onset Alzheimer’s disease (AD).”
    • Also stated in: § INTRODUCTION · hedged
      “A combination of genetic (Karch and Goate, 2015) and functional (Small et al., 2017) studies have implicated endosomal trafficking as a pathogenic biological pathway in the disease.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Karch and Goate, 2015 source

      The Endocytosis section links endocytic genes to late-onset Alzheimer’s risk, and the SORL1 subsection describes APP recycling and altered Aβ levels when SORL1 is absent. Our copy does not identify retromer-dependent trafficking specifically or state that its disruption is pathogenic. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites Small et al., 2017 source
  • Interpretationown data

    The above-normal increase in branching number closer to the cell body is likely the effect of the viral vector.

    “Informatively, this second effect was also observed after AAV9-GFP injections, and thus is likely the effect of the viral vector, as previously described (Mingozzi and High, 2013; Mastakov et al., 2002; Samaranch et al., 2014; Pluvinage and Wyss-Coray, 2017).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Mingozzi and High, 2013 source

      The Introduction discusses immune responses to AAV vectors and mentions their use in the central nervous system, but does not address neuronal branching near the cell body. Searches for AAV9-GFP, dendritic branching, and neuronal morphology found no passage linking the reported increase to the vector. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites Mastakov et al., 2002 source
    • cites Samaranch et al., 2014 source

      The Results and Discussion describe inflammation, immune activation, and neuronal injury after AAV9-GFP delivery. Searches for branching near the cell body and AAV9-GFP effects on branching found no passage assessing branch number or attributing an increase to the viral vector. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
  • Premisecitation

    VPS35 depletion is known to cause enlarged endosomes, a cytopathogenic hallmark of Alzheimer's disease.

    “VPS35 depletion is known to cause enlarged endosomes (Bhalla et al., 2012), a cytopathogenic hallmark of AD (Cataldo et al., 2000)”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Bhalla et al., 2012 source
    • cites Cataldo et al., 2000 source
  • Premisecitation

    Most in vivo mouse studies of retromer in AD have been performed in transgenic mice overexpressing human mutations in APP and PSEN1/2 or FTD-associated mutations in the tau gene MAPT.

    “most in vivo mouse studies have been performed in transgenic mice engineered to overexpress human mutations in APP and PSEN1/2 (Wen et al., 2011; Li et al., 2019a) or FTD-associated mutations in the tau gene MAPT (Vagnozzi et al., 2019; Carosi et al., 2020).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Wen et al., 2011 source
    • cites Li et al., 2019a

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Vagnozzi et al., 2019 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one. 26
  • Probably not a substantial claim. 22

  • It may state two separate claims as one.

    Premisecitation

    Dystrophic microglia are diametrically distinct from hypertrophic microglia, characterized by exuberant overgrowth of microglial processes, typically found in the cortex surrounding amyloid plaques and likely reflective of hyperactive phagocytic clearance.

    “In fact, dystrophic microglia are diametrically distinct from hypertrophic microglia, characterized by an exuberant overgrowth of microglial processes, typically found in the cortex surrounding amyloid plaques and likely reflective of hyperactive phagocytic clearance of extracellular aggregates (Navarro et al., 2018).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Navarro et al., 2018 source

      Split into 2 atoms — 0 confirmed, 1 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    At 3 months of age, VPS35 nsKO mice have no cell or synaptic loss.

    “an age when previous studies have established that there is no cell or synaptic loss in these mice (Simoes et al., 2020).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Simoes et al., 2020 source

      The Results section (“Validating BACE1 substrates and Tau accumulation in mouse CSF”; page not provided) reports no signs of neuronal loss in the hippocampus of 3-month-old Vps35 cKO mice and unchanged pre- and postsynaptic marker expression. The Methods identify these as neuronal-selective knockout mice, but unchanged marker expression does not directly establish that no synapses were lost, and the neuronal-loss assessment was limited to the hippocampus. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim.

    Premisecitation

    Retromer plays a role in transporting SORL1 from the endosome to the cell surface.

    “retromer plays a role in transporting SORL1 from the endosome to the cell surface (Christensen et al., 2020).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Christensen et al., 2020 source

      The Introduction (page unavailable) says sorLA can recycle from the endosome to the cell surface, but identifies retromer with the alternative retrograde route to the Golgi. The Discussion likewise describes retromer-dependent trafficking from the endosome to the Golgi, not directly to the cell surface. Thus the paper supports retromer’s role in sorLA trafficking, but not the stated destination. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    Microglia are a second brain cell type phenotypic of Alzheimer's disease cellular pathologies and play a dominant role in modulating the brain's response to AD's neuronal-based pathologies.

    “Besides neurons, glia and in particular microglia are now considered a second brain cell type phenotypic of AD’s cellular pathologies (Salter and Stevens, 2017; Hansen et al., 2018; Takatori et al., 2019; Streit et al., 2020), which play a dominant role in modulating how the brain responds to AD’s triggering neuronal-based pathologies.”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Salter and Stevens, 2017 source
    • cites Hansen et al., 2018 source

      The Introduction describes microgliosis as a feature of AD histopathology, and the Conclusion describes microglia as crucial players that can protect against amyloid pathology or contribute to neuronal damage. The review does not establish that their role is dominant, and it says their precise involvement in AD remains unsettled. No page numbers are available in our copy. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites Takatori et al., 2019 source

  • It may state two separate claims as one.

    Findingcitation

    AAV9 injected directly into adult brain parenchyma is not expressed in microglia and is minimally expressed in astrocytes.

    “we performed co-labeling via IHC and confirmed the results of previous studies (Castle et al., 2016; Hudry et al., 2016; Schuster et al., 2014; Aschauer et al., 2013; Hinderer et al., 2014; Samaranch et al., 2012), showing that AAV9, when injected directly into the adult brain parenchyma, is not expressed in microglia and minimally expressed in astrocytes (Figure S5).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Castle et al., 2016 source

      Section 2 (page unavailable) says that after intraparenchymal brain injection, AAV9 shows strong neuronal tropism and gene expression rarely colocalizes with astrocyte markers, supporting minimal astrocytic expression. It does not establish that AAV9 is never expressed in microglia or specify that this finding applies to adult brains. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Hudry et al., 2016 source

      The Results section reports sparse GFP expression in cortical astrocytes after direct intraparenchymal injection of conventional AAV9 and exo-AAV9 in mice. It reports no GFP-expressing microglia only after intravenous injection, so that finding does not establish the claim for direct brain injection. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Schuster et al., 2014 source

      The Results section ('AAV9-mediated GFP expression in the CNS'; page unavailable) reports GFP-positive astrocytes associated with blood vessels, supporting astrocyte expression but not establishing that it is minimal. The study examined intrathecal and intravenous delivery, not direct injection into adult brain parenchyma. Its Discussion reports no reactive microglia, which does not establish that microglia lacked AAV9-driven expression. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Accelerated tau secretion represents an early and specific manifestation of tau pathology in Alzheimer's disease distinct from other tauopathies, occurring via active unconventional secretion.

    “It is now understood that accelerated tau secretion represents an early and specific manifestation of tau pathology in AD that is distinct from other tauopathies (Zetterberg, 2017), which occurs via active unconventional secretion (Merezhko et al., 2018).”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Zetterberg, 2017 source

      The Abstract reports increased tau release in Alzheimer’s disease and says CSF tau concentrations are typically unaltered in other tauopathies. The CSF T-tau section says concentrations remain elevated for years, but does not establish accelerated secretion as an early manifestation of tau pathology. The active-unconventional-secretion mechanism is attributed to Merezhko et al., not to Zetterberg, in the citing sentence. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites Merezhko et al., 2018 source

  • Probably not a substantial claim.

    Premisecitation

    The AD-associated microglia response in the hippocampus has been proposed to be linked to tau pathology.

    “Moreover, the AD-associated microglia response in the hippocampus has been proposed to be linked to tau pathology (Shahidehpour et al., 2021; Streit et al., 2020; Navarro et al., 2018).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Shahidehpour et al., 2021 source

      The Results section reports that dystrophic microglia are more common in hippocampal CA1 cases with neurodegenerative pathology, including AD, than in cases without such pathology. The paper does not establish a tau link for that hippocampal response; its Discussion mentions tau in other species, while its References list earlier studies linking AD microglia and tau. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites Streit et al., 2020 source
    • cites Navarro et al., 2018 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Studies have provided proof-of-concept that retromer can be pharmacologically targeted.

    “Notably, studies have already provided the proof-of-concept that retromer can be pharmacologically targeted (Young et al., 2018; Mecozzi et al., 2014)”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites Young et al., 2018 source
    • cites Mecozzi et al., 2014 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Recent studies have established a CSF biomarker of retromer-dependent neuronal dysfunction.

    “recent studies have established a CSF biomarker of retromer-dependent neuronal dysfunction (Simoes et al., 2020).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Simoes et al., 2020 source

      The Discussion identifies a joint increase in CSF tau with n-APLP1 or n-CHL1 as a potential biomarker of impaired retromer-dependent trafficking. But it says such a biomarker 'can be developed,' not that one has been established; the Discussion also notes that precise diagnostic cutoffs could not yet be established. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    An increase in pro-CTSD is a reliable indicator of impaired retromer-dependent trafficking and ultimately lysosomal dysfunction.

    “Thus, an increase in pro-CTSD is considered a reliable indicator of impaired retromer-dependent trafficking (Benes et al., 2008; Rojas et al., 2008; Han et al., 2021), and ultimately lysosomal dysfunction.”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Benes et al., 2008 source
    • cites Rojas et al., 2008 source

      The Results section (Fig. 9) reports that Rab7 or Vps26 depletion increased precursor cathepsin D and interprets this as evidence of impaired transport to lysosomes, consistent with disrupted retromer function. It does not establish that increased pro-CTSD is a reliable, specific indicator of impaired retromer-dependent trafficking or demonstrate broader lysosomal dysfunction. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites Han et al., 2021 source

      The Results (page not provided) say that precursor CTSD accumulation indicates CTSD missorting and report its accumulation after either CASP9 or VPS35 knockdown, alongside reduced lysosomal-enzyme activity in CASP9-deficient cells. They do not establish increased pro-CTSD as a reliable indicator specifically of retromer-dependent trafficking impairment; the paper also observes it with CASP9 deficiency and discusses other endosomal transport components. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim.

    Premisecitation

    Elevation in CSF tau is an early event in Alzheimer's disease tau pathology.

    “Elevation in CSF tau is an early event in AD’s tau pathology (Barthelemy et al., 2020)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Barthelemy et al., 2020 source

  • Probably not a substantial claim.

    Premisecitation

    Loss of glutamate receptors typifies the early synaptic stage of neurodegeneration.

    “A loss of glutamate receptors is what typifies this early synaptic stage of neurodegeneration (Yasuda et al., 1995; Wakabayashi et al., 1999; Qu et al., 2021)”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Yasuda et al., 1995 source

      The Introduction reports that loss of the GluR2/3 receptor subunit in layer II entorhinal neurons occurs before those neurons are lost, relatively early in Alzheimer’s disease. The Discussion also reports reduced GluR1 and GluR2/3 subunits in the entorhinal cortex. These findings support an early receptor change in a specific disease and region, but not the broader claim that glutamate-receptor loss typifies an early synaptic stage of neurodegeneration generally. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites Wakabayashi et al., 1999 source
    • cites Qu et al., 2021

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • It may state two separate claims as one.

    Findingown data

    After VPS35 repletion, the spatial extent of microglia processes is normalized, and for most distal processes, branching number is normalized.

    “First, the spatial extent of the microglia processes was normalized, and for most of the distal processes, there was normalization of the branching number, as indicated by the complete overlap of the WT and AAV9-VPS35 plots after a radius of 17 μm from the cell body (Figure 7B).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    VPS35 depletion leads to an increase in pro-CTSD in CA1 tissue, which is partially rescued by VPS35 repletion.

    “immunoblotting tissue micro-dissected from the CA1 showed that compared with WT mice, VPS35 depletion leads to an increase in the pro-CTSD, which was partially rescued by VPS35 repletion (Figures 5H and 5I).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In VPS35 nsKO conditions, mature-CTSD is also increased, but the ratio of pro-CTSD to mature-CTSD is significantly increased in VPS35 depletion and rescued with VPS35 repletion.

    “In VPS35 nsKO conditions mature-CSTD was also increased, but the ratio of pro-CTSD/mature-CTSD was still significantly increased in the VPS35 depletion and rescued with VPS35 repletion (Figure S4).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Using the optimized delivery protocol, AAV9-VPS35-HA produces broad expression across the dorsal hippocampus and a significant increase in VPS35 in 6-month-old mice.

    “Results showed a broad expression distribution across the dorsal hippocampus, with a significant increase in VPS35 (t = 8.74, p = 0.003) and with no evidence of toxicity (Figures 3B–3D).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    VPS35 depletion in CA1 neurons causes larger SORL1-positive puncta, an effect partially rescued by VPS35 repletion.

    “A reliable effect was, however, observed within CA1 neurons, with larger SORL1-positive puncta in VPS35-depleted neurons, an effect that was partially rescued upon VPS35 repletion (Figures 5F and 5G).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Findingown data

    After VPS35 repletion, there is an above-normal increase in branching number in processes closer to the cell body.

    “The second effect was an above-normal increase in branching number in processes closer to the cell body (Figures 7B and 7C [mid]).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    In vivo, exogenous VPS35 downregulates the corresponding endogenous protein and binds the two other retromer core proteins.

    “As in neuronal culture, a co-immunoprecipitation study with anti-HA antibody showed that exogenous VPS35 downregulates the corresponding endogenous protein, and that exogenous VPS35 binds the two other retromer core proteins (Figure 3E).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    AAV9-VPS35-GFP significantly increases total VPS35 at the middle and highest doses but not at the lowest dose.

    “A significant increase in total VPS35 was observed at both the middle dose (t = −10.74, p < 0.001) and the highest dose (t = −26.02, p < 0.001), but not at the lowest dose (t = −1.53, p = 0.199).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In no-surgery controls, the gliosis observed at 3 months in VPS35 nsKO mice is sustained at 6 months with increases in GFAP, IBA1, and CD11b.

    “In the no-surgery control conditions, the gliosis observed at 3 months in VPS35 nsKO mice was sustained at 6 months with an increase of GFAP (t = −2.74, p = 0.052), IBA1 (t = −8.24, p = 0.001), and another microglial marker CD11b (t = −6.65, p = 0.002) (Figures 6A and 6C).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Across all conditions, APOE levels strongly correlate with GFAP levels and with IBA1 levels.

    “we find that across all conditions APOE levels strongly correlated with GFAP levels (β = 0.84, P < 0.0001), but also with IBA1 levels (β = 0.72, P = 0.002) (Figure 6D).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    APOE is elevated in VPS35 nsKO mice and partially normalized by AAV9-VPS35 repletion.

    “We find that APOE is also elevated in VPS35 nsKO mice (t = −6.02, p = 0.004) (Figures 6A and 6C) and partially normalized by AAV9-VPS35 repletion (t = 2.98, p = 0.018).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In the absence of tau, VPS35 depletion still results in neuronal phenotypes: elevation of APP CTFs and loss of GluA1.

    “Interestingly, in the absence of tau, VPS35 depletion also still resulted in the neuronal phenotypes, an elevation of APP CTFs, and a loss of GluA1.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Findingnone given

    The spread of injected virus and exogenous VPS35 expression was maximal in the dorsal part of CA1.

    “The dorsal part of CA1 was micro-dissected specifically because the spread of injected virus, and exogenous VPS35 expression was maximal in this region.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationcitation

    Documenting that neuronal pathologies were resistant to knocking out tau supports the hypothesis that AD's neuronal and microglia pathology might occur independent of, and in parallel to, tau pathology.

    “Furthermore, documenting that the neuronal pathologies were resistant to knocking out tau supports the hypothesis that AD’s neuronal and microglia pathology might occur independent of, and in parallel to, tau pathology (Small and Petsko, 2020).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Small and Petsko, 2020 source

      Checked before — its earlier verdict is held back until a new check runs.

  • It may state two separate claims as one.

    Interpretationreasoning

    Disrupting retromer-dependent endosomal recycling can regulate both AD-associated neuronal and microglial phenotypes, strengthening and clarifying a causal link between this trafficking route and AD.

    “Mechanistically, showing that disrupting retromer-dependent endosomal recycling can regulate both AD-associated neuronal and microglial phenotypes strengthens and clarifies a causal link between this trafficking route and AD.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Retromer dysfunction is associated with pathogenic cleavage of amyloid precursor protein and loss of hippocampal-enriched glutamate receptors.

    “For neurons, we relied on prior studies that have associated retromer dysfunction with the pathogenic cleavage of the amyloid precursor protein (APP) and the loss of hippocampal-enriched glutamate receptors (Temkin et al., 2017), which typify AD-associated amyloid and synaptic pathology.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Temkin et al., 2017 source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Animals were assigned randomly to experimental groups.

    “Animals were assigned randomly to experimental groups.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Retromer is considered a master conductor of endosomal trafficking.

    “Retromer is considered a “master conductor” of endosomal trafficking (Burd and Cullen, 2014)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Burd and Cullen, 2014 source

  • It may state two separate claims as one.

    Interpretationown data

    The observed microglia alterations are similar to dysmorphic microglia in the hippocampus of AD brains and distinct from hypertrophic microglia in the cortex associated with amyloid plaques.

    “The observed alterations in microglia are similar to the dysmorphic microglia observed in the hippocampus of AD brains (Navarro et al., 2018; Streit et al., 2009, 2020; Davies et al., 2017; Shahidehpour et al., 2021), diametrically distinct from the hypertrophic microglia morphology observed in the cortex and typically associated with amyloid plaques (Navarro et al., 2018).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Navarro et al., 2018 source
    • cites Streit et al., 2009, 2020

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Davies et al., 2017 source

  • It may state two separate claims as one.

    Interpretationown data

    Dysfunction in retromer-dependent endosomal recycling in neurons of the hippocampal formation can recapitulate many of AD's cardinal pathologies, and does so upstream to preexisting amyloid or tau pathology.

    “Taken together with previous studies, the current findings show that dysfunction in retromer-dependent endosomal recycling, in neurons of the hippocampal formation, can recapitulate many of AD’s cardinal pathologies, and that it does so upstream to preexisting amyloid or tau pathology.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Study design and conductnone given

    IBA1 and CD11b are highly expressed in microglia and are commonly used as markers of microglia to study microglial morphology in the brain.

    “To confirm the microglial phenotype, we used antibodies against two proteins that are highly expressed in microglia (IBA1 and CD11b) and are commonly used as markers of microglial to study the microglial morphology in the brain; these proteins, however, are also expressed in peripheral macrophages.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: IBA1 and CD11b staining in brain sections reflects microglia rather than peripheral macrophages.

  • Probably not a substantial claim.

    Premisecitation

    The dorsal CA1 region was chosen because the hippocampus is associated with memory formation.

    “Dorsal CA1 region was chosen because of association of the hippocampus with memory formation (Wittenberg and Tsien, 2002) and also because this region is relatively close to the skull in mice and can be very precisely targeted.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Wittenberg and Tsien, 2002

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim.

    Premisecitation

    Sholl analysis is a standard automated method that can characterize and quantify the complexity and extent of microglial processes.

    “we completed an extensive morphological investigation using Sholl analysis, a standard automated method (Sholl, 1953) that can characterize and quantify the complexity and extent of microglial processes (Ferreira et al., 2014; Morrison and Filosa, 2013; Heindl et al., 2018; Sipe et al., 2016).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Sholl, 1953
    • cites Ferreira et al., 2014 source
    • cites Morrison and Filosa, 2013 source

  • Probably 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 given

    Most of the antibodies used are monoclonal antibodies with minimal non-specific signal.

    “The primary antibodies were selected based on extensive citations by previous studies; most of the antibodies used are monoclonal antibodies with minimal non-specific signal and several of them have been validated by KO testing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Several of the antibodies used have been validated by knockout testing.

    “The primary antibodies were selected based on extensive citations by previous studies; most of the antibodies used are monoclonal antibodies with minimal non-specific signal and several of them have been validated by KO testing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisenone given

    The dorsal CA1 region is relatively close to the skull in mice and can be very precisely targeted.

    “Dorsal CA1 region was chosen because of association of the hippocampus with memory formation (Wittenberg and Tsien, 2002) and also because this region is relatively close to the skull in mice and can be very precisely targeted.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    IBA1 and CD11b are also expressed in peripheral macrophages.

    “To confirm the microglial phenotype, we used antibodies against two proteins that are highly expressed in microglia (IBA1 and CD11b) and are commonly used as markers of microglial to study the microglial morphology in the brain; these proteins, however, are also expressed in peripheral macrophages.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Study design and conductnone given

    All images for microglial structural analysis were taken from the same region of the dorsal hippocampus across all animals.

    “All images for this analysis were taken from the same region of the dorsal hippocampus across all animals.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Primary antibodies were selected based on extensive citations by previous studies.

    “The primary antibodies were selected based on extensive citations by previous studies; most of the antibodies used are monoclonal antibodies with minimal non-specific signal and several of them have been validated by KO testing.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    Optimal dose was identified using a dose response ranging from 4E+9 to 1E+11 vector genomes.

    “Optimal dose was identified using a dose response ranging from 4E+9 to 1E+11 vector genomes.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisenone given

    Only a single endogenous protein is depleted in the retromer knockout models, contrasting with many other AD models that often have multiple exogenous proteins transgenically co-expressed at non-physiological levels.

    “Notably, only a single endogenous protein is depleted in these models, which contrasts to many other AD models that often have multiple exogenous proteins transgenically co-expressed at non-physiological levels.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    All animal procedures were approved by Columbia University IACUC.

    “All animal procedures were approved by Columbia University IACUC.”
    Quote in the paperNot a substantial claim
44 of 44

  • The paper relies on this without support.

    VPS35 knockout mice are embryonic lethal.

    “Nevertheless, attempts to model VPS35 depletion in the mammalian brain have been hindered because VPS35 knockout mice are embryonic lethal.”

  • The paper relies on this without support.

    Tau pathology occurs first and foremost in the hippocampus when and where there are relatively few amyloid plaques.

    “and tau pathology occurs first and foremost in the hippocampus when and where there are relatively few amyloid plaques.”

  • The paper relies on this without support.

    AD-associated pathologies begin in neurons.

    “While AD-associated pathologies begin in neurons, Alois Alzheimer himself recognized the importance of both neuronal and glial pathologies”

  • The paper relies on this without support.

    IBA1 and CD11b staining in brain sections reflects microglia rather than peripheral macrophages.

    “these proteins, however, are also expressed in peripheral macrophages.”
4 of 4

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?

  • VPS35 suppression decreased surface levels of GLUT1/SLC2A1, AMPA receptors GRIA2, GRIA3, GRIA4, NMDA receptors GRIN1, GRIN2b, and SLC4A7.

    “Validating our approach, downregulated proteins included the wellestablished Retromer cargo glucose transporter-1 (GLUT1/SLC2A1) [29], the ionotropic glutamate AMPA receptors (GRIA2, GRIA3, GRIA4) and NMDA receptors (GRIN1, GRIN2b) [80][81][82][83][84][85], as well as many other previously identified proteins including the sodium bicarbonate cotransporter-3 (SLC4A7) (Figure 1D, Supplementary Table”

    From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [82]

    The Results section, “The effects of neuronal VPS35 depletion on neurons and glia” (page not provided), reports reduced GluA1, an AMPA receptor subunit, after neuronal VPS35 depletion. It does not report decreased surface levels of the listed GLUT1, GRIA2–4, GRIN1, GRIN2b, or SLC4A7 proteins; its GluA1 result was measured by immunoblotting, not a surface-level assay. (LLM, conf=0.79)

    Experimental — accuracy not yet measured

  • There are several studies linking Retromer dysfunction to changes in AMPA and NMDA receptor expression and activity in neurons.

    “There are several studies linking Retromer dysfunction to changes in AMPA and NMDA receptor expression and activity in neurons [80][81][82][83][84][85].”

    From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [82]

    The Results (page unavailable) report that neuronal VPS35 depletion reduced GluA1, an AMPA receptor subunit, in the mouse hippocampus; VPS35 repletion normalized its levels. The Discussion also links retromer to glutamate-receptor loss, but our copy does not establish a change in NMDA receptor expression or directly measure receptor activity. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Retromer depletion in neurons has been shown to increase gliosis and lead to dysmorphic microglial morphology in mice, phenotypic of the microglial morphology observed in AD patients.

    “Retromer depletion in neurons has been shown to increase gliosis [82,131], and lead to dysmorphic microglial morphology in mice, phenotypic of the microglial morphology observed in AD patients [82].”

    From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [82]

  • Retromer deficiency or dysregulation has been observed in AD brain and can perturb APOE levels; neuronal Vps35 deletion can elevate APOE in mouse CSF and hippocampus, likely through glial activation.

    “Retromer deficiency or dysregulation which has been observed in AD brain (Small, Kent et al. 2005) can also perturb APOE levels, for example neuronal Vps35 deletion can elevate APOE in mouse CSF (Simoes, Neufeld et al. 2020) as well as hippocampus, likely through glial activation observed with neuronal Vps35 deletion (Qureshi, Berman et al. 2022).”

    From SORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain (2026) · cites this paper as Qureshi, Berman et al. 2022

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Self-check results appear here once an independent check has confirmed them.

Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

  • Cites a retracted work: 10.1038/s41380-019-0453-x

    Info

    The cited work was retracted on 2023-01-25 (notice 10.1038/s41380-023-01973-9), not before this paper was published (2022-01).

    Cited work 10.1038/s41380-019-0453-x · retracted 2023-01-25 · notice 10.1038/s41380-023-01973-9 · this paper published 2022-01

  • Cites a retracted work: 10.1038/s41380-019-0364-x

    Info

    The cited work was retracted on 2022-10-18 (notice 10.1038/s41380-022-01814-1), not before this paper was published (2022-01).

    Cited work 10.1038/s41380-019-0364-x · retracted 2022-10-18 · notice 10.1038/s41380-022-01814-1 · this paper published 2022-01

2 of 2

Citations

Cites

2 retracted

Flagged first, then by citations

Research works printed but not linked: 1

  1. Alzheimer, 1906, Über eine eigenartige Erkrankung der Hirnrinde. “A Characteristic Disease of the Cerebral Cortex”, Neurologisches Centralblatt, 25, 1134

Cited by

Sorted by citations

Related

Metadata

Authors
Qureshi, Y. H., Berman, D. E., Marsh, S. E., Klein, R. L., Patel, V. M., Simoes, S., Kannan, S., Petsko, G. A., Stevens, B., & Small, S. A.
Affiliations
  • Columbia University Irving Medical Center (US)
  • Broad Institute (US)
  • Louisiana State University Health Sciences Center Shreveport (US)
  • Brigham and Women's Hospital (US)
Corresponding author
  • Stevens, Beth
  • Small, Scott A.
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2022-01
Volume
38
Issue
3
Pages
110262
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2021.110262
PMC
PMC8830374
OpenAlex
W4206642644
Cited by
31
References
98
Citations by year
2026: 6 · 2025: 5 · 2024: 9 · 2023: 9 · 2022: 2
FWCI
2.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
Funders
  • Amicus Therapeutics
  • National Institutes of Health (AG008702)
  • Columbia University
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
retromer complex, VPS35, Alzheimer's disease, endosomal trafficking, hippocampal neurons, microglia, amyloid precursor protein cleavage
MeSH terms
Alzheimer Disease, Animals, Neurons, Phenotype, Endosomes, Microglia, Protein Transport, Vesicular Transport Proteins, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

A language model drew the claims from the paper on 2026-11-09, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-09 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Cited sources are checked with a language model’s help (gpt-6-sol).

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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