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Cited by 8Alzheimer's disease research and treatmentsCellular transport and secretionNeuroinflammation and Neurodegeneration Mechanisms

The DOI matches its Crossref record; 48 of the 48 references it cites were found in a registry or an index; 32 of the 53 sources its claims cite were checked for support.

Stabilizing the retromer complex rescues synaptic dysfunction and endosomal trafficking deficits in an Alzheimer’s disease mouse model

Open access
Ramonet, David, Daerr, Anna, Hallbeck, Martin·2025·Acta Neuropathologica Communications
DOI 10.1186/s40478-025-02096-8PMC PMC12424221
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Abstract

Disruptions in synaptic transmission and plasticity are early hallmarks of Alzheimer’s disease (AD). Endosomal trafficking, mediated by the retromer complex, is essential for intracellular protein sorting, including the regulation of amyloid precursor protein (APP) processing. The VPS35 subunit, a key cargo-recognition component of the retromer, has been implicated in neurodegenerative diseases, with mutations such as L625P linked to early-onset AD. Despite growing evidence for retromer dysfunction in AD, its role in synaptic pathology and neuroinflammation remains incompletely understood. Here, we investigate the acute molecular effects of retromer stabilization in the 5xFAD mouse model of AD using the pharmacological chaperones R55 and R33, previously identified to enhance VPS35 stability. Following intracranial stereotaxic injections, we performed transcriptomic profiling, quantitative histology, and immunohistochemistry to assess synaptic function, neuroinflammation, and endosomal trafficking. Our findings reveal that retromer stabilization reverses multiple AD-associated molecular changes. R55 treatment significantly reduced Aβ-related pathology, normalized synaptic gene expression, and restored long-term potentiation (LTP)-associated pathways, including Gria1 (AMPA receptors), Grip1, and semaphorin/plexin signaling. Additionally, retromer stabilization counteracted dysregulated calcium signaling by modulating Ryr2 and L-type calcium channel expression. Beyond synaptic effects, we observed broad transcriptional and structural changes in the endosomal system. Notably, R55 treatment decreased VPS13 family gene expression, implicated in membrane contact site regulation, while increasing RAB7 levels, suggesting enhanced late-endosomal recycling. VPS35-positive vesicles were redistributed away from the nucleus, indicating restored intracellular trafficking dynamics. In the neuroinflammatory domain, retromer stabilization modulated microglial activation, shifting towards a profile characterized by balanced pro-inflammatory (Il1, Nfkb2) and anti-inflammatory (Il4r, Il13ra1, Stat6) markers, consistent with disease-associated microglia (DAM) phenotypes. Together, these findings demonstrate that retromer dysfunction contributes to key AD pathologies, including synaptic dysfunction and neuroinflammation, and that pharmacological retromer stabilization can restore cellular homeostasis. Given that 5xFAD mice lack direct VPS35 mutations, our results suggest that retromer-targeting strategies may be applicable to both familial and sporadic AD, offering a promising therapeutic avenue for modifying disease progression.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In 16-week-old female 5xFAD mice, acute intracranial retromer stabilization with R55 or R33 reversed multiple AD-associated transcriptional and endosomal-trafficking changes 24 h after injection. R55 had stronger effects than R33, normalizing synaptic/LTP-related genes, calcium-handling genes, VPS13/RAB7 endosomal markers, and microglial activation signatures.

Key findings

  • R55 treatment significantly altered 218 of 19,646 detected genes (1.10%) versus vehicle; R33 altered 19 genes (0.10%), and R55 vs R33 differed in only 11 genes (0.05%), suggesting shared mechanism with stronger R55 effects.
  • R55 normalized synaptic and LTP-associated pathways, including Gria1, Grip1, and semaphorin/plexin signaling, and counteracted dysregulated calcium signaling via Ryr2 and L-type calcium channel expression.
  • Retromer stabilization reduced VPS13 family gene expression, increased RAB7 levels, and redistributed VPS35-positive vesicles away from the nucleus; SORL1 particle size and distribution were also normalized.
  • R55 modulated microglial activation toward a profile with balanced pro-inflammatory (Il1, Nfkb2) and anti-inflammatory (Il4r, Il13ra1, Stat6) markers, consistent with disease-associated microglia (DAM) phenotypes.

Methods

  • 16-week-old female 5xFAD/C57BL6 mice received stereotaxic intracranial injections of R55, R33, or vehicle into the lateral parietal associative cortex (500 nL at 100 nL/min; estimated final cortical concentration ~25 µM).
  • Transcriptomic profiling used n = 6 mice per treatment group, with RNA-seq, HISAT2 alignment to GRCm39, and DESeq2 differential expression; histology used an independent cohort of n = 3 per treatment with immunohistochemistry for VPS35, RAB7, VPS13b, SORL1, and IBA1.
  • Analyses included pathway enrichment, comparison with MODEL-AD and cLTP/DAM reference datasets, QuPath-based neuronal segmentation, and ImageJ DiAna particle analysis.

Limitations

  • Stated: the study focuses on acute molecular effects 24 h post-injection, so long-term effects on memory, cognition, and synaptic plasticity can only be speculated; proteomic confirmation and pharmacokinetic/pharmacodynamic data are lacking.
  • Stated: further studies are needed to confirm whether the identified changes have long-term positive or negative effects.
  • Evident from the text: experiments used only 16-week-old female 5xFAD mice, and the acute design does not test behavioral or disease-progression outcomes.

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

Integrity signals

Registry

Crossref · 10.1186/s40478-025-02096-8

Cites

48 of 48 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

32 of 53 cited sources checked · 7 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Disruption in cargo selection can significantly impact synaptic function because synaptic receptors undergo rapid turnover via endocytosis.

    “Given the rapid turnover of synaptic receptors via endocytosis, any disruption in cargo selection can significantly impact synaptic function [13].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [13] Hafner AS, Triesch J (2023) Synaptic logistics: competing over shared resources. Mol Cell Neurosci 125:103858. https://doi.org/10.1016/j.mcn.2023.103858 source

      Section 4, “Resource bottlenecks for synaptic function” (page not provided), says glutamate receptors have among the fastest turnover rates of postsynaptic proteins and that disruptions to their supply could significantly affect responses to neurotransmitter release. It does not say that this turnover occurs via endocytosis or specifically link disrupted cargo selection to impaired synaptic function. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Findingcitation

    No significant changes were observed in transcriptional markers of the TFEB/TFE3 axis and lysosomal degradation, such as ATG7, ATG14, WIPI1, ULK1, ULK2, or SQSTM1.

    “No significant changes were observed in transcriptional markers of this pathway, such as ATG7, ATG14, WIPI1, ULK1, ULK2, or SQSTM1 [44], supporting the interpretation that lysosomal biogenesis was not enhanced after R55 treatment.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [44] Xiao FH, Chen XQ, Yu Q, Ye Y, Liu YW, Yan D, Yang LQ, Chen G, Lin R, Yang L et al (2018) Transcriptome evidence reveals enhanced autophagy-lysosomal function in centenarians. Genome Res 28:1601–1610. https://doi.org/10.1101/gr.220780.117 source

      The Results section on overexpression of autophagy-lysosomal genes identifies WIPI1 as an autophagosome component and SQSTM1 as a marker of autophagic degradation. The paper does not establish that the listed genes showed no significant transcriptional changes, nor does it assess their response to R55 treatment; its centenarian comparison instead reports up-regulation of autophagy-lysosomal genes. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
  • Premisecitation

    In vitro, R55 and R33 increased VPS35 and VPS26 protein levels in mouse primary cortical neurons.

    “In vitro, these compounds increased VPS35 and VPS26 protein levels in mouse primary cortical neurons and reduced APP processing, lowering endogenous Aβ42 and Aβ40 levels at low micromolar concentrations (5 µM) [26].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [26] Mecozzi VJ, Berman DE, Simoes S, Vetanovetz C, Awal MR, Patel VM, Schneider RT, Petsko GA, Ringe D, Small SA (2014) Pharmacological chaperones stabilize retromer to limit APP processing. Nat Chem Biol 10:443–449. https://doi.org/10.1038/nchembio.1508 source

      The Results section, “Pharmacological chaperones increase retromer in neurons,” reports that R55 increased both Vps35 and Vps26 protein levels, while R33 increased Vps35; it does not report an increase in Vps26 with R33. The Online Methods section, “Neuronal cultures,” identifies cortical neurons as the cultures used for western blot assays. Page numbers are unavailable in our copy. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
  • Premisecitation

    The retromer complex influences APP processing by directing its trafficking within the endosomal system.

    “The retromer complex influences APP processing by directing its trafficking within the endosomal system, and alterations in this pathway precede Aβ deposition in AD [9].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [9] Cataldo AM, Peterhoff CM, Troncoso JC, Gomez-Isla T, Hyman BT, Nixon RA (2000) Endocytic pathway abnormalities precede amyloid β deposition in sporadic Alzheimer’s disease and Down syndrome. Am J Pathol 157:277–286. https://doi.org/10.1016/S0002-9440(10)64538-5 source

      The paper’s opening summary reports endosomal abnormalities at preclinical stages of sporadic AD, when Aβ deposition was restricted to the entorhinal region. Its discussion also links early endosomes to APP processing, but neither passage identifies a retromer complex or says it directs APP trafficking. No page number is supplied for these passages. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Findingcitation

    Of Ryr2-associated regulators, only Jph4 showed a weak response to R55.

    “Of Ryr2-associated regulators [38], only Jph4 showed a weak response to R55”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [38] Takeshima H, Hoshijima M, Song L-S (2015) Ca2+ microdomains organized by junctophilins. Cell Calcium 58:349–356. https://doi.org/10.1016/j.ceca.2015.01.007 source
  • Probably not a substantial claim. 24
  • It may state two separate claims as one. 41
  • The quote only partly states this claim. 1

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

    Premisecitation

    In Alzheimer's disease, beta-amyloid (Aβ) accumulates within synapses, impairing neurotransmitter release, receptor signalling, and dendritic spine stability, strongly implicating Aβ in synaptic pathology.

    “In AD, beta-amyloid (Aβ) accumulates within synapses, impairing neurotransmitter release, receptor signalling, and dendritic spine stability, strongly implicating Aβ in synaptic pathology [7, 28].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [7] Bukke VN, Archana M, Villani R, Romano AD, Wawrzyniak A, Balawender K, Orkisz S, Beggiato S, Serviddio G, Cassano T (2020) The dual role of glutamatergic neurotransmission in Alzheimer’s disease: from pathophysiology to pharmacotherapy. Int J Mol Sci 21:7452. https://doi.org/10.3390/ijms21207452 source

      The Introduction reports Aβ species at synapses and describes their synaptotoxic effects. Section 3.3 links Aβ to altered receptor signalling and dendritic spine collapse. However, it says Aβ enhances glutamate release from presynaptic neurons rather than impairing neurotransmitter release. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [28] Meftah S, Gan J (2023) Alzheimer’s disease as a synaptopathy: evidence for dysfunction of synapses during disease progression. Front Synaptic Neurosci. https://doi.org/10.3389/fnsyn.2023.1129036 source

      Section 4 reports that Aβ affects NMDA receptors and synaptic vesicle dynamics, and that dendritic spines are lost near amyloid plaques in mouse models. It does not establish that Aβ accumulates within synapses in people with Alzheimer’s disease; its location-specific evidence concerns plaques near synapses, not Aβ within them. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

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

    Premisecitation

    The VPS35 D620N mutation is linked to autosomal dominant Parkinson's disease (PARK17).

    “Mutations in VPS35, such as D620N, are linked to autosomal dominant Parkinson’s disease (PARK17) [42, 46]”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [42] Vilariño-Güell C, Wider C, Ross OA, Dachsel JC, Kachergus JM, Lincoln SJ, Soto-Ortolaza AI (2011) VPS35 mutations in Parkinson disease. Am J Hum Genet 89:162–167. https://doi.org/10.1016/j.ajhg.2011.06.001 source

      The Abstract links VPS35 p.Asp620Asn (D620N) to an autosomal-dominant Parkinson disease kindred and reports the mutation in additional affected families. Our copy does not identify this condition as PARK17; a search for that designation found no passage supporting that part of the claim. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [46] Zimprich A, Benet-Pagès A, Struhal W, Graf E, Eck SH, Offman MN, Haubenberger D (2011) A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease. Am J Hum Genet 89:168–175. https://doi.org/10.1016/j.ajhg.2011.06.008 source

      The Abstract reports that VPS35 p.Asp620Asn (D620N) cosegregated with late-onset Parkinson disease in three families, including autosomal-dominant inheritance. Our copy does not use the PARK17 designation, so it does not verify that part of the claim. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    VPS35 regulates retromer assembly, stability, and cargo recognition.

    “A key component of the retromer complex is VPS35, which regulates its assembly, stability, and cargo recognition [6].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [6] Bonifacino JS, Hurley JH (2008) Retromer. Curr Opin Cell Biol 20:427–436. https://doi.org/10.1016/j.ceb.2008.03.009 source

      The Introduction (page unavailable) describes Vps35 binding Vps26 and Vps29, and reports cargo binding to Vps35, supporting its roles in retromer assembly and cargo recognition. It does not establish that Vps35 regulates retromer stability; the discussion of complex stability points instead to possible stabilization by cargo tails. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim.

    Premisecitation

    The endolysosomal pathway is crucial for intracellular trafficking including cell membrane vesicle transport and recycling.

    “The endolysosomal pathway is crucial for intracellular trafficking including cell membrane vesicle transport and recycling [31].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [31] Neel E, Chiritoiu-Butnaru M, Fargues W, Denus M, Colladant M, Filaquier A, Stewart SE, Lehmann S, Zurzolo C, Rubinsztein DC et al (2024) The endolysosomal system in conventional and unconventional protein secretion. J Cell Biol. https://doi.org/10.1083/jcb.202404152 source

  • Probably not a substantial claim.

    Premisecitation

    The effect of R55 and R33 is primarily by restoring the function and localization of the retromer complex.

    “It is now believed that the effect of R55 and R33 is primarily by restoring the function and localization of the retromer complex [10].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [10] Follett J, Bugarcic A, Yang Z, Ariotti N, Norwood SJ, Collins BM, Parton RG, Teasdale RD (2016) Parkinson disease-linked Vps35 R524W mutation impairs the endosomal association of retromer and induces alpha-synuclein aggregation. J Biol Chem 291:18283–18298. https://doi.org/10.1074/jbc.M115.703157 source

      The results on Vps35 mutant localization (Fig. 5) show that R55 increased endosomal localization and membrane recruitment of R524W-containing retromer, though it did not fully restore membrane levels. The Discussion suggests a possible mechanism for that effect, but our copy does not establish that restoring retromer function and localization is the primary mechanism of both agents; a search for R33 found no passage addressing it. (LLM, conf=0.86)

      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

    Previous studies have shown a stagnation of large endosomes both in AD and in 5xFAD and impaired recycling pathway in 5xFAD in mice of almost the same age.

    “Previous studies have shown a stagnation of large endosomes both in AD and in 5xFAD [9, 24] and impaired recycling pathway, in 5xFAD in mice of almost the same age [24].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [9] Cataldo AM, Peterhoff CM, Troncoso JC, Gomez-Isla T, Hyman BT, Nixon RA (2000) Endocytic pathway abnormalities precede amyloid β deposition in sporadic Alzheimer’s disease and Down syndrome. Am J Pathol 157:277–286. https://doi.org/10.1016/S0002-9440(10)64538-5 source
    • cites [24] Mariani MM, Malm T, Lamb R, Jay TR, Neilson L, Casali B, Medarametla L, Landreth GE (2017) Neuronally-directed effects of RXR activation in a mouse model of Alzheimer’s disease. Sci Rep 7:42270. https://doi.org/10.1038/srep42270 source

      The Results section reports accumulation of APP-related proteins and SORLA in four-month-old 5XFAD neurons, which the authors interpret as impaired protein processing and vesicular trafficking. The Discussion describes generalized endolytic dysregulation. Neither passage establishes that large endosomes stagnate or that the recycling pathway specifically is impaired; the separate claim about AD is also cited to another source. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Vps35 KO impaired microglial activation in response to Aβ.

    “Similarly, Vps35 KO impaired microglial activation in response to Aβ [33].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [33] Ren X, Yao L, Wang Y, Mei L, Xiong W-C (2022) Microglial VPS35 deficiency impairs Aβ phagocytosis and Aβ-induced disease-associated microglia, and enhances Aβ associated pathology. J Neuroinflammation 19:61. https://doi.org/10.1186/s12974-022-02422-0 source

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

    Premisecitation

    The retromer complex plays a role in microglial function, influencing microglial activation states that are critical in Alzheimer's disease pathogenesis.

    “Interestingly, the retromer complex also plays a role in microglial function, influencing microglial activation states that are critical in AD pathogenesis [33].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [33] Ren X, Yao L, Wang Y, Mei L, Xiong W-C (2022) Microglial VPS35 deficiency impairs Aβ phagocytosis and Aβ-induced disease-associated microglia, and enhances Aβ associated pathology. J Neuroinflammation 19:61. https://doi.org/10.1186/s12974-022-02422-0 source

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

    Interpretationcitation

    This coordinated shift in crosstalk between microglial polarization and astrocytic responses mirrors findings reported in other AD studies.

    “This coordinated shift in crosstalk between microglial polarization and astrocytic responses mirrors findings reported in other AD studies [45].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [45] Xie L, Zhang N, Zhang Q, Li C, Sandhu AF, Iii GW, Lin S (2020) Inflammatory factors and amyloid β-induced microglial polarization promote inflammatory crosstalk with astrocytes. Aging. https://doi.org/10.18632/aging.103663 source

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

    Premisecitation

    The D620N mutation disrupts VPS35 binding to WASH complex proteins, affecting actin nucleation, while AD-linked VPS35 mutations (e.g., L625P) impair VPS35-VPS26-VPS29 assembly.

    “The D620N mutation disrupts VPS35 binding to WASH complex proteins, affecting actin nucleation, while AD-linked VPS35 mutations (e.g., L625P) impair VPS35-VPS26-VPS29 assembly [25, 34].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [25] McGough IJ, Steinberg F, Jia BPA, McMillan KJ, Heesom KJ, Whone AL (2014) Retromer binding to FAM21 and the WASH complex Is perturbed by the Parkinson disease-linked VPS35(D620N) mutation. Curr Biol 24:1670–1676. https://doi.org/10.1016/j.cub.2014.06.024 source

      The Comparative Interactome Analysis and FAM21 In Vitro sections report reduced binding of VPS35(D620N) to the actin-nucleating WASH complex. They do not establish that actin nucleation itself was altered. The paper does not address the AD-linked L625P assembly claim; its heterotrimer result concerns D620N, which retains VPS26–VPS29 binding. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [34] Rovelet-Lecrux A, Charbonnier C, Wallon D, Nicolas G, Seaman MNJ, Pottier C, Breusegem SY (2015) De novo deleterious genetic variations target a biological network centered on Aβ peptide in early-onset Alzheimer disease. Mol Psychiatry 20:1046–1056. https://doi.org/10.1038/mp.2015.100 source

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

    Premisecitation

    Sorl1 distribution is altered both in APP overexpressing AD models such as 5xFAD and in Sorl1 mutations linked to AD pathology.

    “Sorl1 distribution that has been reported to be altered both in APP overexpressing AD models such as 5xFAD and in Sorl1 mutations that have been linked to AD pathology [29].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [29] Mishra S, Knupp A, Kinoshita C, Williams CA, Rose SE, Martinez R, Theofilas P, Young JE (2023) Pharmacologic enhancement of retromer rescues endosomal pathology induced by defects in the Alzheimer’s gene SORL1. Stem Cell Reports 18:2434–2450. https://doi.org/10.1016/j.stemcr.2023.10.011 source

      The Results section identifies SORL1 variants associated with increased Alzheimer’s disease risk. It reports altered localization of APP and VPS35 in SORL1-deficient neurons, not altered distribution of SORL1 itself; our copy also does not report a 5xFAD or other APP-overexpressing model. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    R55 enhances VPS35 assembly without affecting WASH binding.

    “Notably, R55 enhances VPS35 assembly without affecting WASH binding [4].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [4] Berman DE, Ringe D, Petsko GA, Small SA (2015) The use of pharmacological retromer chaperones in Alzheimer’s disease and other endosomal-related disorders. Neurotherapeutics 12:12–18. https://doi.org/10.1007/s13311-014-0321-y source

      The ‘Small Molecules as Retromer Chaperones’ section reports that R55 stabilizes the retromer complex and increases its levels in hippocampal neurons, supporting the assembly-related point. The ‘Retromer in Other Diseases’ section discusses impaired WASH binding caused by a VPS35 mutation, but does not say whether R55 affects WASH binding. Page numbers were not provided in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Premisecitation

    The estimated final cortical concentration of R55/R33 after a 500 nL injection exceeds the estimated dissociation constant for VPS35 stabilization (~5 μM) and the IC50 for Aβ reduction (~12 μM) in primary neurons.

    “This concentration exceeds the estimated dissociation constant (Kd) for VPS35 stabilization (~ 5 µM) and the IC₅₀ for Aβ reduction (~ 12 µM) in primary neurons, as previously described (Mecozzi et al., 2014).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Mecozzi et al., 2014 source
    • The authors state this as an assumption: The final cortical concentration of R55/R33 after a 500 nL injection is approximately 25 µM, assuming homogeneous distribution.

  • It may state two separate claims as one.

    Premisecitation

    VPS35 dysfunction leads to increased Aβ production and exosomal release.

    “VPS35 dysfunction leads to APP accumulation in early endosomes, increased Aβ production and exosomal release, and enlarged axonal endosomes [9, 16, 20].”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [9] Cataldo AM, Peterhoff CM, Troncoso JC, Gomez-Isla T, Hyman BT, Nixon RA (2000) Endocytic pathway abnormalities precede amyloid β deposition in sporadic Alzheimer’s disease and Down syndrome. Am J Pathol 157:277–286. https://doi.org/10.1016/S0002-9440(10)64538-5 source

      The Discussion (page unavailable) reports increased Aβ secretion from cell lines with enhanced hydrolase trafficking to early endosomes. It does not identify VPS35 dysfunction as the cause or describe exosomal release, so it supports only the broader Aβ-related part of the claim. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [16] Jiang Y, Rigoglioso A, Peterhoff CM, Pawlik M, Sato Y, Bleiwas C, Stavrides P (2016) Partial BACE1 reduction in a Down syndrome mouse model blocks Alzheimer-related endosomal anomalies and cholinergic neurodegeneration: role of APP-CTF. Neurobiol Aging. https://doi.org/10.1016/j.neurobiolaging.2015.11.013 source

      The Introduction discusses APP processing and endosomal dysfunction, and the Results describe enlarged early endosomes in Down syndrome mice. Searches for VPS35, retromer dysfunction, and exosomal release found no passage linking VPS35 dysfunction to increased Aβ production or exosomal release; the cited paper therefore does not verify the attributed claim. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites [20] Kim S, Sato Y, Mohan PS, Peterhoff C, Pensalfini A, Rigoglioso A, Jiang Y, Nixon RA (2016) Evidence that the Rab5 effector APPL1 mediates APP-βCTF-induced dysfunction of endosomes in Down syndrome and Alzheimer’s disease. Mol Psychiatry 21:707–716. https://doi.org/10.1038/mp.2015.97 source

      The Discussion identifies lowered VPS35 as a possible contributor to rab5 endosome dysfunction, but does not say it increases Aβ production or exosomal release. Searches for VPS35 with Aβ production and exosomal release found no passage in our copy establishing either claimed effect. (LLM, conf=0.73)

      Experimental — accuracy not yet measured

  • It may state two separate claims as one.

    Findingown data

    Both R55 and R33 modulated gene expression in the same direction, with R55 exerting stronger effects.

    “Notably, a volcano plot of WP2075 genes (Fig. 2F) confirmed that both R55 and R33 modulated gene expression in the same direction, with R55 exerting stronger effects.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    The AD-related pathway WP2075 was significantly altered, along with synaptic organization pathways and other CNS-related phenotypes.

    “The AD-related pathway WP2075 was significantly altered, along with synaptic organization pathways and other CNS-related phenotypes.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Network analysis of the R55-regulated genes identified 247 interactions with an average node degree of 2.38, significantly exceeding the expected 101 interactions from a random dataset (p = 1.10e-16).

    “Network analysis of the R55-regulated genes identified 247 interactions with an average node degree of 2.38 (Fig. 2B), significantly exceeding the expected 101 interactions from a random dataset (p = 1.10e-16), demonstrating that R55 selectively modulates interconnected pathways.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. The quote only partly states this claim.

    Findingown data

    Immunohistochemistry of the R55 microinjected cortex revealed an increase in RAB7 protein levels.

    “an increase in RAB7 and VPS35 protein levels remained unchanged (Fig. 6), all consistent with the gene expression results.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    In R55-treated mice, VPS35-positive vesicles formed dense clusters and were significantly shifted away from the nucleus.

    “However, in R55-treated mice, VPS35-positive vesicles formed dense clusters and were significantly shifted away from the nucleus (Fig. 6), indicative of enhanced or restored endosomal maturation, potentially driven by normalized expression of VPS13 and RAB7.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingnone given

    R55 treatment increased γ-secretase components while reducing Sorl1 and Col25a1 expression.

    “R55 treatment increased γ-secretase components while reducing Sorl1 and Col25a1 expression.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The effect was largely specific to AD-related pathways, as genes from the Parkinson's disease-associated WP2371 pathway showed minimal changes, with none reaching significance in the R55 vs. vehicle comparison.

    “This effect was largely specific to AD-related pathways, as genes from the Parkinson’s disease-associated WP2371 pathway showed minimal changes, with none reaching significance in the R55 vs. vehicle comparison.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    We have identified a range of retromer-regulated cargos, including membrane receptors and synaptic proteins, that are dysregulated in early AD and restored by retromer stabilization.

    “We have identified a range of retromer-regulated cargos, including membrane receptors and synaptic proteins, that are dysregulated in early AD and restored by retromer stabilization.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingnone given

    R55 treatment increased both pro-inflammatory mediators (Il1, Nfkb2) and pro-trophic glial markers (Il4r, Il13ra1), as well as downstream anti-inflammatory transcription factors (Stat6, Stat3).

    “In the neuroinflammatory domain, R55 treatment increased both pro-inflammatory mediators (Il1, Nfkb2) and pro-trophic glial markers (Il4r, Il13ra1), as well as downstream anti-inflammatory transcription factors (Stat6, Stat3).”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Core retromer proteins (Vps35, Vps26a, Vps29) remained unchanged following R55 treatment and during disease progression (MODEL-AD).

    “Interestingly, core retromer proteins (Vps35, Vps26a, Vps29) remained unchanged following R55 treatment and during disease progression (MODEL-AD), but their known cargos and associated proteins showed widespread alterations.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    In vehicle-treated brains, the main peak of distance from the nuclear envelope is at 5.2 μm, with a second maximum at 1.7 μm consisting of larger particle sizes.

    “When measuring the distance from the nuclear envelope, the main peak is at 5.2 μm, there is a second maximum at 1.7 μm consisting of larger particle sizes.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    Retromer stabilization modulated microglial activation, shifting towards a profile characterized by balanced pro-inflammatory (Il1, Nfkb2) and anti-inflammatory (Il4r, Il13ra1, Stat6) markers, consistent with disease-associated microglia (DAM) phenotypes.

    “In the neuroinflammatory domain, retromer stabilization modulated microglial activation, shifting towards a profile characterized by balanced pro-inflammatory (Il1, Nfkb2) and anti-inflammatory (Il4r, Il13ra1, Stat6) markers, consistent with disease-associated microglia (DAM) phenotypes.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Immunohistochemistry confirmed that Vps13 protein levels decreased following R55 treatment, while RAB7 expression increased.

    “Immunohistochemistry confirmed that Vps13 protein levels decreased following R55 treatment, while RAB7 expression increased”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The model that includes both MODEL-AD and microglial activation has a better AIC and is significantly better than the others (likelihood ratio test vs. MODEL-AD alone: p = 0.003).

    “The model that includes both MODEL-AD and microglial activation has a better AIC and is significantly better than the others (likelihood ratio test vs. MODEL-AD alone: p = 0.003).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    In vehicle-treated brains almost half of the particles are less than 1 μm from the nuclear envelope, while in R55-treated brains only 20% of the particles remain at this close position.

    “Furthermore, in the vehicle-treated brains almost half of the particles (5th contour line on the overlap) are less than 1 μm from the nuclear envelope while in the R55-treated brains, only 20% of the particles (3rd contour line on the overlap) remain at this close position.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    logFC.m4, log2FC.DAMfromHOM, and log2FC.DAM2fromDAM1 each contribute significantly to the model.

    “logFC.m4, log2FC.DAMfromHOM, log2FC.DAM2fromDAM1 contribute significant separately”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    R33 treatment resulted in 19 differentially expressed genes (0.10%), with most showing changes similar to R55 but of lower magnitude.

    “R33 treatment resulted in 19 differentially expressed genes (0.10%), with most showing changes similar to R55 but of lower magnitude.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The VPS35 L625P variant has been associated with early-onset Alzheimer's disease.

    “while the L625P variant has been associated with early-onset AD [34].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Rovelet-Lecrux A, Charbonnier C, Wallon D, Nicolas G, Seaman MNJ, Pottier C, Breusegem SY (2015) De novo deleterious genetic variations target a biological network centered on Aβ peptide in early-onset Alzheimer disease. Mol Psychiatry 20:1046–1056. https://doi.org/10.1038/mp.2015.100 source

  • It may state two separate claims as one.

    Interpretationreasoning

    Functional changes to the retromer occur not through expression changes, with extensive effects on the endosomal system and many AD-related cellular pathways.

    “This implies functional changes to the retromer that are not through expression changes, that has extensive effects on the endosomal system and many AD related cellular pathways.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Aβ colocalizes with VPS35-positive endosomes.

    “with Aβ colocalizing with VPS35-positive endosomes [1].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Ansell-Schultz A, Reyes JF, Samuelsson M, Hallbeck M (2018) Reduced retromer function results in the accumulation of amyloid-beta oligomers. Mol Cell Neurosci 93:18–26. https://doi.org/10.1016/j.mcn.2018.09.003 source

  • It may state two separate claims as one.

    Interpretationown data

    The redistribution of VPS35-positive vesicles is indicative of enhanced or restored endosomal maturation, potentially driven by normalized expression of VPS13 and RAB7.

    “indicative of enhanced or restored endosomal maturation, potentially driven by normalized expression of VPS13 and RAB7.”
    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

    Researchers were blinded to treatment identity until the completion of data analysis.

    “Tissue assignments for drug or vehicle treatment were randomized, and researchers were blinded to treatment identity until the completion of data analysis.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Premisecitation

    Dysfunctional retromer linked to neurodegenerative diseases is not primarily caused by loss of expression of Vps35 but by decreased endosomal association causing loss of function that can be mitigated by retromer stabilizing compounds such as R55 and R33.

    “Our results supports previous reports that dysfunctional retromer linked to neurodegenerative diseases is not primarily caused by loss of expression of Vps35 but by decreased endosomal association causing loss of function that can be mitigated by retromer stabilizing compounds such as R55 and R33 [10].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Follett J, Bugarcic A, Yang Z, Ariotti N, Norwood SJ, Collins BM, Parton RG, Teasdale RD (2016) Parkinson disease-linked Vps35 R524W mutation impairs the endosomal association of retromer and induces alpha-synuclein aggregation. J Biol Chem 291:18283–18298. https://doi.org/10.1074/jbc.M115.703157 source

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

  • It may state two separate claims as one.

    Interpretationown data

    The decrease in Vps13 and increase in RAB7 suggests restored endosomal maturation.

    “this suggests restored endosomal maturation.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Aβ oligomers increase cholesterol concentration at synapses, promoting Aβ/PrP complexes that disrupt NMDAR signaling via GRIN2a/GRIN2b S-nitrosylation.

    “Aβ oligomers increase cholesterol concentration at synapses, promoting Aβ/PrP complexes that disrupt NMDAR signaling via GRIN2a/GRIN2b S-nitrosylation [3].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Benarroch EE (2018) Glutamatergic synaptic plasticity and dysfunction in Alzheimer disease: emerging mechanisms. Neurology 91:125–132. https://doi.org/10.1212/WNL.0000000000005807 source

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

    Premisecitation

    The Vps13 complex regulates endosomal recycling towards the Golgi, mitochondria, and autophagosomes by promoting organelle bilayer bridging, and has been implicated in mitochondrial dysfunction in neurodegenerative diseases, including atypical PARK23.

    “The Vps13 complex regulates endosomal recycling towards the Golgi, mitochondria, and autophagosomes by promoting organelle bilayer bridging, and has been implicated in mitochondrial dysfunction in neurodegenerative diseases, including atypical PARK23 [40].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Ugur B, Hancock-Cerutti W, Leonzino M, Camilli P (2020) Role of VPS13, a protein with similarity to ATG2, in physiology and disease. Current Opin Genet Dev. https://doi.org/10.1016/j.gde.2020.05.027 source

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

  • It may state two separate claims as one.

    Interpretationown data

    Retromer dysfunction contributes to key Alzheimer's disease pathologies, including synaptic dysfunction and neuroinflammation.

    “Together, these findings demonstrate that retromer dysfunction contributes to key AD pathologies, including synaptic dysfunction and neuroinflammation, and that pharmacological retromer stabilization can restore cellular homeostasis.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    RyRs interact functionally with L-type calcium channels (Cacna1c, Cacna1d, Cacna1e), particularly in CA1 pyramidal neurons, where calcium-induced calcium release contributes to synaptic plasticity.

    “Furthermore, RyRs interact functionally with L-type calcium channels (Cacna1c, Cacna1d, Cacna1e), particularly in CA1 pyramidal neurons, where calcium-induced calcium release contributes to synaptic plasticity [35].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Sahu G, Turner RW (2021) The molecular basis for the calcium-dependent slow afterhyperpolarization in CA1 hippocampal pyramidal neurons. Front Physiol. https://doi.org/10.3389/fphys.2021.759707 source

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

  • It may state two separate claims as one.

    Interpretationreasoning

    Retromer stabilization influences not only endosomal cargo selection but also endosomal anchoring to other organelles.

    “Our findings suggest that retromer stabilization influences not only endosomal cargo selection but also endosomal anchoring to other organelles.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim.

    Interpretationreasoning

    Retromer stabilization could mitigate disease progression.

    “raising the possibility that retromer stabilization could mitigate disease progression.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    There is limited understanding of the therapeutic potential of retromer stabilization in in vivo Alzheimer's disease models, exacerbated by the retraction of several key publications in the field.

    “However, despite these promising results, there is limited understanding of the therapeutic potential of retromer stabilization in in vivo AD models, exacerbated by the retraction of several key publications in the field [22, 41].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] Li J-G, Chiu J, Praticò D (2023) Retraction note to: full recovery of the Alzheimer’s disease phenotype by gain of function of vacuolar protein sorting 35. Mol Psychiatry 28:965–965. https://doi.org/10.1038/s41380-022-01814-1 source
    • cites [41] Vagnozzi AN (2023) Retraction note: VPS35 regulates Tau phosphorylation and neuropathology in Tauopathy. Mol Psychiatry 28:1828–1828. https://doi.org/10.1038/s41380-023-01973-9 source

  • It may state two separate claims as one.

    Premisecitation

    Loss of VPS35 impairs Gria1 (AMPA) receptor insertion and disrupts LTP, while restoring VPS35 reverses these deficits.

    “Loss of VPS35 impairs Gria1 (AMPA) receptor insertion and disrupts LTP, while restoring VPS35 reverses these deficits [39].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [39] Temkin P, Morishita W, Goswami D, Arendt K, Chen L, Malenka R (2017) The retromer supports AMPA receptor trafficking during LTP. Neuron 94(74–82):75. https://doi.org/10.1016/j.neuron.2017.03.020 source

  • It may state two separate claims as one.

    Interpretationreasoning

    The normalization of Gria1 and Grip1 expression is significant because Grip1 is essential for AMPA receptor endosomal sorting and membrane targeting.

    “the latter being essential for AMPA receptor endosomal sorting and membrane targeting.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Grip1 is essential for AMPA receptor endosomal sorting and membrane targeting.

  • It may state two separate claims as one.

    Interpretationown data

    Retromer dysfunction can contribute to many AD related alterations and retromer stabilizing drugs have the potential to counteract these effects.

    “Although our results suggests that retromer dysfunction can contribute to many AD related alterations and that the retromer stabilizing drugs have the potential to counteract these effects, further studies are needed to confirm these findings.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    SORL1 expression has a reciprocal role to prototypical cargos such as transferrin in cell surface recycling.

    “SORL1 expression has been shown to have a reciprocal role prototypical cargos such as transferrin to in cell surface recycling [30].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Mishra S, Knupp A, Szabo MP, Williams CA, Kinoshita C, Hailey DW, Wang Y, Andersen OM, Young JE (2022) The Alzheimer’s gene SORL1 is a regulator of endosomal traffic and recycling in human neurons. Cell Mol Life Sci 79:162. https://doi.org/10.1007/s00018-022-04182-9 source

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

    Study design and conductnone given

    Tissue assignments for drug or vehicle treatment were randomized.

    “Tissue assignments for drug or vehicle treatment were randomized, and researchers were blinded to treatment identity until the completion of data analysis.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Genetic variations in VPS13 genes are emerging risk factors for sporadic, late-onset AD, with VPS13 variants exceeding even ApoE in risk contribution.

    “Genetic variations in VPS13 genes are emerging risk factors for sporadic, late-onset AD, with VPS13 variants exceeding even ApoE in risk contribution [27].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Meda SA, Narayanan B, Liu J, Perrone-Bizzozero NI, Stevens MC, Calhoun VD, Glahn DC (2012) A large scale multivariate parallel ICA method reveals novel imaging-genetic relationships for Alzheimer’s disease in the ADNI cohort. Neuroimage 60:1608–1621. https://doi.org/10.1016/j.neuroimage.2011.12.076 source

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

  • It may state two separate claims as one.

    Premisecitation

    The neuronal ryanodine receptor (Ryr2) is overactivated in AD, leading to enhanced receptor-operated calcium entry and decreased buffering capacity.

    “The neuronal ryanodine receptor (Ryr2) is overactivated in AD, leading to enhanced receptor-operated calcium entry and decreased buffering capacity [18, 21].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [18] Kelliher M, Fastbom J, Cowburn RF, Bonkale W, Ohm TG, Ravid R, Sorrentino V, O’Neill C (1999) Alterations in the ryanodine receptor calcium release channel correlate with Alzheimer’s disease neurofibrillary and beta-amyloid pathologies. Neuroscience 92:499–513. https://doi.org/10.1016/s0306-4522(99)00042-1 source
    • cites [21] Lacampagne A, Liu X, Reiken S, Bussiere R, Meli AC, Lauritzen I, Teich AF (2017) Post-translational remodeling of ryanodine receptor induces calcium leak leading to Alzheimer’s disease-likepathologies and cognitive deficits. Acta Neuropathol 134:749–767. https://doi.org/10.1007/s00401-017-1733-7 source

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

    Study design and conductown data

    All samples had an RNA integrity number (RIN) exceeding 8.5.

    “RNA integrity was assessed using Bioanalyzer RNA 6000 Nano Chips (Agilent), and all samples had an RNA integrity number (RIN) exceeding 8.5.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    Stabilizing the retromer complex enhances endosomal recycling, synaptic receptor trafficking, and microglial activation states.

    “and that stabilizing the retromer complex enhances endosomal recycling, synaptic receptor trafficking, and microglial activation states.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Interpretationreasoning

    The observed redistribution of VPS35-positive vesicles away from the nucleus suggests that endosomes are repositioned towards the plasma membrane, likely improving membrane protein recycling.

    “The observed redistribution of VPS35-positive vesicles away from the nucleus suggests that endosomes are repositioned towards the plasma membrane, likely improving membrane protein recycling”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Interpretationown data

    A large majority of the originally 'red' genes now change with the same sign, consistent with microglial activation after R55 treatment.

    “This shows that a large majority of the originally”
    Quote in the paperSubstantial claim
56 of 56

  • The paper relies on this without support.

    The role of retromer dysfunction in synaptic pathology and neuroinflammation remains incompletely understood.

    “Despite growing evidence for retromer dysfunction in AD, its role in synaptic pathology and neuroinflammation remains incompletely understood.”

  • The paper relies on this without support.

    The broader molecular mechanisms underpinning retromer-mediated neuroprotection remain unclear.

    “Furthermore, while in vitro data suggest Aβ involvement, the broader molecular mechanisms underpinning retromer-mediated neuroprotection remain unclear.”

  • The authors state this as an assumption.

    The final cortical concentration of R55/R33 after a 500 nL injection is approximately 25 µM, assuming homogeneous distribution.

    “Although pharmacokinetic data for R55 and R33 is not available, the estimated final cortical concentration following a 500 nL injection was approximately 25 µM, assuming homogeneous distribution.”

  • The paper relies on this without support.

    5xFAD mice lack direct VPS35 mutations.

    “Given that 5xFAD mice lack direct VPS35 mutations, our results suggest that retromer-targeting strategies may be applicable to both familial and sporadic AD, offering a promising therapeutic avenue for modifying disease progression.”

  • The paper relies on this without support.

    VPS13 family proteins are critical for endosomal function.

    “Notably, both R33 and R55 treatment resulted in consistent and significant changes in the entire Vps13 domain-containing family, which are critical for endosomal function.”

  • The paper relies on this without support.

    5xFAD mice lack genetic alterations in VPS35 or other retromer components.

    “As 5xFAD mice lack genetic alterations in VPS35 or other retromer components”

  • The paper relies on this without support.

    Phagocytic receptors and cytokine receptors utilize retromer-mediated recycling in glia.

    “Given that phagocytic receptors and cytokine receptors utilize retromer-mediated recycling in glia”

  • The paper relies on this without support.

    The retromer complex regulates Aβ processing.

    “Given that the retromer complex regulates Aβ processing, we examined key AD-related cargos.”

  • The paper relies on this without support.

    Endosomal trafficking, mediated by the retromer complex, plays a pivotal role in synaptic function by regulating intracellular protein transport.

    “Endosomal trafficking, mediated by the retromer complex, plays a pivotal role in synaptic function by regulating intracellular protein transport.”

  • The paper relies on this without support.

    Grip1 is essential for AMPA receptor endosomal sorting and membrane targeting.

    “the latter being essential for AMPA receptor endosomal sorting and membrane targeting.”

  • The paper relies on this without support.

    Disruptions in synaptic transmission and plasticity are early hallmarks of AD.

    “Disruptions in synaptic transmission and plasticity are early hallmarks of AD.”

  • The paper relies on this without support.

    Defective intracellular calcium homeostasis, particularly endoplasmic reticulum (ER) calcium leakage, is an early event in AD-linked synaptic dysfunction.

    “Defective intracellular calcium homeostasis, particularly endoplasmic reticulum (ER) calcium leakage, is an early event in AD-linked synaptic dysfunction.”
12 of 12

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?

  • Stabilisation of Retromer expression is neuroprotective.

    “with stabilisation of Retromer expression being neuroprotective [49][50][51][52].”

    From Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling (2026) · cites this paper as [52]

    The Results section, “Retromer complex stabilization reverses synaptic deficits in 5xFAD mice” (page unavailable), describes potential neuroprotective effects of retromer-directed treatment and reports reversal of AD-related changes. But it explicitly says core retromer protein expression remained unchanged: the treatment stabilized retromer function, not retromer expression. The finding is also limited to a mouse model. (LLM, conf=0.90)

    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.

  • Figure 2 volcano plot has conflicting panel and pathway labels

    Minor

    The results place the volcano plot in Fig. 2F and identify its genes as WP2075; the figure caption labels the volcano plot as panel E and identifies WP2045.

  • Figure 8 caption gives two different scales for Figure 8

    Minor

    The caption says Figure 8 presents mean Z-normalized values, then lists Figure 8 among figures showing log2 fold changes relative to vehicle controls.

  • Reported Sorl1 particle-size peak lies outside the stated range

    Minor

    The stated particle-size range ends at 0.3 μm2, but one of the reported peaks is at 0.36 μm2.

3 of 3

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

    Major

    The cited work was retracted on 2023-01-25 (notice 10.1038/s41380-023-01973-9), before this paper was published (2025-09-10). Its authors could have known.

    Cited work 10.1038/s41380-019-0453-x · retracted 2023-01-25 · notice 10.1038/s41380-023-01973-9 · this paper published 2025-09-10

  • Cites a retracted work: 10.1038/s41380-022-01814-1

    Info

    The cited work was retracted; the date of the notice is not on record.

    Cited work 10.1038/s41380-022-01814-1 · retraction date not known · this paper published 2025-09-10

  • Cites a retracted work: 10.1038/s41380-023-01973-9

    Info

    The cited work was retracted; the date of the notice is not on record.

    Cited work 10.1038/s41380-023-01973-9 · retraction date not known · this paper published 2025-09-10

3 of 3

Citations

Cites

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Metadata

Authors
Ramonet, D., Daerr, A., & Hallbeck, M.
Affiliations
Linköping University (SE)
Corresponding author
Ramonet, David
ORCID
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2025-09-10
Volume
13
Issue
1
Pages
190-190
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/s40478-025-02096-8
PMC
PMC12424221
OpenAlex
W4414094801
Cited by
7
References
48
Citations by year
2026: 5 · 2025: 1
FWCI
1.83
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • KTH Publication Database DiVA (KTH Royal Institute of Technology) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Swedish Research Council (2019-01016)
  • Swedish Alzheimer foundation
  • Swedish Brain Foundation
  • Kurt and Helena Walldéns research foundation
  • Hans-Gabriel and Alice Trolle-Wachtmeister Foundation for Medical Research
  • Swedish Dementia Foundation
  • Linköping University and Region Östergötland
  • Linköping 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, 5xFAD mice, pharmacological chaperones, synaptic dysfunction, endosomal trafficking, amyloid-beta, neuroinflammation, microglial activation, disease-associated microglia, long-term potentiation, calcium signaling, RyR2, L-type calcium channels, Vps13, Rab7, APP processing, gene expression profiling
MeSH terms
Alzheimer Disease, Animals, Disease Models, Animal, Humans, Mice, Transgenic, Endosomes, Synapses, 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).

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