Global identification of neuronal and astrocytic integral membrane proteins that require Retromer for their endosomal recycling

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

Genetic studies have identified many genes associated with the endosomal network as causal for neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis.

“Genetic studies have identified many genes associated with the endosomal network to be causal for numerous neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis [1][2][3][4][5][6][7].”

• cites [1] sourcePartly supported

  The Discussion (page unavailable) reports associations between retromer-related genes and Alzheimer’s disease risk, and states that rare VPS35 mutations cause Parkinson’s disease. It does not address amyotrophic lateral sclerosis, and its Alzheimer’s findings establish association rather than showing that the identified variants are causal. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [2] sourceNot checked — no full text of the source
• cites [3] 2014, Genetic variation of the retromer subunits VPS26A/B-VPS29 in Parkinson’s disease, Neurobiol Aging sourcePartly supported

  The Introduction identifies a mutation in the retromer gene VPS35 as a rare cause of Parkinson’s disease. The paper does not address Alzheimer’s disease or amyotrophic lateral sclerosis, and its Discussion says mutations in the other retromer genes studied do not play a major role in Parkinson’s disease risk in this population. It therefore supports one example, not the broader claim attributed to it. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [4] sourceNot checked — no full text of the source
• cites [5] sourcePartly supported

  The section “Genetics lead the way to understanding Parkinson’s disease pathogenesis” (page unavailable) links familial Parkinson’s disease genes to the endolysosomal system. The cited paper does not establish the corresponding claim about causal endosomal-network genes in Alzheimer’s disease or amyotrophic lateral sclerosis; searches for those diseases did not find supporting discussion. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [6] sourcePartly supported

  The Interpretation section (page not provided) identifies late-onset Alzheimer’s susceptibility genes and describes endocytosis or intracellular trafficking as potential disease mechanisms. The Discussion (page not provided) reports rare damaging variants in Alzheimer’s-associated genes, but the paper does not establish that many endosomal-network genes are causal, or address Parkinson’s disease or amyotrophic lateral sclerosis. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [7] sourcePartly supported

  The Introduction links SORL1, a protein involved in sorting APP, to Alzheimer’s disease risk, and the Discussion describes a SORL1 variant that disrupts APP sorting. The paper does not establish that many endosomal-network genes cause neurodegenerative disorders, nor does it address Parkinson’s disease or amyotrophic lateral sclerosis. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

Probably not a substantial claim.

Neuronal endosomal swelling is classed as an early hallmark of Alzheimer's disease indicative of a perturbation in endosomal cargo sorting.

“In addition, neuronal endosomal swelling has been classed as an early hallmark of Alzheimer's disease indicative of a perturbation in endosomal cargo sorting [8,9,56].”

• cites [8] sourceNot checked — no full text of the source
• cites [9] sourcePartly supported

  The section “EP Activation Precedes Other Known Neuropathology in SAD” reports swollen neuronal early endosomes in pre-AD brains, detectable before amyloid accumulation or neurofibrillary pathology. The Discussion links these changes to altered endosomal fusion and recycling, but the cited passages do not establish that the swelling specifically indicates a perturbation in cargo sorting. Page numbers are unavailable in our copy. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [56] sourcePartly supported

  The paper reports enlarged neuronal early endosomes in Alzheimer’s disease autopsies and significantly more large endosomes in neurons derived from two patients (Abstract; no page given). Its references include a study describing endocytic abnormalities before amyloid deposition, but the paper does not establish that the swelling indicates a perturbation in endosomal cargo sorting. (LLM, conf=0.84)

  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.

SNX27 dysfunction is implicated in neurodegeneration and Down's syndrome, which greatly increases the risk for developing Alzheimer's disease.

“Importantly, SNX27 dysfunction is implicated in neurodegeneration and Down's syndrome, which greatly increases the risk for developing Alzheimer's disease [63][64][65].”

• cites [63] sourcePartly supported

  The Discussion reports that reduced SNX27 expression contributes to synaptic dysfunction in Down’s syndrome, and the paper describes an SNX27 defect associated with infantile neurodegeneration. It discusses Alzheimer’s disease in relation to retromer dysfunction, but does not state that Down’s syndrome greatly increases the risk of developing Alzheimer’s disease. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [64] sourceNot checked — no full text of the source
• cites [65] sourcePartly supported

  The Discussion section on the miR-155–C/EBPβ–SNX27 pathway says that loss of SNX27 may help explain synaptic dysfunction, memory difficulties and neurodegeneration in Down syndrome. Our copy does not state that Down syndrome greatly increases the risk of developing Alzheimer’s disease, so that part of the sentence is unsupported by this source. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

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

SNX12 has been implicated in Alzheimer's disease through modulation of amyloid precursor protein (APP) processing via an interaction with BACE1.

“SNX12 has also been implicated in Alzheimer's disease through modulation of amyloid precursor protein (APP) processing via an interaction with BACE1 [73].”

• cites [73] Zhao Y , Wang Y , Yang J , Wang X , Zhao Y , Zhang X , et al. Sorting nexin 12 interacts with BACE1 and regulates BACE1-mediated APP processing. Mol Neurodegener. 2012;7:30. sourceSupported

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

Mutations in APP are causal for Alzheimer's disease, with abnormal processing of APP and the generation of toxic amyloid-β aggregates being hallmarks of Alzheimer's pathology.

“Mutations in APP are causal for Alzheimer's disease with abnormal processing of APP and the generation of toxic amyloid-β aggregates hallmarks of Alzheimer's pathology [89].”

• cites [89] sourceSupported

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

In previous work, an increase in APP surface expression in VPS35 KO H4 cells was reported and hypothesised to be due to an increase in lysosomal exocytosis.

“In previous work we reported an increase in APP surface expression in VPS35 KO H4 cells and hypothesised that this was due to an increase in lysosomal exocytosis [79].”

• cites [79] sourceSupported

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

Through this dual interaction SNX27 regulates the retrieval and recycling of hundreds of cargoes to the plasma membrane.

“Through this dual interaction SNX27 regulates the retrieval and recycling of hundreds of cargoes to the plasma membrane [26,29,31,58,59].”

• cites [26] sourcePartly supported

  The Results and discussion section says SNX27-mediated recycling requires both PDZ-motif binding and association with the endosome membrane, and identifies SNX27 as a mediator of endosome-to-plasma-membrane sorting. It does not establish that SNX27 regulates hundreds of cargoes; the study focuses on β2AR, while noting other receptors with PDZ-dependent recycling. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [29] sourcePartly supported

  The Discussion describes two independent SNX27 interactions involved in cargo retrieval and recycling toward the plasma membrane. But the Results report 122 proteins reduced at the surface after SNX27 depletion, with 81 also affected by retromer depletion; this does not support the claim that SNX27 regulates hundreds of cargoes. Page numbers are not available in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [31] sourcePartly supported

  In the passage labelled Abstract (page unavailable), the paper reports that SNX27 binds a receptor’s PDZ motif and associates with retromer tubules through the WASH complex, promoting recycling to the plasma membrane. It demonstrates this pathway for β2AR and β1AR and suggests that many other cargoes may use it; it does not establish that SNX27 regulates hundreds of cargoes. (LLM, conf=0.89)

  Experimental — accuracy not yet measured
• cites [58] sourcePartly supported

  The Abstract describes SNX27 binding both cargo motifs and the retromer subunit VPS26, and the Results show that disrupting the SNX27–VPS26 interaction prevents GLUT1 recycling to the plasma membrane. The paper reports more than 80 SNX27-retromer-dependent transmembrane cargoes, not hundreds; it does not establish the claimed number. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [59] McMillan KJ , Banks PJ , Hellel FL , Carmichael RE , Clairfeuille T , Evans AJ , et al. Sorting nexin-27 regulates AMPA receptor trafficking through the synaptic adhesion protein LRFN2. Elife. 2021;10. sourcePartly supported

  The Introduction (page not provided) describes SNX27’s two interactions and says they enable retrieval of internalized proteins and recycling to the plasma membrane. It does not establish that hundreds of cargoes undergo this process. The Results report 212 SNX27-interacting proteins in cortical neurons, but do not identify all of them as recycling cargoes. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

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

SNX27 interacts with SNX-BAR proteins SNX1 and SNX2 and the WASH complex to couple sequence-dependent retrieval of SNX27 cargoes with tubule formation during cargo recycling.

“SNX27 also interacts with the SNX-BAR (Bin/Amphiphysin/Rvs) proteins SNX1 and SNX2 [27,28,31,62] and the WASH complex [37] to couple sequence-dependent retrieval of SNX27 cargoes with tubule formation during the process of cargo recycling.”

• cites [27] sourceSupported
• cites [28] sourcePartly supported

  The Discussion (page unavailable) says SNX1/SNX2–SNX5/SNX6 heterodimers couple sequence-dependent cargo recognition to tubulo-vesicular carrier formation. It does not attribute that mechanism to SNX27 cargoes or show SNX27 interacting with SNX1/SNX2; it describes SNX27 and WASH as interactions of Retromer, a separate complex. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [31] sourcePartly supported

  The paper reports that WASH-complex components co-purify with SNX27 and concludes that this connectivity helps SNX27 direct PDZ-dependent cargo sorting through retromer tubules (passage labeled Abstract; Fig. 5e–f). It supports the WASH interaction and sequence-dependent tubule entry, but does not establish that SNX27–WASH coupling drives tubule formation. The SNX1/SNX2 interaction is attached to other citations in the citing sentence. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [62] 2021, All ways lead to Rome: assembly of retromer on membranes with different sorting nexins, Signal Transduct Target Ther sourceSupported
• cites [37] sourceSupported

It may state two separate claims as one.

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”

• cites [29] sourceSupported
• cites [80] sourcePartly supported

  The Results section, “Retromer is required for functional surface expression of synaptic glutamate receptors” (page unavailable), reports reduced AMPA- and NMDA-mediated synaptic currents after VPS35 knockdown and identifies internalized GluA2-containing AMPA receptors. It does not establish decreased surface levels for each listed GRIA and GRIN subunit. In the citing sentence, the citations to this paper accompany the glutamate receptors, not GLUT1 or SLC4A7. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [81] sourceNot checked — no full text of the source
• cites [82] sourcePartly supported

  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
• cites [83] sourceNot checked — no full text of the source
• cites [84] sourcePartly supported

  The Results (Fig. 5; page not provided) show reduced cell-surface GluA2 (GRIA2) in VPS35-deficient neurons. They do not report reduced surface levels of GRIA3, GRIA4, GRIN1, or GRIN2B; the Discussion mentions NMDA receptors only when describing another study. The separate GLUT1 citation in the citing sentence is not attributed to this paper, and this paper does not establish a surface-level decrease for SLC4A7. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [85] sourcePartly supported

  The Results section, “The retromer regulates GLR-1 recycling” (page unavailable), reports that vps-35 mutants had fewer and less intense GLR-1 puncta, supporting a retromer-dependent effect on a C. elegans AMPA-type receptor. It does not establish decreased surface levels of the named GRIA or GRIN subunits, GLUT1/SLC2A1, or SLC4A7. In the citing sentence, this source is cited alongside other papers for the glutamate-receptor portion, not specifically for GLUT1. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

The VPS35(D620N) mutation causes an autosomal dominant form of Parkinson's disease.

“Disease causing mutations in Retromer have been identified in patients, including the VPS35(D620N) mutation which causes an autosomal dominant form of Parkinson's disease [53,54]”

• cites [53] sourceSupported
• cites [54] sourceSupported

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

SNX3 directly binds to a subset of cargo containing the sequence motif [+/-]-x-∅-x-[L/M], with many of these cargoes trafficked through the retrograde endosome-to-TGN pathway.

“SNX3 directly binds to a subset of cargo containing the poorly defined sequence motif [+/-]-x-∅-x-[L/M] (∅ -bulky aromatic residue) with many of these cargoes trafficked through the retrograde endosome-to-TGN pathway [25,30,66,67].”

• cites [25] sourcePartly supported

  The Results section reports that SNX3 directly binds the VPS26–VPS29–VPS35 retromer complex and participates in Wntless trafficking. The Abstract says the cargo-selective retromer subcomplex—not SNX3—binds a sorting motif in cargo proteins. The copy does not identify the claimed [+/-]-x-∅-x-[L/M] motif or establish direct SNX3 binding to cargo bearing it. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [30] sourcePartly supported

  The Results section reports that Grd19p, the yeast SNX3 homologue, directly binds the Ftr1p recycling signal; the Discussion also identifies cargo sorted through the Grd19p–retromer pathway, including proteins retrieved to the Golgi. But the Discussion does not establish the claimed sequence motif. It says the signals appear diverse, a phenylalanine mutation did not affect Ftr1p recycling, and Grd19p probably recognizes structural features rather than a strict linear sequence. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [66] sourcePartly supported

  The Results section, “A Mechanism for Cargo Recognition” (page unavailable), shows that the DMT1-II recycling signal contacts SNX3 and VPS26 at a binding site for a related ØX(L/M) motif. But “DMT1-II Binding is Concomitant With Interaction of SNX3 with Retromer” reports no detectable binding to isolated SNX3. The paper describes DMT1-II cycling between endosomes and the plasma membrane; although the Introduction says retromer also transports cargo to the TGN, it does not establish that many SNX3-recognized cargoes take that route. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [67] sourcePartly supported

  The Introduction (page unavailable) says SNX3-retromer associates with Wntless through two Φ-X-[L/M] motifs and retrieves Wntless from early endosomes to the Golgi. It identifies VPS35, rather than cargo, as the protein SNX3 directly binds. The cited passages do not establish the fuller [+/-]-x-∅-x-[L/M] motif or that many cargoes bearing it take this route. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

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

Retromer associates with accessory proteins and cargo adaptors including sorting nexins, the WASH complex, RAB GTPase regulators including TBC1D5 and ANKRD27/VARP, and RME8.

“To function, Retromer associates with accessory proteins and cargo adaptors including sorting nexins (SNXs) [24][25][26][27][28][29][30][31][32][33][34], the WASH complex [35][36][37][38][39], RAB GTPase regulators including TBC1D5 and ANKRD27/VARP [40][41][42][43][44][45][46], and RME8 [47].”

• cites [24] sourceSupported
• cites [25] sourceSupported
• cites [26] sourcePartly supported

  The Introduction identifies SNX27 as a sorting nexin involved in PDZ-directed recycling, supporting its inclusion among sorting proteins. But the cited paper does not establish that SNX27 associates with Retromer; a search for “retromer” found no passage making that link. The other protein groups in the sentence have separate citations and are not attributed to this source. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [27] sourceSupported
• cites [28] sourceSupported
• cites [29] sourceSupported
• cites [30] sourceSupported
• cites [31] sourceSupported
• cites [32] sourceNot checked — no full text of the source
• cites [33] sourceSupported

Probably not a substantial claim.

ADAM10 cleaves APP in a non-amyloidogenic manner.

“ADAM10 cleaves APP in a non-amyloidogenic manner [101,102].”

• cites [101] 2022, The transmembrane domain of the amyloid precursor protein is required for antiamyloidogenic processing by alpha-secretase ADAM10, J Biol Chem sourceSupported
• cites [102] sourceNot checked — no full text of the source

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

The endosomal network is a key biological pathway affected in neurodegenerative pathology.

“These studies, alongside clinical evidence [8][9][10][11][12][13][14], highlight the endosomal network as a key biological pathway affected in neurodegenerative pathology.”

• cites [8] sourceNot checked — no full text of the source
• cites [9] sourcePartly supported

  The paper reports early endocytic-pathway abnormalities in sporadic Alzheimer’s disease and Down syndrome, supporting the endosomal network’s importance in those conditions. However, the section “EP Abnormalities Are Not Observed in Other Neurodegenerative Disorders or Normal Aging” reports no comparable endosomal enlargement in the other neurodegenerative diseases examined, so the broader claim needs qualification. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [10] sourceSupported
• cites [11] sourceSupported
• cites [12] sourcePartly supported

  The Introduction identifies endosomal trafficking as a pathogenic pathway in Alzheimer’s disease, and the Discussion links impaired endosomal recycling to its pathology. The claim extends that finding to neurodegenerative pathology generally; the paper’s substantive discussion here is specific to Alzheimer’s disease. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [13] sourceNot checked — no full text of the source
• cites [14] sourceSupported

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

Through its FERM domain, SNX27 may associate with cargoes containing a NPxY or NxxY sorting motif, with a preference for sequences phosphorylated at the tyrosine residue.

“Through its FERM domain, SNX27 may also associate with cargoes containing a NPxY or NxxY sorting motif (x refers to any residue), with SNX27 showing a preference for sequences that are phosphorylated at the tyrosine residue [29,60,61].”

• cites [29] sourcePartly supported

  The Discussion (page unavailable) says SNX27’s FERM-like domain can engage NPxY–NxxY sorting motifs and suggests that it may bind cargo through those motifs. It does not state that SNX27 prefers motifs phosphorylated at the tyrosine residue; searches for phosphorylated tyrosine and phosphotyrosine did not find that preference in our copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [60] sourceSupported
• cites [61] sourcePartly supported

  The Results (page not provided) show that SNX27 and its FERM-like domain bind an APP peptide containing an NPxY motif, and the Discussion identifies NPxY cargo binding as a function of SNX27. The passages do not establish binding to NxxY motifs or a preference for tyrosine-phosphorylated sequences; the tyrosine-to-alanine test concerns a mutation, not phosphorylation. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

The SNX3-Retromer assembly is essential for the sequence-dependent retrieval and recycling of cargoes.

“An additional cargo adaptor complex essential for the sequence-dependent retrieval and recycling of cargoes is the sorting nexin-3 (SNX3)-Retromer assembly [25,30,66,67].”

• cites [25] sourcePartly supported

  The Discussion (page not specified) identifies an SNX3–retromer pathway that retrieves and recycles Wntless (Wls), supporting the assembly’s role in cargo recycling. It does not establish that SNX3–retromer retrieval is sequence-dependent for cargoes generally; the Discussion says the authors did not observe an interaction between SNX3 and Wls. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites [30] sourceSupported
• cites [66] sourcePartly supported

  The Introduction identifies a binding site for canonical recycling signals at the VPS26–SNX3 interface. The Results section on DMT1-II binding shows that SNX3–retromer interactions are required to sort DMT1-II out of endosomes into recycling intermediates. The paper does not establish that this assembly is essential for retrieval and recycling of cargoes generally. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [67] sourceSupported

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

Humans express a SNX3 homologue, SNX12, which shares a 79.5% protein sequence identity.

“Of note, humans express a SNX3 homologue, SNX12, which shares a 79.5% protein sequence identity [72].”

• cites [72] sourceSupported

It may state two separate claims as one.

Suppressing protein expression rather than using a knockout model is physiologically relevant to neurodegenerative patients where Retromer levels are reduced, in contrast with Retromer KO which is embryonically lethal.

“By suppressing protein expression rather than using a knockout (KO) model our approach is physiologically relevant to neurodegenerative patients where Retromer levels are reduced, in contrast with Retromer KO which is embryonically lethal [78].”

• cites [78] sourceSupported

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

Human Retromer is a stable heterotrimer of VPS35, either VPS26A or VPS26B, and one of three VPS29 isoforms, and regulates endosomal retrieval and trafficking of numerous cargoes away from the degradative pathway.

“Human Retromer is a stable heterotrimer of vacuolar protein sorting protein 35 (VPS35), either VPS26A or VPS26B [20,21], and one of three VPS29 isoforms [22,23], and regulates the endosomal retrieval and trafficking of numerous cargoes away from the degradative pathway [23].”

• cites [20] sourceNot checked — no full text of the source
• cites [21] sourceNot checked — no full text of the source
• cites [22] 2025, Identification of a VPS29 isoform with restricted association to Retriever and Retromer accessory proteins through autoinhibition, Proc Natl Acad Sci U S A sourceSupported
• cites [23] Collins BM , Cullen PJ . Separation of powers: A key feature underlying the neuroprotective role of Retromer in age-related neurodegenerative disease? Curr Opin Cell Biol. 2025;94:102516. sourcePartly supported

  The Introduction section on the yeast retromer–SNX–BAR pentamer describes a stable human VPS26:VPS35:VPS29 heterotrimer, VPS26A and VPS26B, and endosomal cargo retrieval and recycling. It says there are “at least three VPS29 orthologs,” however, rather than establishing the claim’s exact count of three isoforms. No page number is available in our copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

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

Stabilisation of Retromer expression is neuroprotective.

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

• cites [49] sourcePartly supported

  The Introduction (page not provided) describes retromer as neuroprotective and reports that stabilizing it in cells reduces toxic-protein accumulation in disease models. It discusses stabilization of retromer’s structure and function, however, not stabilization of its expression; that specific part of the claim is unsupported. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [50] sourcePartly supported

  The Results report that stabilizing retromer increased retromer protein levels in cultured hippocampal neurons and reduced Aβ accumulation. The Discussion says this may shift APP toward a neuroprotective processing pathway, but the paper does not demonstrate that retromer stabilization itself protects neurons; it presents therapeutic benefit as a possibility for future study. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites [51] 2018, Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer’s Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein, Stem Cell Reports sourcePartly supported

  The Results report that stabilizing the retromer complex with R33 reduced Aβ and phosphorylated TAU in human stem-cell-derived neurons; the Discussion calls these effects potentially beneficial. The paper does not establish neuroprotection directly, and it tests stabilization of the complex rather than stabilization of retromer expression. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [52] 2025, Stabilizing the retromer complex rescues synaptic dysfunction and endosomal trafficking deficits in an Alzheimer’s disease mouse model, Acta Neuropathol Commun sourcePartly supported

  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

It may state two separate claims as one.

VPS35 suppression resulted in an increase in LRFNs (LRFN1, 2 and 4) at the neuronal surface, suggesting that SNX27 can act independently to Retromer in the trafficking of a sub-set of cargoes, potentially through the ESCPE-1 complex.

“Surprisingly, VPS35 suppression resulted in an increase in LRFNs (LRFN1, 2 and 4) at the neuronal surface (Figure 2C) suggesting that SNX27 can act independently to Retromer in the trafficking of a sub-set of cargoes, potentially through the ESCPE-1 complex [27,28].”

• cites [27] sourcePartly supported

  The Results section reports that SNX27 binds ESCPE-1 even when SNX27 mutants cannot bind Retromer, supporting a Retromer-independent physical interaction. It does not establish Retromer-independent trafficking of a cargo subset; the Discussion instead describes Retromer as essential for retrieval of the cargos studied. The neuronal LRFN surface increase is presented as the citing authors’ own Figure 2C result, not as a finding from this source. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [28] sourcePartly supported

  The Discussion (page unavailable) identifies ESCPE-1 as a cargo-sorting complex functionally distinct from Retromer, supporting the proposed independent pathway in broad terms. It does not show that SNX27 uses ESCPE-1 or acts independently of Retromer; instead, it describes SNX27 as a Retromer interactor. The LRFN surface increase is presented as the citing authors’ Figure 2C result, not as a finding of this source. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

There was an increase in surface expression of VAMP/synatobrevin-2, syntaxin-1A (STX1A) and synaptotagmin-7 (SYT7), all of which have been associated with lysosomal exocytosis, further highlighting an important role for Retromer in maintaining lysosomal health.

“Moreover, we found an increase in surface expression of vesicle-associated membrane protein 2 (VAMP/synatobrevin-2), syntaxin-1A (STX1A) and synaptotagmin-7 (SYT7) (Figure 2C), all of which have been associated with lysosomal exocytosis [90,91], further highlighting an important role for Retromer in maintaining lysosomal health.”

• cites [90] Bhatt AM , Singh B , Singh P , Setty SRG . STX1A localizes to the lysosome and controls its exocytosis. Mol Biol Cell. 2025:mbcE25040196. sourceNot checked — no full text of the source
• cites [91] sourcePartly supported

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

  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.

The low-density lipoprotein receptor family has essential roles in lipid and cholesterol transport, with LRP1 also implicated in the astrocytic uptake and degradation of amyloid-β.

“This family of receptors have essential roles in lipid and cholesterol transport, with LRP1 also implicated in the astrocytic uptake and degradation of amyloid-β [106-108].”

• cites [106] sourceNot checked — no full text of the source
• cites [107] sourcePartly supported

  The section “LRP1 regulates Aβ metabolism in astrocytes” reports reduced Aβ uptake and clearance after LRP1 knockdown, supporting the astrocytic part of the claim. The passages in our copy do not establish the broader claim that the receptor family has essential roles in lipid and cholesterol transport; searches for that point found no supporting passage. Page numbers were not available in the indexed copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [108] sourcePartly supported

  The Discussion (page unavailable) states that astrocytic Aβ uptake can be blocked by deleting Lrp1 and that astrocyte-mediated Aβ degradation depends on LRP1. It does not substantiate the broader claim that this receptor family has essential roles in lipid and cholesterol transport; the only cholesterol-transporter wording found is in a cited reference title. (LLM, conf=0.82)

  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.

Oxidation of cysteine residues in VPS35 in response to intracellular ROS acts as a preventative mechanism against oxidative stress, highlighting Retromer as a modulator of this pathway.

“Recent work identified oxidation of cysteine residues in VPS35 in response to intracellular ROS as a preventative mechanism against oxidative stress, highlighting Retromer as a modulator of this pathway [130].”

• cites [130] sourceSupported

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

Glutamate plays roles in cells including imparting antioxidant effects via synthesis of reduced glutathione (GSH).

“In addition to its role as an excitatory neurotransmitter, glutamate also plays other important roles in cells including imparting antioxidant effects via the synthesis of reduced glutathione (GSH) [118].”

• cites [118] sourceSupported

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

Changes in APP processing and formation of toxic amyloid-β aggregates are a key characteristic of Alzheimer's disease pathology.

“Changes in APP processing and the formation of toxic amyloid-β aggregates are a key characteristic of Alzheimer's disease pathology [89].”

• cites [89] sourceSupported

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

Excitotoxicity has been associated with several neurodegenerative disorders as well as epilepsy.

“Excitotoxicity has been associated with several neurodegenerative disorders as well as epilepsy [124,125].”

• cites [124] Todd AC , Hardingham GE . The Regulation of Astrocytic Glutamate Transporters in Health and Neurodegenerative Diseases. Int J Mol Sci. 2020;21(24). sourceSupported
• cites [125] Green JL , Dos Santos WF , Fontana ACK . Role of glutamate excitotoxicity and glutamate transporter EAAT2 in epilepsy: Opportunities for novel therapeutics development. Biochem Pharmacol. 2021;193:114786. sourcePartly supported

  The 'Glutamate Excitotoxicity and Epilepsy' section links excitotoxicity to seizures and discusses motor-neuron degeneration in an ALS-related model. It does not substantiate the broader claim that excitotoxicity is associated with several neurodegenerative disorders; the discussion identifies ALS but not several such disorders. (LLM, conf=0.82)

  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.

Retromer is implicated in the trafficking of the microglia receptor TREM2, with mutations in TREM2 associated with an increased risk for developing AD.

“Retromer has also been implicated in the trafficking of the microglia receptor Triggering receptor expressed on myeloid cells 2 (TREM2), with mutations in TREM2 associated with an increased risk for developing AD [154, 155].”

• cites [154] sourcePartly supported

  The Discussion (page not provided) states that heterozygous rare TREM2 variants predispose to Alzheimer's disease and describes TREM2 in microglia. It does not implicate retromer in TREM2 trafficking; searches for retromer trafficking and VPS35 returned no supporting passage. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [155] sourcePartly supported

  The Results (Replication Series) report that a TREM2 variant was associated with increased Alzheimer’s disease risk, and the Discussion identifies TREM2 as a receptor expressed on microglia. The paper does not address retromer or its role in TREM2 trafficking, so it supports only part of the cited sentence. (LLM, conf=0.89)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

VPS35 deficiency leads to a similar increase in APP-related proteins APLP1 and APLP2 at the cell surface, which are thought to be processed by secretases in the same way as APP.

“As has been shown previously, VPS35 deficiency also leads to a similar increase in APP-related proteins APLP1 and APLP2 at the cell surface, which are thought to be processed by secretases in the same way as APP [79,93,141].”

• cites [79] sourceSupported
• cites [93] sourcePartly supported

  The Discussion reports that APP, APLP1, and APLP2 are cleaved by BACE 1, supporting the secretase-processing portion of the claim. The paper does not report VPS35 deficiency or an increase in APLP1 and APLP2 at the cell surface. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [141] Simoes S , Neufeld JL , Triana-Baltzer G , Moughadam S , Chen EI , Kothiya M , et al. Tau and other proteins found in Alzheimer’s disease spinal fluid are linked to retromer-mediated endosomal traffic in mice and humans. Sci Transl Med. 2020;12(571). sourcePartly supported

  The Results section on CSF proteins in Vps35 knockout mice (page unavailable) reports elevated APLP1, APLP2, and APP fragments and identifies all three as BACE1 substrates. The Discussion (page unavailable) says BACE1 cleaves them at endosomal membranes. The paper does not show that APLP1 or APLP2 increases at the cell surface, so the claimed location is unsupported. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

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

Previous papers have reported an effect of SNX27 depletion on inhibitory synapse function through trafficking of NLG2.

“previous papers have reported an effect of SNX27 depletion on inhibitory synapse function through trafficking of the inhibitory synapse adhesion molecule Neuroligin-2 (NLG2) [77,129].”

• cites [77] sourceNot checked — no full text of the source
• cites [129] sourceSupported

It may state two separate claims as one.

The low-density lipoprotein receptors have been shown to interact with SNX17 through their NPxY motifs within their intracellular domains, with SNX17 interacting with the endosomal sorting complex Retriever.

“The low-density lipoprotein receptors have been shown to interact with SNX17 [109, 110] through their NPxY motifs within their intracellular domains, with SNX17 interacting with the endosomal sorting complex Retriever [111][112][113][114].”

• cites [109] sourceNot checked — no full text of the source
• cites [110] sourceSupported
• cites [111] sourceSupported
• cites [112] 2025, Selective cargo and membrane recognition by SNX17 regulates its interaction with Retriever, EMBO RepNot checked yet
• cites [113] sourceSupported
• cites [114] sourceSupported

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

SNX27 interacts with Presenillin-1, regulating γ-secretase activity, with SNX27 depletion leading to increased Aβ production.

“SNX27 has been shown to interact with Presenillin-1, regulating γ-secretase activity, with SNX27 depletion leading to increased Aβ production [137].”

• cites [137] sourceSupported

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

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].”

• cites [80] sourceSupported
• cites [81] sourceNot checked — no full text of the source
• cites [82] sourcePartly supported

  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

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

α-secretase cleavage of APP by ADAM10 is inversely related to BACE1 mediated β-secretase cleavage.

“However, the α-secretase cleavage of APP by ADAM10 has also been shown to be inversely related to BACE1 mediated β-secretase cleavage [101, 102, 136].”

• cites [101] 2022, The transmembrane domain of the amyloid precursor protein is required for antiamyloidogenic processing by alpha-secretase ADAM10, J Biol Chem sourceSupported
• cites [102] sourceNot checked — no full text of the source
• cites [136] sourceSupported

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

Disturbances in glutamatergic and GABAergic systems have been heavily implicated in neurodegenerative pathology.

“Indeed, disturbances in the glutamatergic and GABAergic systems have been heavily implicated in neurodegenerative pathology [86-88, 123, 126-128], and previous papers have reported an effect of SNX27 depletion on inhibitory synapse function through trafficking of the inhibitory synapse adhesion molecule Neuroligin-2 (NLG2) [77,129].”

• cites [86] sourceNot checked — no full text of the source
• cites [87] sourceNot checked — no full text of the source
• cites [88] Capsoni S , Arisi I , Malerba F , D’Onofrio M , Cattaneo A , Cherubini E . Targeting the Cation-Chloride Co-Transporter NKCC1 to Re-Establish GABAergic Inhibition and an Appropriate Excitatory/Inhibitory Balance in Selective Neuronal Circuits: A Novel Approach for the Treatment of Alzheimer’s Disease. Brain Sci. 2022;12(6). sourceSupported
• cites [123] sourcePartly supported

  The Abstract and Discussion (pages unavailable) report that disrupting astroglial glutamate transport raises extracellular glutamate and causes neuronal degeneration, supporting the glutamatergic part of the claim. The passages do not address GABAergic disturbances, so this paper does not support that part. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [126] sourceNot checked — no full text of the source
• cites [127] 2018, A bell-shaped dependence between amyloidosis and GABA accumulation in astrocytes in a mouse model of Alzheimer’s disease, Neurobiol Aging sourceNot checked — no full text of the source
• cites [128] sourcePartly supported

  The Abstract (page unavailable) lists glutamate excitotoxicity among proposed mechanisms of memory impairment in Alzheimer’s disease, and the Discussion (page unavailable) reports that increased astrocytic GABA impairs synaptic function and memory in Alzheimer’s mouse models. These passages support involvement of both systems in Alzheimer’s disease, but not the broader claim that disturbances in both have been heavily implicated across neurodegenerative pathology. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

AlphaFold modelling predicted a direct interaction of ADAM10 with SNX3-Retromer, with a binding motif consistent with previously published SNX3-Retromer cargo.

“AlphaFold modelling additionally predicted a direct interaction of ADAM10 with SNX3-Retromer, with a binding motif consistent with previously published SNX3-Retromer cargo [66].”

• cites [66] sourceSupported

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

Synthesis of GSH is primarily regulated by system XC-, comprised of SLC3A2 (4F2hc), which acts as a chaperone for membrane localisation and stability of SLC7A11.

“The synthesis of GSH is primarily regulated by system XC -, comprised of the single-pass transmembrane protein SLC3A2 (4F2hc), which is thought to act as a chaperone for the membrane localisation and stability of the glutamate/cysteine antiporter SLC7A11 [119].”

• cites [119] sourcePartly supported

  The Introduction (page not provided) identifies system xc− as the SLC7A11–SLC3A2 heterodimer and says SLC3A2 is necessary for trafficking it to the plasma membrane. It also links cystine uptake through system xc− to increased GSH synthesis under redox stress, but does not say system xc− primarily regulates GSH synthesis or that SLC3A2 stabilizes SLC7A11. (LLM, conf=0.88)

  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.

SNX17-Retriever assembles into a larger complex, Commander, with perturbation of this complex implicated in neurodevelopmental disorders.

“SNX17-Retriever assembles into a larger complex, Commander, with perturbation of this complex implicated in neurodevelopmental disorders [111-114, 148-150].”

• cites [111] sourceSupported
• cites [112] 2025, Selective cargo and membrane recognition by SNX17 regulates its interaction with Retriever, EMBO RepNot checked yet
• cites [113] sourcePartly supported

  The Results section reports that SNX17 associates with Retriever and that the CCC complex helps recruit Retriever to endosomes. Our copy does not call the larger assembly “Commander” or link perturbation of it to neurodevelopmental disorders (searched: Commander, neurodevelopmental, intellectual disability). No page numbers were provided for these passages. (LLM, conf=0.83)

  Experimental — accuracy not yet measured
• cites [114] sourcePartly supported

  The Introduction states that Retriever associates with CCC to form the larger Commander assembly, and the paper documents SNX17 binding to Retriever. Our copy does not state that perturbation of Commander is implicated in neurodevelopmental disorders; the cited reference title links Commander to Ritscher-Schinzel syndrome but does not establish that broader claim in this paper. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites [148] sourceSupported
• cites [149] sourceSupported
• cites [150] sourcePartly supported

  The Introduction (page not provided) describes SNX17 as an adaptor associated with Retriever and the CCC complex in a shared sorting pathway. It also links genes in that pathway to intellectual disability and Ritscher-Schinzel syndrome with developmental delay. Our copy does not identify the larger assembly as “Commander” or state that SNX17-Retriever assembles into it. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

LRP1 has been implicated in the uptake and degradation of amyloid-β and tau.

“which has been implicated in the uptake and degradation of amyloid-β and tau [107, 147].”

• cites [107] sourcePartly supported

  The Results section, “LRP1 regulates Aβ metabolism in astrocytes” (page unavailable), reports reduced Aβ42 uptake and clearance after LRP1 knockdown, supporting the amyloid-β portion. No passage in our copy supports the attributed claim about tau uptake or degradation (searched: “tau uptake degradation LRP1” and “tau”). (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites [147] sourcePartly supported

  The Results section on the CRISPR screens identifies LRP1 as a major receptor for neuronal uptake of monomeric tau, but not fibrillar tau (page unavailable). The Results section on LRRK2 measures amyloid-β uptake without attributing it to LRP1, and the Introduction says the uptake assays limited the relevance of tau degradation. Our copy therefore does not support the claims about LRP1-mediated amyloid-β uptake or degradation of either protein. (LLM, conf=0.88)

  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.

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].”

• cites [82] sourceSupported
• cites [131] 2020, Coupling of terminal differentiation deficit with neurodegenerative pathology in Vps35-deficient pyramidal neurons, Cell Death Differ sourcePartly supported

  The Results section (‘Concurrence of neurodegenerative and reactive glial responses’) reports increased reactive astrogliosis and altered microglial morphology in mice with neuronal Vps35 deficiency. It describes larger microglial cell bodies and shorter processes, but does not compare that morphology with microglia in AD patients. No page number is available in our copy. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Probably not a substantial claim. The authors may not put it forward as true.

The increase in APP and related proteins on the surface of both neurons and astrocytes is due to an increase in lysosomal exocytosis.

“We hypothesise that the increase in APP and related proteins on the surface of both neurons and astrocytes is due to an increase in lysosomal exocytosis, based on our proteomic data also showing a significant increase of lysosomal proteins at the cell surface, as well as previous data illustrating an essential role for Retromer in lysosomal health [79].”

• cites [79] sourceSupported

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

Model quality and interface confidence were assessed using the interfacial iPTM scores, pDockQ2 score calculated based on ipSAE.

“Model quality and interface confidence were assessed using the interfacial iPTM scores, pDockQ2 score calculated based on ipSAE [160-162].”

• cites [160] Dunbrack RL . Rēs ipSAE loquunt: What’s wrong with AlphaFold’s ipTM score and how to fix it. bioRxiv. 2025:2025.02.10.637595.Not matched

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

• cites [161] sourcePartly supported

  The Methods (‘pDockQ’) and Results (‘Distinguishing acceptable from incorrect models’; page unavailable) support using an interface-based score to assess model quality. They describe pDockQ, calculated from interface plDDT and the number of interface contacts, not pDockQ2 calculated from ipSAE. The passages do not establish use of interfacial iPTM scores either. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites [162] Zhu W , Shenoy A , Kundrotas P , Elofsson A . Evaluation of AlphaFold-Multimer prediction on multi-chain protein complexes. Bioinformatics. 2023;39(7). sourcePartly supported

  Section 2.6 describes ipTM as a model-quality estimate and introduces pDockQ2 to estimate the quality of individual interfaces. It calculates pDockQ2 from interfacial predicted aligned error (PAE) and pLDDT, not ipSAE. Section 3.3 likewise says pDockQ2 considers PAEs between chains. (LLM, conf=0.90)

  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.

SNX27 has been implicated in Aquaporin 4 (AQP4) trafficking, with a loss of AQP4 leading to ventriculomegaly.

“and has been implicated in Aquaporin 4 (AQP4) trafficking with a loss of AQP4 in leading to ventriculomegaly [158].”

• cites [158] 2021, Kidins220 deficiency causes ventriculomegaly via SNX27-retromer-dependent AQP4 degradation, Mol Psychiatry sourceSupported

It may state two separate claims as one.

In astrocytes, 80 membrane proteins were depleted (log2 fold change -0.26, p ≤ 0.05) and 114 membrane proteins were increased (log2 fold change +0.26, p ≤ 0.05) after SNX27 suppression compared with control 1.

“whilst 80 membrane proteins were depleted (log2 fold change -0.26, p ≤ 0.05) and 114 membrane proteins were increased (log2 fold change +0.26, p ≤ 0.05) after SNX27 suppression (Supplementary Figure 4D, Supplementary Table 6) compared with the control 1 shRNA treated cells.”

It may state two separate claims as one.

Kainate receptors, metabotropic glutamate receptors, and glutamate transporters including SLC1A1/EAAT3 and SLC1A2/EAAT2/GLT1 were all significantly reduced at the neuronal surface after VPS35 suppression.

“Kainate receptors, metabotropic glutamate receptors and glutamate transporters (including SLC1A1/EAAT3 and SLC1A2/EAAT2/GLT1) were all found to be significantly reduced at the neuronal surface after VPS35 suppression (Figure 2C).”

It may state two separate claims as one.

For enriched proteins in neurons, 22 integral proteins were enriched by both SNX27 and VPS35 suppression, 48 proteins were enriched by both SNX3/SNX12 and VPS35 suppression, and only 10 proteins were shared across all conditions.

“For the enriched proteins there were 22 integral proteins enriched by both SNX27 and VPS35 suppression and 48 proteins enriched by both SNX3/SNX12 and VPS35 suppression.Of these only 10 proteins were shared across all conditions (Figure 1H and Supplementary Figure 3C).”

It may state two separate claims as one.

SLC4A7 surface expression was decreased by SNX27 and SNX3/SNX12 suppression, validated biochemically: 47% reduction after SNX27 suppression (p = 0.0001), 82% reduction after VPS35 suppression (p < 0.0001), n = 3, one-way ANOVA; and 70% reduction after SNX3/SNX12 suppression (p = 0.0012, n = 3, unpaired t-test).

“SLC4A7 surface expression was also decreased by SNX27 and SNX3/SNX12 suppression which we validated biochemically using surface biotinylation, streptavidin affinity capture coupled with quantitative western analysis (47% reduction after SNX27 suppression (p = 0.0001), 82% reduction after VPS35 suppression (p < 0.0001), n = 3, one-way ANOVA) and a 70% reduction after SNX3/SNX12 suppression (p = 0.0”

It may state two separate claims as one.

VPS35 suppression led to endosomal swelling in rat cortical neurons, and enlarged endosomes were also found in SNX27 and SNX3/SNX12 suppressed neurons.

“As previously reported, VPS35 suppression led to endosomal swelling in the rat cortical neurons [79], with enlarged endosomes also found in our SNX27 and SNX3/SNX12 suppressed neurons, indicative of a trafficking defect (Supplementary Figure 1A).”

• cites [79] sourceNot checked yet

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

It may state two separate claims as one.

Of the depleted proteins in SNX27-suppressed neurons, LRFN2, SLC1A3 (EAAT1/GLAST), and SLC4A7 were included, all of which contain a Type I PDZbm in their carboxy terminal tail.

“Of the depleted proteins these included the synaptic adhesion protein LRFN2, the glutamate transporter SLC1A3 (EAAT1/GLAST), and the sodium bicarbonate cotransporter-3 SLC4A7, all of which contain a Type I PDZbm in their carboxy terminal tail.”

It may state two separate claims as one.

Comparing across suppression conditions in neurons, 60 integral membrane proteins were decreased by both SNX27 and VPS35 suppression, 71 proteins were decreased by both SNX3/SNX12 and VPS35 suppression, and 39 proteins were shared across all conditions.

“Comparing across the different suppression conditions, 60 integral membrane proteins were decreased by both SNX27 and VPS35 suppression whilst 71 proteins were decreased by both SNX3/SNX12 and VPS35 suppression.Of these, 39 proteins were shared across all conditions (Figure 1G and Supplementary Figure 3B).”

It may state two separate claims as one.

In SNX27-suppressed neuronal cultures, 170 integral proteins were depleted (log2 fold change -0.26, p ≤ 0.05) and 107 integral proteins were enriched (log2 fold change +0.26, p ≤ 0.05) compared with control 1.

“For SNX27 suppressed neuronal cultures, 170 integral proteins were depleted (log2 fold change -0.26, p ≤ 0.05) and 107 integral proteins were enriched (log2 fold change +0.26, p ≤ 0.05) compared with the control 1 shRNA treated neuronal cultures (Figure 1E, Supplementary Table 1).”

It may state two separate claims as one.

In astrocytes, VPS35 suppression (53% increase, p = 0.0349, n = 3, one-way ANOVA), SNX27 suppression (71% increase, p = 0.0102, n = 3, one-way ANOVA) and SNX3/SNX12 suppression (62% increase, p = 0.0317, n = 3, unpaired t-test) significantly increased endosome size compared to controls.

“Interestingly, similar to the neurons we found a significant increase in the size of the endosomes in our VPS35 (53% increase, p = 0.0349, n = 3, one-way ANOVA), SNX27 (71% increase, p = 0.0102, n = 3, oneway ANOVA) and SNX3/SNX12 (62% increase, p = 0.0317, n = 3, unpaired t-test) suppressed astrocytes compared to the relevant non-targeting shRNA treated controls (Figure 3C-D).”

It may state two separate claims as one.

In astrocytes, of 4609 quantified proteins, 137 membrane proteins were depleted (log2 fold change -0.26, p ≤ 0.05) and 56 membrane proteins were increased at the surface after VPS35 suppression (log2 fold change +0.26, p ≤ 0.05).

“Of a total of 4609 quantified proteins, 137 membrane proteins were depleted (log2 fold change -0.26, p ≤ 0.05) and 56 membrane proteins were increased at the surface after VPS35 suppression (log2 fold change +0.26, p ≤ 0.05) (Supplementary Figure 4C, Supplementary Table 6)”

It may state two separate claims as one.

Taken together, the proteomic analysis highlights several essential neuronal pathways affected by Retromer, SNX27 and SNX3/SNX12 dysfunction including the glutamatergic and GABAergic pathways, APP processing, amyloid-β uptake and lysosomal exocytosis.

“Taken together, our proteomic analysis highlights several essential neuronal pathways affected by Retromer, SNX27 and SNX3/SNX12 dysfunction including the glutamatergic and GABAergic pathways, APP processing, amyloid-β uptake and lysosomal exocytosis.”

It may state two separate claims as one.

Whilst there was a trend towards an increase in surface LAMP1 expression by western analysis after VPS35 and SNX27 suppression, the data did not reach significance.

“Whilst we did see a trend towards an increase in surface LAMP1 expression by western analysis after VPS35 and SNX27 suppression, the data did not reach significance.”

It may state two separate claims as one.

There was a significant increase in the surface expression of LAMP-1 after VPS35 suppression in the proteomic data, indicating an increase in lysosomal exocytosis.

“We also found a significant increase in the surface expression of the lysosomal-associated membrane protein-1 (LAMP-1) after VPS35 suppression in our proteomic data indicating an increase in lysosomal exocytosis (Figure 1D, Figure 2C).”

It may state two separate claims as one.

In VPS35-suppressed neuronal cultures, of 5214 quantified proteins, 133 integral proteins were significantly depleted (log2 fold change -0.26, p < 0.05) and 82 membrane proteins were enriched (log2 fold change +0.26, p < 0.05) compared with control 1.

“For the VPS35 suppressed neuronal cultures of a total of 5214 quantified proteins, 133 integral proteins were significantly depleted (log2 fold change -0.26, p < 0.05) and 82 membrane proteins were enriched (log2 fold change +0.26, p < 0.05) when compared with the control 1 shRNA treated neuronal cultures (Figure 1D, Supplementary Table 1).”

It may state two separate claims as one.

Similar to neuronal cultures, GO highlighted proteins involved in APP processing and amyloid-β response to be significantly upregulated in VPS35-suppressed astrocyte cultures, including an increase in surface APP expression.

“Similar to the neuronal cultures, GO highlighted proteins involved in APP processing and amyloid-β response to be significantly upregulated in the VPS35 suppressed astrocyte cultures, including an increase in surface APP expression (Figure 4C, Supplementary Figure 4I).”

It may state two separate claims as one.

There was evidence of an increase in the surface expression of the APP CTF in astrocytes, but the protein level was difficult to quantify.

“There was also evidence of an increase in the surface expression of the APP CTF but in astrocytes the protein level was difficult to quantify (Figure 4D).”

It may state two separate claims as one.

For increased proteins in astrocytes, 30 proteins were enriched at the surface after SNX27 and VPS35 suppression, 8 proteins were enriched after SNX3/SNX12 and VPS35 suppression, and only 5 proteins were shared across all conditions.

“For the increased proteins there were 30 proteins enriched at the surface after SNX27 and VPS35 suppression and 8 proteins enriched at the surface after SNX3/SNX12 and VPS35 suppression.Of these only 5 proteins were shared across all conditions (Figure 4B and Supplementary Figure 4G).”

It may state two separate claims as one.

Proteomic data in neurons found an increase in APP and BACE1 at the surface and a decrease in ADAM10 with SNX3/SNX12-Retromer suppression.

“In our proteomic data in neurons, we found an increase in APP and BACE1 at the surface and a decrease in ADAM10 with SNX3/SNX12-Retromer suppression.”

It may state two separate claims as one.

Comparing across neuronal and astrocytic proteomic datasets, 31 proteins were depleted from the cell surface in both neurons and astrocytes following VPS35 suppression, and 7 proteins were enriched in both cell types.

“Comparing across the neuronal and astrocytic proteomic datasets 31 proteins were depleted from the cell surface in both neurons and astrocytes (Figure 5A, Supplementary Figure 5A) and 7 proteins were enriched in both cell types following VPS35 suppression (Figure 5B, Supplementary Figure 5B).”

It may state two separate claims as one.

The GABAergic pathway is a key pathway affected after Retromer suppression, with many GABA receptor subunits decreased at the neuronal surface.

“In addition to the glutamatergic pathway, our analyses also highlighted the GABAergic pathway as a key pathway affected after Retromer suppression, with many of the GABA receptors subunits decreased at the neuronal surface.”

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

The number of high confidence predictions for a direct interaction with SNX3-Retromer is relatively low.

“The relatively low number of high confidence predictions for a direct interaction with SNX3-Retromer, however, may indicate that many of the proteins significantly altered in this condition are an indirect consequence of the role of SNX3/SNX12 in Retromer localisation to the endosomal retrieval subdomain.”

It may state two separate claims as one.

Comparing across suppression conditions in astrocytes, 60 membrane proteins were decreased by both SNX27 and VPS35 suppression, 61 proteins were decreased by both SNX3/SNX12 and VPS35 suppression, and 31 proteins were shared across all conditions.

“Comparing across the different suppression conditions, 60 membrane proteins were decreased by both SNX27 and VPS35 suppression whilst 61 proteins were decreased by both SNX3/SNX12 and VPS35 suppression suggesting that there are a similar number of cargoes for each Retromer-SNX complex.Of these, 31 proteins were shared across all conditions (Figure 4A and Supplementary Figure 4F).”

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

AlphaFold3 predicted a model of SNX3-Retromer binding to the cytoplasmic tail of ADAM10, compared to the published structure bound to DMT1-II.

“AlphaFold3 predicted model of SNX3-Retromer binding to the cytoplasmic tail of ADAM10, compared to the published structure bound to DMT1-II (PDB 5f0I).”

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

AlphaFold2 predicted a model of SNX27 interacting with the PDZbm in the cytoplasmic tail of SLC1A1 and SLC1A3.

“AlphaFold2 predicted model of SNX27 interacting with the PDZbm in the cytoplasmic tail of SLC1A1 and SLC1A3.”

It may state two separate claims as one.

Suppression of VPS35, SNX27, or SNX3/SNX12 significantly alters the surface proteome of rat cortical astrocytes.

“Venn diagrams displaying membrane proteins with significantly (F) downregulated (log2 fold change < -0.263) or (G) upregulated (log2 fold change > 0.263) surface abundance across SNX3/SNX12 (yellow), VPS35 (pink) and SNX27 (blue) depleted rat cortical astrocytes (p < 0.05) relative to control non-targeting shRNAs.”

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

SNX3-Retromer has been implicated in regulating the expression of proteins present at the cell surface.

“Moreover, SNX3-Retromer has also been implicated in regulating the expression of proteins present at the cell surface [30,[69][70][71]”

• cites [30,[69][70][71]Not matched

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

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

The de novo mutation VPS35(L625P) has been associated with early onset Alzheimer's disease.

“and the de novo mutation VPS35(L625P) which has been associated with early onset Alzheimer's disease [55].”

• cites [55] sourceNot checked — no full text of the source

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

The loss of LRFN2 was only by 18%, suggesting that it may be necessary to suppress SNX27 expression even further to see an effect on AMPA receptor expression.

“The loss of LRFN2 however was only by 18% suggesting that it may be necessary to suppress SNX27 expression even further to see an effect on AMPA receptor expression [59].”

• cites [59] McMillan KJ , Banks PJ , Hellel FL , Carmichael RE , Clairfeuille T , Evans AJ , et al. Sorting nexin-27 regulates AMPA receptor trafficking through the synaptic adhesion protein LRFN2. Elife. 2021;10. sourceNot checked yet

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

Retromer expression is significantly decreased in neurodegenerative patients.

“Retromer expression is significantly decreased in neurodegenerative patients [10][11][12][13][14]48]”

• cites [10][11][12][13][14]48]Not matched

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

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

Disturbances in the glutamatergic and GABAergic systems and an imbalance in the excitatory-inhibitory pathways are heavily implicated in neurodegenerative pathology.

“This is of interest as disturbances in the glutamatergic and GABAergic systems and an imbalance in the excitatory-inhibitory pathways are heavily implicated in neurodegenerative pathology [86][87][88].”

• cites [86] sourceNot checked — no full text of the source
• cites [87] sourceNot checked — no full text of the source
• cites [88] Capsoni S , Arisi I , Malerba F , D’Onofrio M , Cattaneo A , Cherubini E . Targeting the Cation-Chloride Co-Transporter NKCC1 to Re-Establish GABAergic Inhibition and an Appropriate Excitatory/Inhibitory Balance in Selective Neuronal Circuits: A Novel Approach for the Treatment of Alzheimer’s Disease. Brain Sci. 2022;12(6). sourceNot checked yet

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

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

SNX3 and SNX12 depletion have been shown to affect neurite outgrowth.

“Moreover, SNX3 and SNX12 depletion have been shown to affect neurite outgrowth [74][75][76].”

• cites [74] sourceNot checked — no full text of the source
• cites [75] sourceNot checked — no full text of the source
• cites [76] sourceNot checked — no full text of the source

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

Single nucleotide polymorphisms in SNX3 are associated with Alzheimer's disease.

“and single nucleotide polymorphisms (SNPs) in SNX3 are associated with Alzheimer's disease [1].”

• cites [1] sourceNot checked yet

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

It may state two separate claims as one.

Surface biotinylation was validated by western blotting, showing enrichment of the surface protein N-cadherin, which was unaffected after VPS35, SNX27 or SNX3/SNX12 suppression, and a lack of labelling of the abundant cytosolic protein β-actin.

“The efficiency of the surface biotinylation was validated by western blotting, showing an enrichment of the surface protein N-cadherin, which was unaffected after VPS35, SNX27 or SNX3/SNX12 suppression, and a lack of labelling of the abundant cytosolic protein β-actin (Supplementary Figure 2A).”

It may state two separate claims as one.

These astrocyte cultures expressed the glutamate transporter SLC1A3/GLAST and the calcium binding protein S100β, both of which are primarily expressed in astrocytes.

“These cells also expressed the glutamate transporter SLC1A3/GLAST, and the calcium binding protein S100β (Figure 3A), both of which are primarily expressed in astrocytes.”

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

SNX3 has a PX domain and, alongside Rab7A, is important for facilitating Retromer's localisation to the endosome.

“SNX3 also has a PX domain and, alongside Rab7A, has been shown to be important for facilitating Retromer's localisation to the endosome [1,25,68].”

• cites [1] sourceNot checked yet

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

• cites [25] sourceNot checked yet

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

• cites [68] sourceNot checked — no full text of the source

Probably not a substantial claim.

To control for SNX3 and SNX12 double suppression, nontargeting controls co-expressing both GFP and mCherry were used concurrently (Control 2).

“To control for the SNX3 and SNX12 double suppression, nontargeting controls co-expressing both GFP and mCherry were used concurrently (Control 2).”

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

Impairment of glutamate uptake leads to overexcitation of glutamate receptors on the post-synapse, elevated calcium influx, and ultimately excitotoxicity and neuronal death.

“Impairment of glutamate uptake leads to overexcitation of glutamate receptors present on the post-synapse leading to elevated calcium influx, and ultimately excitotoxicity and neuronal death [86,123].”

• cites [86] sourceNot checked — no full text of the source
• cites [123] sourceNot checked yet

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

DAPI was used to count the number of cells using Image J across 10 images/experiment (>400 cells/experiment) across 3 independent experimental repeats (30 images in total).

“DAPI was used to count the number of cells using Image J across 10 images / experiment (>400 cells/experiment) across 3 independent experimental repeats (30 images in total).”

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

Cell viability was measured from 2 technical repeats/condition with 4 readings per sample across three independent experiments.

“Cell viability was measured from 2 technical repeats/condition with 4 readings per sample across three independent experiments.”

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

The reduction in surface expression of SLC3A2 with SNX3/SNX12 suppression may be an indirect consequence, for example through trafficking of an independent adaptor protein.

“indicating that the reduction in surface expression of SLC3A2 with SNX3/SNX12 suppression may be an indirect consequence, for example through trafficking of an independent adaptor protein (Supplementary Table 5).”

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

Rat primary cultures were prepared in accordance with the UK Animal (Scientific Procedures) Act 1986.

“Rat primary cultures were prepared in accordance with the UK Animal (Scientific Procedures) Act 1986.”

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

The reduction of SORLA at the surface may also affect APP processing.

“which may also affect APP processing.”

Probably not a substantial claim.

All statistical analysis was performed on data from a minimum of 3 independent experimental repeats.

“All statistical analysis was performed on data from a minimum of 3 independent experimental repeats.”

Probably not a substantial claim.

For all proteomic comparisons, the p-value was adjusted using the Benjamini-Hochberg FDR method.

“For all comparisons, the p-value was adjusted using the Benjamini-Hochberg FDR method.”

Probably not a substantial claim. It may be too vague to check against evidence. It may state two separate claims as one.

Our work identifies new avenues of research and the potential for additional therapeutic targets in the treatment of neurodegenerative disease.

“Our work identifies new avenues of research and the potential for additional therapeutic targets in the treatment of neurodegenerative disease.”

Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

Our in-silico modelling is lacking post-translational modifications and membrane interactions, which may be required for the binding of SNX3-Retromer to cargo.

“Alternatively, our in-silico modelling is lacking post-translational modifications and membrane interactions, which may be required for the binding of SNX3-Retromer to cargo.”

It may state two separate claims as one.

Our data highlight a role for Retromer in the trafficking of metabotropic glutamate receptors and excitatory amino acid transporters.

“Moreover, our data has highlighted a role for Retromer in the trafficking of metabotropic glutamate receptors, which are involved in intracellular signalling pathways leading to changes in synaptic function, and the excitatory amino acid transporters which are important for glutamate uptake.”

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

Any cells that did not express S100β or the shRNA were discounted, and EEA1 Mean Area was calculated between 25-82 cells analysed per condition/experiment.

“Any cells that did not express S100β or the shRNA were discounted and the EEA1 Mean Area (µm2) calculated (between 25 -82 cells analysed per condition/experiment).”

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

Many of the proteins significantly altered upon SNX3/SNX12 suppression are an indirect consequence of the role of SNX3/SNX12 in Retromer localisation to the endosomal retrieval subdomain.

“The relatively low number of high confidence predictions for a direct interaction with SNX3-Retromer, however, may indicate that many of the proteins significantly altered in this condition are an indirect consequence of the role of SNX3/SNX12 in Retromer localisation to the endosomal retrieval subdomain.”

• AssumptionRests on an assumption: SNX3/SNX12 plays a role in Retromer localisation to the endosomal retrieval subdomain.

Probably not a substantial claim. It may be too vague to check against evidence.

The limited crossover between neuronal and astrocytic datasets highlights the importance of investigating the effect of Retromer perturbation in different cell types.

“This limited crossover highlights the importance of investigating the effect of Retromer perturbation in different cell types.”

Probably not a substantial claim. It may be too vague to check against evidence.

Our study provides new insight and increases understanding of the cargoes that depend on Retromer and its cargo adaptors SNX27 and SNX3/SNX12 for their surface expression in both neurons and astrocytes.

“Our study provides new insight and increases our understanding of the cargoes that depend on Retromer and its cargo adaptors SNX27 and SNX3/SNX12 for their surface expression in both neurons and astrocytes.”

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

Low-density lipoprotein receptors contain NPxY motifs and depend on the SNX17-Retriever endosomal sorting complex for their trafficking.

“The low-density lipoprotein receptors contain NPxY motifs and have been shown to depend on the SNX17-Retriever endosomal sorting complex for their trafficking [109, 110].”

• cites [109] sourceNot checked — no full text of the source
• cites [110] sourceNot checked yet

It may state two separate claims as one.

SLC1A1, like SLC1A3, contains a Type I PDZbm in its carboxy-terminal tail indicative of high affinity binding to SNX27, with the data suggesting that these transporters depend on the SNX27-Retromer complex for their trafficking.

“SLC1A1, like SLC1A3, contains a Type I PDZbm in its carboxy-terminal tail indicative of high affinity binding to SNX27 with our data suggesting that these transporters depend on the SNX27-Retromer complex for their trafficking.”

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

VPS35 deficiency specifically increases β-cleavage of APP, primarily thought to be driven by reduced trafficking of APP away from endosomes, resulting in increased exposure to BACE1 cleavage.

“Previous studies have demonstrated that VPS35 deficiency specifically increases β-cleavage of APP, which is primarily thought to be driven by the reduced trafficking of APP away from endosomes, resulting in increased exposure to BACE1 cleavage [135].”

• cites [135] sourceNot checked — no full text of the source

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

Total protein levels were normalised to β-actin, and surface protein levels were normalised to N-cadherin.

“Total proteins levels were normalised to the protein loading control (β-actin) whilst surface protein levels were normalised to the control protein N-cadherin.”

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

System XC - plays a key role in maintaining redox homeostasis inside cells via the uptake of cystine in exchange for glutamate, a key step in the synthesis of GSH required for reactive oxygen species (ROS)-detoxifying enzymes.

“System XC -plays a key role in maintaining redox homeostasis inside cells via the uptake of cystine in exchange for glutamate, a key step in the synthesis of GSH required for reactive oxygen species (ROS)-detoxifying enzymes [119].”

• cites [119] sourceNot checked yet

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

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

All solutions were pre-chilled to 4°C and all steps were carried out on ice to prevent internalisation during surface biotinylation.

“All solutions were pre-chilled to 4°C and all steps were carried out on ice to prevent internalisation.”

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

Perturbation of the lysosomal system and an increase in lysosomal exocytosis are increasingly being associated with neurodegenerative disease.

“Perturbation of the lysosomal system and an increase in lysosomal exocytosis are increasingly being associated with neurodegenerative disease [79,[142][143][144][145][146].”

• cites [79,[142][143][144][145][146]Not matched

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

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

Retromer, SNX3 and SNX12 have all been shown to affect APP processing and trafficking.

“Retromer, SNX3 and SNX12 have all been shown to affect APP processing and trafficking [55,73,[103][104][105]134], with this study further highlighting a significant role.”

• cites [55,73,[103][104][105]134]Not matched

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

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

AMPA and NMDA receptors are expressed in astrocytes with roles in glial excitability and neuronal activity.

“AMPA and NMDA receptors have been shown to be expressed in astrocytes with roles in glial excitability and neuronal activity [121,122].”

• cites [121] sourceNot checked — no full text of the source
• cites [122] 2020, NMDA Receptors in Astrocytes, Neurochem Res sourceNot checked yet

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

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

These glutamate transporters are essential to remove glutamate from the synaptic cleft, terminating neuronal transmission and thereby preventing aberrant glutamatergic signalling and excitotoxicity.

“These transporters are essential to remove glutamate from the synaptic cleft, terminating neuronal transmission and thereby preventing aberrant glutamatergic signalling and excitotoxicity [115,116].”

• cites [115] sourceNot checked — no full text of the source
• cites [116] sourceNot checked — no full text of the source

It may state two separate claims as one.

Knockout of SNX27 in mice leads to severe neuronal death and early lethality.

“Indeed, knockout of SNX27 in mice leads to severe neuronal death and early lethality [65] and SNX27 mutations in humans have been linked to epileptic seizures [63,64].”

• cites [65] sourceNot checked yet

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

SLC1A1 is primarily expressed in neurons, particularly at the pre-synapse, while SLC1A2 and SLC1A3 are primarily astrocytic.

“SLC1A1 is thought to be primarily expressed in neurons particularly at the pre-synapse whilst SLC1A2 and SLC1A3 are thought to be primarily astrocytic [117].”

• cites [117] Magi S , Piccirillo S , Amoroso S , Lariccia V . Excitatory Amino Acid Transporters (EAATs): Glutamate Transport and Beyond. Int J Mol Sci. 2019;20(22). sourceNot checked yet

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

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

SNX27 and Retromer interact with SORLA, which traffics APP and limits its amyloidogenic proteolysis.

“Furthermore, SNX27 and Retromer interact with the sortilin-related receptor SORLA, which traffics APP and limits its amyloidogenic proteolysis [12,[138][139][140].”

• cites [12,[138][139][140]Not matched

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

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

The amount of glutamate present in the media was measured from 2 technical repeats/condition with 2 readings per sample across three independent experiments.

“The amount of glutamate present in the media was measured from 2 technical repeats/condition with 2 readings per sample across three independent experiments.”

Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.

Accumulating evidence has highlighted Retromer as a major neuroprotective component across an array of neurodegenerative diseases.

“Accumulating evidence has highlighted Retromer as a major neuroprotective component across an array of neurodegenerative diseases.”

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

Glial cells including astrocytes, microglia and oligodendrocytes are essential for brain homeostasis and are increasingly being associated with neurodegenerative disease.

“However, glial cells including astrocytes, microglia and oligodendrocytes, are essential for brain homeostasis and are increasingly being associated with neurodegenerative disease [151].”

• cites [151] 2025, Neuroglia in neurodegeneration: Alzheimer, Parkinson, and Huntington disease, Handb Clin Neurol sourceNot checked — no full text of the source

It may state two separate claims as one.

The study identified the mechanistic basis for the recycling of several key disease associated pathways including glutamatergic and GABAergic pathways, APP processing and amyloid response, and lipoprotein receptor family.

“we have identified the mechanistic basis for the recycling of several key disease associated pathways including the glutamatergic and GABAergic pathways, APP processing and amyloid response, and the lipoprotein receptor family.”

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