SORLA up-regulation suppresses pathological effects in aged tauopathy mouse brain

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

Expression of human APOE4 can enhance C1q accumulation and increase astrocyte-mediated synaptic pruning in mouse brain; iPSC-derived APOE4/E4 organoids feature enhanced apoptosis and impaired synaptic integrity compared to APOE3/E3 organoids.

“Previous studies have shown that expression of human APOE4 can enhance C1q accumulation and increase astrocyte-mediated synaptic pruning in mouse brain (Chung, Verghese et al. 2016); similarly, iPSC-derived APOE4/E4 organoids feature enhanced apoptosis and impaired synaptic integrity compared to APOE3/E3 organoids (Zhao, Fu et al. 2020).”

• cites Chung, Verghese et al. 2016 sourceDisputed

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

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured
• cites Zhao, Fu et al. 2020 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. It may state two separate claims as one.

SORLA has been previously shown to be an important regulator of endolysosomal trafficking, and downregulation of endosomal retromer components has been observed in AD.

“SORLA has been previously shown to be an important regulator of endolysosomal trafficking, and downregulation of endosomal retromer components has been observed in AD (Small, Simoes-Spassov et al. 2017).”

• cites Small, Simoes-Spassov et al. 2017 sourcePartly supported

  In “Endosomal Traffic Jams Can Occur as an Upstream Event” (page not provided), the paper identifies SORL1/SORLA as involved in trafficking cargo through endosomal pathways. It links retromer alterations to AD-related endosomal dysfunction, but the passages do not report an observed downregulation of retromer components in AD. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

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

Pharmacological enhancement of retromer function has been shown to upregulate SORLA and reduce Aβ and tau pathology in a 3xTg AD mouse model.

“Interestingly, pharmacological enhancement of retromer function has been shown to upregulate SORLA and reduce Aβ and tau pathology in a 3xTg AD mouse model (Li, Chiu et al. 2020).”

• cites Li, Chiu et al. 2020 sourceSupported

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

SORLA-mediated neuroprotective effects involve reduction in Aβ levels through various mechanisms, including trafficking of APP from the endosome to the Golgi or cell surface, thus attenuating amyloidogenic APP cleavage by BACE1 at late endosomes.

“SORLA-mediated neuroprotective effects involve reduction in Aβ levels through various mechanisms, including trafficking of APP from the endosome to the Golgi (Fjorback, Seaman et al. 2012) or cell surface (Huang, Zhao et al. 2016), thus attenuating amyloidogenic APP cleavage by BACE1 at late endosomes.”

• cites Fjorback, Seaman et al. 2012 sourceNot checked yet

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

• cites Huang, Zhao et al. 2016 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.

Large-scale exome-sequencing studies implicate a significant correlation between loss-of-function SORLA variants and AD onset.

“Large-scale exome-sequencing studies implicate a significant correlation between loss-of-function SORLA variants and AD onset (Raghavan, Brickman et al. 2018), and growing evidence”

• cites Raghavan, Brickman et al. 2018 sourceSupported

It may state two separate claims as one.

Apoe and C1q are key drivers of pathological degeneration in PS19 brain, with previous studies showing deletion of Apoe or C1q can suppress degenerative features such as ventricular dilation PS19 mouse brain.

“Apoe and C1q are key drivers of pathological degeneration in PS19 brain, with previous studies showing deletion of Apoe (Shi, Manis et al. 2019) or C1q (Dejanovic, Wu et al. 2022) can suppress degenerative features such as ventricular dilation PS19 mouse brain.”

• cites Shi, Manis et al. 2019 sourceSupported
• cites Dejanovic, Wu et al. 2022 sourcePartly supported

  The Results section, “C1q deletion reduces neurodegeneration in P301S mice” (page unavailable), reports that C1q knockout lessened brain-volume loss and delayed hippocampal atrophy in P301S mice. Figure 1 identifies ventricular enlargement in P301S mice, but the copy does not report a direct measurement showing that C1q deletion suppressed ventricular enlargement. The source supports reduced degeneration, but not that specific example of its suppression. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

Alterations in microglia activation state have been observed in PS19 mouse brain, and various DAM signatures have been shown to be induced in PS19 microglia.

“Alterations in microglia activation state have been observed in PS19 mouse brain, and various DAM signatures (Keren-Shaul, Spinrad et al. 2017) have been shown to be induced in PS19 microglia (Wang, Fan et al. 2022).”

• cites Keren-Shaul, Spinrad et al. 2017 sourceSupported
• cites Wang, Fan et al. 2022 sourceSupported

It may state two separate claims as one.

SORLA has been previously shown to regulate and traffic neuronal components, including sorting/trafficking the GDNF/GFRa1 complex, regulating calpain-dependent degradation of synapsin, and trafficking glutamate receptors such as GLUA1.

“Indeed, SORLA has been previously regulate and traffic neuronal components, including sorting/trafficking the GDNF/GFRa1 complex (Glerup, Lume et al. 2013), regulating calpain-dependent degradation of synapsin (Hartl, Nebrich et al. 2016), and trafficking glutamate receptors such as GLUA1 (Mishra, Knupp et al. 2022), which could consequently affect neurodegenerative outcome.”

• cites Glerup, Lume et al. 2013 sourceSupported
• cites Hartl, Nebrich et al. 2016 sourceSupported
• cites Mishra, Knupp et al. 2022 sourceSupported

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

Pharmacological stabilization of the retromer complex can attenuate amyloidogenic APP processing in primary cultured mouse neurons.

“VPS26 haploinsufficiency in mice have been shown to elevate amyloidogenic APP processing, Aβ accumulation, and induce synaptic defects (Muhammad, Flores et al. 2008), and pharmacological stabilization of the retromer complex can attenuate amyloidogenic APP processing in primary cultured mouse neurons (Mecozzi, Berman et al. 2014).”

• cites Mecozzi, Berman et al. 2014 sourceSupported

It may state two separate claims as one.

Reduced SORLA levels have been reported in AD patient lymphoblasts and brain, indicating that SORLA loss of function may be linked to AD pathogenesis.

“Reduced SORLA levels have been reported in AD patient lymphoblasts (Scherzer, Offe et al. 2004) and brain (Andersen, Reiche et al. 2005), indicating that SORLA loss of function may be linked to AD pathogenesis.”

• cites Scherzer, Offe et al. 2004 sourceNot checked — no full text of the source
• cites Andersen, Reiche et al. 2005 sourceSupported

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

SORLA is a component of the retromer endosomal trafficking complex and has been observed to bind VSP26 and SNX27 subunits of the retromer complex within the C-terminal tail domain.

“SORLA is a component of the retromer endosomal trafficking complex and has been observed to bind VSP26 (Fjorback, Seaman et al. 2012) and SNX27 (Huang, Zhao et al. 2016) subunits of the retromer complex within the C-terminal tail domain.”

• cites Fjorback, Seaman et al. 2012 sourceSupported
• cites Huang, Zhao et al. 2016 sourceSupported

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

Some SORLA variants such as the dimerization-deficient Y1816C or R953C may be linked to dominant causality in AD.

“growing evidence suggests that some SORLA variants such as the dimerization-deficient Y1816C (Jensen, Raska et al. 2024) or R953C (Fazeli, Child et al. 2024) may be linked to dominant causality in AD (Scheltens, De Strooper et al. 2021).”

• cites Jensen, Raska et al. 2024 sourceSupported
• cites Fazeli, Child et al. 2024 sourcePartly supported

  The Discussion reports genetic and functional evidence supporting R953C pathogenicity: all five affected offspring carried the variant. It does not establish dominant causality in this family; the affected mother lacked R953C, and the father’s genotype was unavailable. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Scheltens, De Strooper et al. 2021 sourcePartly supported

  The Introduction > Genetics section reports rare protein-damaging SORL1 variants in the context of Alzheimer’s disease risk. It does not identify Y1816C or R953C, describe either as dimerization-deficient, or link SORL1 variants to dominant causality. No page number is available for this passage in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

Subsequent studies have further demonstrated the association of SORL1 coding variants with late onset AD.

“Subsequent studies have further demonstrated the association of SORL1 coding variants with late onset AD (Vardarajan, Zhang et al. 2015, Cuccaro, Carney et al. 2016, Holstege, van der Lee et al. 2017, Louwersheimer, Cohn-Hokke et al. 2017).”

• cites Vardarajan, Zhang et al. 2015 sourceSupported
• cites Cuccaro, Carney et al. 2016 sourceSupported
• cites Holstege, van der Lee et al. 2017 sourcePartly supported

  The Results (Combined analysis) show that rare, strongly damaging SORL1 variants are associated with increased AD risk. However, the paper does not establish that association specifically for late-onset AD: the Methods (Samples) describe a mixed-onset discovery sample and an early-onset replication sample. The Introduction mentions late-onset AD in discussing earlier studies, rather than as a separate finding of this study. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Probably not a substantial claim.

Deletion of murine SORLA (Sorl1) showed enhanced Aβ accumulation in cortex.

“Reduced SORLA expression was originally linked to AD (Scherzer, Offe et al. 2004), while deletion of murine SORLA (Sorl1) showed enhanced Aβ accumulation in cortex (Andersen, Reiche et al. 2005).”

• cites Andersen, Reiche et al. 2005 sourceSupported

It may state two separate claims as one.

SORLA reduces APP and BACE1 interactions while directly binding and facilitating Aβ internalization and lysosomal degradation.

“In addition, SORLA reduces APP and BACE1 (Spoelgen, von Arnim et al. 2006) interactions while directly binding and facilitating Aβ internalization and lysosomal degradation (Caglayan, Takagi-Niidome et al. 2014, Liu, Zhu et al. 2020).”

• cites Spoelgen, von Arnim et al. 2006 sourceSupported
• cites Caglayan, Takagi-Niidome et al. 2014 sourceNot checked — no full text of the source
• cites Liu, Zhu et al. 2020 sourcePartly supported

  The Results section on the SORL1–TREM2–APOE regulatory axis reports that SORL1 loss or suppression reduces Aβ binding and uptake in human ESC-derived microglia, supporting a role in internalization. It does not show that SORLA directly binds Aβ or facilitates its lysosomal degradation. The APP–BACE1 interaction clause is attached to a different citation. (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.

C1q is a component of the complement pathway that accumulates at synapses to promote selective synaptic pruning during brain development and mediates pathological elimination of synapses where microglia engulf or 'prune' synapses.

“Both Apoe and C1q are also biologically associated with synaptic function; C1q is a component of the complement pathway that accumulates at synapses to promote selective synaptic pruning during brain development (Huttenlocher 1979, Feinberg 1982) and mediates pathological elimination of synapses where microglia engulf or “prune” synapses (Hong, Beja-Glasser et al. 2016).”

• cites Huttenlocher 1979Not matched

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

• cites Feinberg 1982 sourceNot checked — no full text of the source
• cites Hong, Beja-Glasser et al. 2016 sourceSupported

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

The Semaphorin protein family comprises an extracellular Sema domain as well as a Plexin-Semaphorin-Integrin domain required for mediating homotypic and heterotypic interactions.

“The Semaphorin protein family comprises an extracellular Sema domain as well as a Plexin-Semaphorin-Integrin domain required for mediating homotypic and heterotypic interactions (Zhou, Gunput et al. 2008),(Carulli, de Winter et al. 2021).”

• cites Zhou, Gunput et al. 2008 sourceNot checked — no full text of the source
• cites Carulli, de Winter et al. 2021 sourcePartly supported

  The Introduction (page not provided) says semaphorins have an extracellular Sema domain followed by a Plexin–Semaphorin–integrin domain. It attributes dimerization and interaction specificity to the Sema domain, but does not say the Plexin–Semaphorin–integrin domain is required for homotypic and heterotypic interactions. (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.

SORLA deletion as well as AD-associated Y1816C, G511R, E270K and Y141C variants can promote endosomal enlargement and dysregulated trafficking of targets such as APP and GLUA1 in iPSC-derived neurons.

“SORLA deletion as well as AD-associated Y1816C, G511R, E270K and Y141C variants can promote endosomal enlargement (Knupp, Mishra et al. 2020, Hung, Tuck et al. 2021, Mishra, Knupp et al. 2023, Jensen, Raska et al. 2024) and dysregulated trafficking of targets such as APP and GLUA1 in iPSC-derived neurons (Mishra, Knupp et al. 2022).”

• cites Knupp, Mishra et al. 2020 sourceSupported
• cites Hung, Tuck et al. 2021 sourcePartly supported

  The Results section, “Complete loss of SORL1 results in early endosome enlargement and lysosome dysfunction” (page unavailable), reports enlarged early endosomes in heterozygous and homozygous SORL1-null iPSC-derived neurons. This supports the deletion portion of the endosomal-enlargement claim, but the cited paper does not establish that the four named variants cause enlargement. The trafficking clause is attributed to a different citation in the citing sentence. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Mishra, Knupp et al. 2023 sourceSupported

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

Tau is associated with synaptic dysfunction; tau phosphorylation results in dissociation from microtubules, tau redistribution to somatodendritic compartments and synaptic dysfunction.

“Tau has been shown to be associated with synaptic dysfunction, and while tau is normally associated with and stabilizes microtubules, tau phosphorylation results in dissociation from microtubules, tau redistribution to somatodendritic compartments and synaptic dysfunction (Hoover, Reed et al. 2010, Noble, Hanger et al. 2013, Spires-Jones and Hyman 2014).”

• cites Hoover, Reed et al. 2010 sourcePartly supported

  The Discussion states that phosphorylated tau traffics to somatodendritic regions and enters dendritic spines, causing synaptic dysfunction. It also says phosphorylation changes disrupt tau–microtubule interactions, but describes the proposed release of tau from microtubules as something that “might” occur. The claim presents that release as an established step. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Noble, Hanger et al. 2013 sourceSupported
• cites Spires-Jones and Hyman 2014 sourceSupported

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

The hTau-KI human MAPT knock-in mouse model lacks apparent tau pathology, but enhances tau propagation with exposure to AD-derived tau aggregates.

“The hTau-KI human MAPT knock-in mouse model lacks apparent tau pathology, but has been shown to enhance tau propagation with exposure to AD-derived tau aggregates (Hashimoto, Matsuba et al. 2019, Saito, Mihira et al. 2019).”

• cites Hashimoto, Matsuba et al. 2019 sourcePartly supported

  The Introduction (page not provided) identifies hTau-KI mice as expressing human tau and reports no overt pathological changes in mice produced by crossing them with App knock-in mice. The paper does not report enhanced tau propagation in hTau-KI mice after exposure to AD-derived tau aggregates; its Discussion mentions aggregate seeding only in general terms. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Saito, Mihira et al. 2019 sourceSupported

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

Astrocytes feature distinctive DAA signatures in 5xFAD mice that are also altered in PS19 brain.

“Astrocytes also feature distinctive DAA signatures in 5xFAD mice (Habib, McCabe et al. 2020) that are also altered in PS19 brain (Koutsodendris, Blumenfeld et al. 2023).”

• cites Habib, McCabe et al. 2020 sourceSupported
• cites Koutsodendris, Blumenfeld et al. 2023 sourceSupported

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

Expression of β-neurexins decreases in J20 AD mouse brain; Nrxn1 is downregulated in human AD astrocytes.

“Expression of β-neurexins are also observed to decrease in J20 AD mouse brain (Naito, Tanabe et al. 2017); Nrxn1 was also seen to be downregulated in human AD astrocytes (Lau, Cao et al. 2020).”

• cites Naito, Tanabe et al. 2017 sourceSupported
• cites Lau, Cao et al. 2020 sourceSupported

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

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

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

• cites Small, Kent et al. 2005 sourceNot checked — no full text of the source
• cites Simoes, Neufeld et al. 2020 sourceCould not verify

  The citation to Simoes et al. is attached to the claim that neuronal Vps35 deletion elevates APOE in mouse CSF. The Results describe a CSF proteomic screen in neuronal-selective Vps35 knockout mice, but the reported elevations concern proteins including APLP1, CHL1, and tau; searches for APOE and apolipoprotein E found no passage reporting an APOE increase. The hippocampal and glial-activation claims are attributed to a different citation. (LLM, conf=0.76)

  Experimental — accuracy not yet measured
• cites Qureshi, Berman et al. 2022 sourceSupported

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

In AD, C1q is involved in pathologically labeling synapses for microglial elimination in response to Aβ proteotoxicity in J20 (hAPP) and PS19 mice, as well as astrocyte-mediated synapse elimination in PS19 mouse brain.

“In AD, C1q is also involved in pathologically labeling synapses for microglial elimination in response to Aβ proteotoxicity in J20 (hAPP) (Hong, Beja-Glasser et al. 2016), as well as PS19 mice (Zhong, Sheng et al. 2023), as well as astrocyte-mediated synapse elimination in PS19 mouse brain (Dejanovic, Wu et al. 2022).”

• cites Hong, Beja-Glasser et al. 2016 sourceSupported
• cites Zhong, Sheng et al. 2023 sourcePartly supported

  The Introduction says C1q accumulates at synapses in tauopathy mouse models, and the PS19 findings report complement-associated synapse loss and increased microglial engulfment. But PS19 is a tauopathy model; this paper does not attribute its PS19 findings to Aβ proteotoxicity. The citing sentence assigns the J20 and astrocyte findings to other citations, so those are not assessed here. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Dejanovic, Wu et al. 2022 sourceSupported

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

Many of the activated DAM signatures observed in 5xFAD microglia are also observed in other models of neurodegeneration including ALS or MS.

“many of the activated “disease-associated microglia” (DAM) signatures observed in 5xFAD microglia (Keren-Shaul, Spinrad et al. 2017) are also observed in other models of neurodegeneration (neurodegenerative microglia, MGnD) including amyotrophic lateral sclerosis (ALS), or multiple sclerosis (MS) (Krasemann, Madore et al. 2017).”

• cites Keren-Shaul, Spinrad et al. 2017 sourceSupported
• cites Krasemann, Madore et al. 2017 sourceSupported

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

Sema4d/PlxnB2 interactions were implicated in glial activation in response to EAE demyelination models of MS.

“Sema4d/PlxnB2 interactions were also implicated in glial activation in response to EAE demyelination models of MS (Clark, Gutierrez-Vazquez et al. 2021).”

• cites Clark, Gutierrez-Vazquez et al. 2021 sourceSupported

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

Cells with scds doublet score >0.75 were labeled as doublets and removed from downstream analysis.

“Cells with scds doublet score >0.75 were labeled as doublets and removed from downstream analysis.”

• cites Bais and Kostka 2020 sourcePartly supported

  The Discussion (page unavailable) says scds scores and ranks cells by how doublet-like they are, and that the score can inform decisions to exclude cells before downstream analysis. It does not specify a >0.75 cutoff or report removing cells at that threshold; that appears to be the citing authors’ analysis choice. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

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

Normalized GeoMx expression data for astrocytes, neurons, and microglia were batch corrected separately using removeBatchEffect with brain regions as batches.

“Normalized expression data for astrocytes (GFAP), neurons (NeuN), and microglia (Iba1) were batch corrected separately using removeBatchEffect from Limma version 3.52.4 (Ritchie, Phipson et al. 2015) using brain regions collected as batches.”

• cites Ritchie, Phipson et al. 2015 sourceSupported

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

C1q expression in microglia is an important component of astrocyte activation, with implications for microglia/astrocyte crosstalk in AD.

“C1q expression in microglia is also an important component of astrocyte activation, with implications for microglia/astrocyte crosstalk in AD (Liddelow, Guttenplan et al. 2017).”

• cites Liddelow, Guttenplan et al. 2017 sourceSupported

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

Neurexins at neuronal presynaptic terminals typically interact with neuroligins at post-synaptic densities, and mediate downstream intracellular signaling cascades through a C-terminal class II PDZ motif through interactions with CASK and protein 4.1.

“Neurexins at neuronal presynaptic terminals typically interact with neuroligins at post-synaptic densities, and mediate downstream intracellular signaling cascades through a C-terminal class II PDZ motif through interactions with the MAGUK protein kinase CASK (Hata, Butz et al. 1996) and protein 4.1 (Biederer and Sudhof 2001).”

• cites Hata, Butz et al. 1996 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
• cites Biederer and Sudhof 2001 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.

Neurexin/neuroligin interactions have been observed in neurons/astrocyte interactions potentially mediating astrocyte morphology and synaptogenesis.

“In addition to mediating synaptic function at neuronal junctions, neurexin/neuroligin interactions have been observed in neurons/astrocyte interactions potentially mediating astrocyte morphology and synaptogenesis (Stogsdill, Ramirez et al. 2017).”

• cites Stogsdill, Ramirez et al. 2017 sourceSupported

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

PlxnB1 correlates with Aβ pathology and cognitive impairment in human AD brain.

“PlxnB1 correlates with Aβ pathology and cognitive impairment in human AD brain (Mostafavi, Gaiteri et al. 2018)”

• cites Mostafavi, Gaiteri et al. 2018 sourceSupported

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

Plxnb1 can regulate microglia/astrocyte distancing and activation, where Plxnb1 deletion can enhance plaque compaction and reduce neuroinflammation in AD (APP/PS1) mouse brain.

“can regulate microglia/astrocyte distancing and activation, where Plxnb1 deletion can enhance plaque compaction and reduce neuroinflammation in AD (APP/PS1) mouse brain (Huang, Wang et al. 2024).”

• cites Huang, Wang et al. 2024 sourceSupported

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

Activation of microglia and astrocytes is a common feature of AD and other tauopathies.

“Activation of microglia and astrocytes is a common feature of AD and other tauopathies (Di Benedetto, Burgaletto et al. 2022, Chen and Yu 2023, Deng, Wu et al. 2024)”

• cites Di Benedetto, Burgaletto et al. 2022 sourcePartly supported

  Section 2.4 states that microglia and astrocytes become activated around senile plaques in AD brains. The paper discusses tau pathology in AD, but the passages do not establish that activation of both cell types is a common feature of other tauopathies. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites Chen and Yu 2023 sourcePartly supported

  The section “Neuroinflammation: a link between tau and AD” describes activation of both microglia and astrocytes in AD. The section on tau propagation says astrocytic tau pathology occurs in AD and other tauopathies, but does not establish that activation of both cell types is a common feature of other tauopathies. Page numbers are unavailable in our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites Deng, Wu et al. 2024Not 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.

A two-step strategy was used to identify and remove potential doublets and multiplets from the snRNAseq data.

“We used a two-step strategy to identify and remove potential doublets and multiplets.”

• cites Wolock et al., 2019 sourcePartly supported

  The Introduction describes Scrublet as a two-step method for identifying multiplets, and STAR Methods describes removing likely doublets. The paper focuses on doublets in single-cell RNA-seq data; it does not establish that the citing authors used the strategy on snRNA-seq data or that it detects higher-order multiplets. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Bais and Kostka 2020 sourcePartly supported

  The Introduction identifies doublets (or multiplets) as a quality-control concern, and the Discussion describes scds methods for annotating doublets. The paper does not describe the citing authors’ two-step strategy, removal of flagged nuclei, or its use on snRNA-seq data. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

Since SORLA expression is thought to be reduced or downregulated by AD-associated stop-gain variants, it is likely that SORLA dysfunction is deleterious to tau pathogenesis.

“Since SORLA expression is thought to be reduced (Scherzer, Offe et al. 2004, Andersen, Reiche et al. 2005) or downregulated by AD-associated stop-gain variants (Pottier, Hannequin et al. 2012, Nicolas, Charbonnier et al. 2016, Holstege, van der Lee et al. 2017), it is likely that SORLA dysfunction is deleterious to tau pathogenesis.”

• cites Scherzer, Offe et al. 2004 sourceNot checked — no full text of the source
• cites Andersen, Reiche et al. 2005 sourceSupported
• cites Pottier, Hannequin et al. 2012 sourceNot checked — no full text of the source

It may state two separate claims as one.

Tau seeding and aggregation, neuroinflammation, as well as PlxnB1/B2 induction are exacerbated in PS19 hippocampus with SORLA deletion.

“Tau seeding and aggregation, neuroinflammation, as well as PlxnB1/B2 induction are exacerbated in PS19 hippocampus with SORLA deletion.”

It may state two separate claims as one.

snRNA-seq analysis reveals suppression of PS19- signatures with SORLA upregulation, including proinflammatory induction of Plxnb1/Plxnb2 in glia.

“snRNA-seq analysis reveals suppression of PS19- signatures with SORLA upregulation, including proinflammatory induction of Plxnb1/Plxnb2 in glia.”

It may state two separate claims as one.

In neurons, Apoe was downregulated in PS19 vs WT and upregulated in SORLA TG/PS19 vs PS19 by snRNA-seq analysis.

“In contrast to upregulation of APOE in PS19 vs WT hippocampus in our proteomics dataset, we observed downregulation of Apoe in PS19 vs WT in neurons, and upregulation of Apoe in SORLA TG/PS19 vs PS19 comparisons by snRNA-seq analysis (cluster 1, Figure S5D, E).”

It may state two separate claims as one.

In 9-month-old PS19 hippocampus, Nrxn1 puncta were significantly reduced in astrocytes and microglia, with a trending decrease in neurons.

“We observed significantly reduced Nrxn1 puncta in astrocytes and microglia, as well as a trending decrease in Nrxn1 puncta in neurons in PS19 hippocampus; we observed significant elevation of Nrxn1 puncta in neurons and trending elevations in Nrxn1 puncta in PS19/TG compared to PS19 hippocampus (Figure S6K).”

It may state two separate claims as one.

In microglia, KO_PS19 vs KO has more DEGs compared to KO_PS19 vs PS19, and DAM signatures are significantly upregulated in KO_PS19 hippocampus compared to KO.

“In microglia, we observed more KO_PS19 vs KO DEGs compared to KO_PS19 vs PS19 (Figure S7I, Table S4), and DAM signatures showed significant upregulation in KO_PS19 hippocampus compared to KO (Figure S7J–L).”

It may state two separate claims as one.

PS19 astrocytes featured increased numbers of DAA Cluster 2 astrocytes, which were reduced in TG_PS19 hippocampus.

“PS19 astrocytes featured increased numbers of DAA Cluster 2 astrocytes, which were reduced in TG_PS19 hippocampus (Figure 5A, lower graph).”

It may state two separate claims as one.

Reclustered astrocyte snRNA-seq profiles revealed 5 clusters, with disease-associated astrocytes (DAA) residing primarily in Cluster 2.

“Reclustered astrocyte snRNA-seq profiles revealed 5 clusters (Clusters 0 through 4) (Figure 5A, B and Figure S4A, B), with disease-associated astrocytes (DAA) residing primarily in Cluster 2 (Figure 5B–D and S4C).”

It may state two separate claims as one.

Apoe and C1q were induced in 9-month-old PS19 hippocampus and normalized to near-WT levels in SORLA TG/PS19 animals.

“We found Apoe (Figure 3D–F) and C1q (Figure 3G, H) were induced in 9MO hippocampus, and consequently normalized to near-WT levels in SORLA TG/PS19 animals (Figure 3D–H).”

It may state two separate claims as one.

Nrxn1 was downregulated in all PS19 glial cell types and upregulated in SORLA TG/PS19 astrocytes and oligodendrocytes.

“Interestingly, Nrxn1 was downregulated in all PS19 glial cell types and upregulated in SORLA TG/PS19 astrocytes and oligodendrocytes (Figure S6I).”

It may state two separate claims as one.

In comparing proteomic profiles in PS19 vs TG and TG_P19 vs TG groups, C1qa, C1qb and C1qc were enriched in the GO KEGG 'complement and coagulation cascades' pathway; Apoe, Cryab, and C1qa, C1qb and C1qc were also enriched in GO CC PS19-specific (PS19 vs TG) DEPs.

“In comparing proteomic profiles in PS19 vs TG and TG_P19 vs TG groups, we observed enrichment of C1qa, C1qb and C1qc in the GO KEGG “complement and coagulation cascades” pathway; Apoe, Cryab, and C1qa, C1qb and C1qc were also enriched in GO CC PS19-specific (PS19 vs TG) DEPs (Figure S1F, G; Table S2).”

It may state two separate claims as one.

SORLA upregulation largely reversed GO CC components related to 'glutamatergic synapse' DEGs, as well as other components related to neurons, including DEGs related to GO CC 'neuron projection', 'dendrite', and 'axons'.

“SORLA upregulation largely reversed GO CC components related to “glutamatergic synapse” DEGs (Figure 6D–F), as well as other components related to neurons, including DEGs related to GO CC “neuron projection”, “dendrite”, and “axons” (Figure 6D).”

It may state two separate claims as one.

SORLA deletion increases expression of astrocyte DAA DEGs over PS19 (Aqp4, Clu, Serpina3n, Ctsb) and over KO (Aqp4, Clu, Serpina3n, C4b).

“We find that SORLA deletion can increase expression of astrocyte DAA DEGs over PS19 (KO_PS19 vs PS19; Aqp4, Clu, Serpina3n, Ctsb) as well as KO (KO_PS19 vs KO; Aqp4, Clu, Serpina3n, C4b) (Figure 8B, C and Figure S7F; Table S4)”

It may state two separate claims as one.

DAM-like DEPs including Fth1, Ctsd, Apoe, Ctsz and Cd63 were induced in PS19 hippocampus and largely attenuated in SORLA TG/PS19 animals.

“We observed induction of DAM-like DEPs in PS19 hippocampus, including Fth1, Ctsd, Apoe, Ctsz and Cd63, that were largely attenuated in SORLA TG/PS19 animals (Figure 3A).”

It may state two separate claims as one.

In PS19/TG compared to PS19 hippocampus, Nrxn1 puncta were significantly elevated in neurons and showed trending elevations.

“We observed significantly reduced Nrxn1 puncta in astrocytes and microglia, as well as a trending decrease in Nrxn1 puncta in neurons in PS19 hippocampus; we observed significant elevation of Nrxn1 puncta in neurons and trending elevations in Nrxn1 puncta in PS19/TG compared to PS19 hippocampus (Figure S6K).”

It may state two separate claims as one.

Proteomic analysis revealed shifts in synaptic proteins and microglial activation state in tau-burdened hippocampus compared to WT, and pathological changes in proteins including Apoe and C1q were reduced with SORLA upregulation.

“Proteomic analysis revealed shifts in synaptic proteins and microglial activation state in tau-burdened hippocampus compared to wildtype (WT) animals; pathological changes in proteins including key drivers of tau pathology such as Apoe and C1q were reduced with SORLA upregulation.”

It may state two separate claims as one.

P2ry12 was downregulated in PS19 hippocampus and normalized in SORLA TG/PS19 animals.

“In addition, we observed downregulation of the microglia homeostatic marker P2ry12 in PS19 hippocampus which was normalized in SORLA TG/PS19 animals (Figure S2F, G).”

It may state two separate claims as one.

SORLA upregulation enhanced uptake of tau oligomers in cultured neurons and microglia, and enhancement of tau trafficking to late/endosomes and lysosomes were observed in microglia.

“SORLA upregulation could reverse reduced expression of synaptic components such as Nrxn1 in astrocytes, neurons and microglia of PS19 hippocampus, and while SORLA upregulation enhanced uptake of tau oligomers in cultured neurons and microglia, enhancement of tau trafficking to late/endosomes and lysosomes were observed in microglia.”

It may state two separate claims as one.

C1qa was upregulated in PS19 microglia and reduced in SORLA TG/PS19 hippocampus.

“In agreement with our proteomics analysis, we also observed upregulation of C1qa in PS19 microglia which was reduced in SORLA TG/PS19 hippocampus (Figure 4F).”

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

PCA revealed good clustering of replicate animals from each genotype.

“Principal Component Analysis (PCA) revealed good clustering of replicate animals from each genotype (Figure 2A), with the highest number of differentially expressed proteins (DEPs) identified when comparing PS19 vs WT hippocampus (Figure 2B, C, and Figure S1A, B; Table S1).”

It may state two separate claims as one.

SORLA deletion increases Sema4D levels in KO_PS19 vs PS19 in 9MO hippocampus, with no significant change in het_PS19 over PS19.

“We observed increased Sema4D levels in KO_PS19 vs PS19 by immunoblot, with no significant change in het_PS19 over PS19 in 9MO hippocampus (Figure S7C, D).”

It may state two separate claims as one.

Human SORLA (SORL1) expression was not detected in WT and PS19 samples and was upregulated in neurons, glial cell types, and other cell types in SORLA TG/PS19.

“As expected, we did not detect human SORLA (SORL1) expression in WT and PS19 samples, and we observed upregulation of human SORLA (SORL1) in neurons, glial cell types such as astrocytes, oligodendrocytes, oligodendrocyte precursor cells (OPC’s) and microglia, as well as other cell types including pericytes, VLMC and endothelial cells (Figure S3C).”

It may state two separate claims as one.

Of the 42 GO CC 'synapse'-related DEPs, DEPs were downregulated in PS19 compared to other genotypes in one cluster (Cluster 1), whereas one cluster featured DEPs induced in PS19 hippocampus compared to other groups (Cluster 2).

“Of the 42 GO CC “synapse”-related DEPs, DEPs were downregulated in PS19 compared to other genotypes in one cluster (Cluster 1, Figure 2F), whereas one cluster featured DEPs induced in PS19 hippocampus compared to other groups (Cluster 2, Figure 2F).”

It may state two separate claims as one.

SORLA suppressed pathological upregulation of Sema4D receptors, PlxnB1 and PlxnB2, while its deletion increased PlxnB1/PlxnB2 levels in PS19 hippocampus.

“In addition, SORLA suppressed pathological upregulation of Sema4D receptors, PlxnB1 and PlxnB2, while its deletion increased PlxnB1/PlxnB2 levels in PS19 hippocampus.”

It may state two separate claims as one.

There is a significant increase in PlxnB1 and PlxnB2 levels in CA3 and DG regions in SORLA KO/PS19 as well as GFAP and Iba1 staining respectively compared to PS19 alone.

“We observed a significant increase in PlxnB1 and PlxnB2 levels in CA3 and DG (Figure 8D–G, and Figure S8F, G) regions in SORLA KO/PS19 as well as GFAP and Iba1 staining respectively compared to PS19 alone.”

It may state two separate claims as one.

Nrxn1 is downregulated in response to tau proteotoxicity in PS19 hippocampus over glial and neuronal cell types, and its expression is restored with SORLA upregulation.

“Our observations here indicate that neurexins, namely Nrxn1 is also downregulated in response to tau proteotoxicity in PS19 hippocampus over glial and neuronal cell types, and its expression is restored with SORLA upregulation.”

It may state two separate claims as one.

Nrxn1 is downregulated in PS19 hippocampus across glia and neuronal cell types and is restored with SORLA upregulation.

“we observed downregulation of the synaptic cell-adhesion receptor, Nrxn1 in PS19 hippocampus across glia and neuronal cell types which was restored with SORLA upregulation.”

It may state two separate claims as one.

PlxnB1 and PlxnB2 are markedly upregulated in PS19 hippocampus compared to WT in the hippocampal CA3 region, and this is suppressed in SORLA TG/PS19 animals.

“Since we observed marked upregulation of PlxnB1 and PlxnB2 in PS19 hippocampus compared to WT in the hippocampal CA3 region which was suppressed in SORLA TG/PS19 animals (Figure 7B, C)”

It may state two separate claims as one.

Plxnb1 and Plxnb2 are both highly upregulated in astrocytes and microglia in PS19 respectively.

“Our observations that Plxnb1 and Plxnb2 are both highly upregulated in astrocytes and microglia in PS19 respectively”

It may state two separate claims as one.

SORLA upregulation can attenuate both microglia and astrocyte activation.

“As our results strongly indicate that SORLA upregulation can attenuate both microglia and astrocyte activation”

It may state two separate claims as one.

SORLA upregulation enhances tau uptake in both neurons and microglia, and increases tau trafficking to late endosomes/lysosomes in microglia.

“Our results indicate that SORLA upregulation enhances tau uptake in both neurons and microglia, and increases tau trafficking to late endosomes/lysosomes in microglia.”

It may state two separate claims as one.

PlxnB1 levels in SORLA KO hippocampus are comparable to WT, and appear elevated in PS19 DG region.

“We found PlxnB1 levels in SORLA KO hippocampus comparable to WT, and appeared to be elevated in PS19 DG region (Figure S8F, G).”

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

SORL1 variants were initially identified in association with late-onset AD, and siRNA-mediated SORLA downregulation enhanced amyloidogenic APP trafficking and processing.

“SORL1 variants were initially identified in SORL1 locus in association with late-onset AD, and siRNA-mediated SORLA downregulation enhanced amyloidogenic APP trafficking and processing (Rogaeva, Meng et al. 2007).”

• cites Rogaeva, Meng et al. 2007 sourceNot checked yet

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

GWAS have linked SORLA (SORL1, LR11) gene variants with altered AD risk.

“Recent genome wide association studies (GWAS) have linked multiple gene variants with altered AD risk, including the class I membrane receptor endosomal trafficking factor, SORLA, or “Sortilin-related receptor containing LDLR class A repeats” (SORL1, LR11) (Lambert, Ibrahim-Verbaas et al. 2013, Kunkle, Grenier-Boley et al. 2019).”

• cites Lambert, Ibrahim-Verbaas et al. 2013Not matched

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

• cites Kunkle, Grenier-Boley et al. 2019Not matched

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

It may state two separate claims as one.

SORLA upregulation reverses pathological effects in aged PS19 mouse brain, including tau phosphorylation and seeding, ventricle dilation, synapse loss, LTP impairment and glial hyperactivation.

“Here, we show that transgenic SORLA upregulation (SORLA TG) can reverse pathological effects in aged PS19 (P301S tau) mouse brain, including tau phosphorylation and seeding, ventricle dilation, synapse loss, LTP impairment and glial hyperactivation.”

It may state two separate claims as one.

These results suggest that genes related to synaptic maintenance and function were potentially altered in PS19 hippocampus, and largely attenuated in SORLA TG/PS19 animals.

“These results suggest that genes related to synaptic maintenance and function were potentially altered in PS19 hippocampus, and largely attenuated in SORLA TG/PS19 animals.”

It may state two separate claims as one.

Together, these results indicate that global SORLA upregulation can suppress pathological glial activation and synaptic signatures in PS19 hippocampus.

“Together, these results indicate that global SORLA upregulation can suppress pathological glial activation and synaptic signatures in PS19 hippocampus.”

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

Nlgn1-Nrxn1 interaction stabilize and facilitate proper function of synaptic junctions.

“Nlgn1-Nrxn1 interaction stabilize and facilitate proper function of synaptic junctions (Sudhof 2008).”

• cites Sudhof 2008 sourceNot checked yet

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

It may state two separate claims as one.

Together these results suggest that SORLA deletion can potentially enhance while SORLA upregulation can attenuate pathology in neurons in vivo.

“Together these results suggest that SORLA deletion can potentially enhance while SORLA upregulation can attenuate pathology in neurons in vivo.”

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

Pharmacological retromer enhancement can reduce Aβ and ptau levels in iPSC-derived neurons with AD-associated SORLA variants (G511R, E270K, Y141C) or deletion/haploinsufficiency.

“Similarly, pharmacological retromer enhancement can reduce Aβ and ptau levels in iPSC-derived neurons with AD-associated SORLA variants (G511R, E270K, Y141C) or deletion/haploinsufficiency (Mishra, Knupp et al. 2023).”

• cites Mishra, Knupp et al. 2023 sourceNot checked yet

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

It may state two separate claims as one.

SORLA upregulation could attenuate neurogenerative phenotypes such as brain atrophy, as well as various transcripts related to synaptic proteins, indicating that SORLA upregulation has strong neuroprotective effects in neurons.

“SORLA upregulation could attenuate neurogenerative phenotypes such as brain atrophy, as well as various transcripts related to synaptic proteins, indicating that SORLA upregulation has strong neuroprotective effects in neurons.”

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

SORLA variants have also been identified in inherited late-onset AD, and familial SORLA variants have also been linked to early onset AD in European populations.

“Interestingly, SORLA variants have also been identified in inherited late-onset AD (Fernandez, Black et al. 2016), and familial SORLA variants have also been linked to early onset AD in European populations (Pottier, Hannequin et al. 2012, Nicolas, Charbonnier et al. 2016, Verheijen, Van den Bossche et al. 2016).”

• cites Fernandez, Black et al. 2016Not matched

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

• cites Pottier, Hannequin et al. 2012 sourceNot checked — no full text of the source
• cites Nicolas, Charbonnier et al. 2016 sourceNot checked — no full text of the source

It may state two separate claims as one.

Together, our results indicate that SORLA upregulation can reverse neuronal signatures and targets in PS19 hippocampus, and enhance tau uptake and trafficking to lysosomes in neurons.

“Together, our results indicate that SORLA upregulation can reverse neuronal signatures and targets in PS19 hippocampus, and enhance tau uptake and trafficking to lysosomes in neurons. However, retromer levels are not significantly perturbed in PS19 neurons or PS19 mouse brain.”

It may state two separate claims as one.

SORLA upregulation prevents pathological ventricular enlargement, tau phosphorylation and seeding, synaptic loss, impaired synaptic plasticity and glial hyperactivation in transgenic PS19 mouse hippocampus expressing human P301S tau.

“Here, we provide evidence that SORLA upregulation prevents pathological ventricular enlargement, tau phosphorylation and seeding, synaptic loss, impaired synaptic plasticity and glial hyperactivation in transgenic PS19 mouse hippocampus expressing human P301S tau.”

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

Reduced SORLA expression was originally linked to AD.

“Reduced SORLA expression was originally linked to AD (Scherzer, Offe et al. 2004), while deletion of murine SORLA (Sorl1) showed enhanced Aβ accumulation in cortex (Andersen, Reiche et al. 2005).”

• cites Scherzer, Offe et al. 2004 sourceNot checked — no full text of the source

It may state two separate claims as one.

This suggests that while SORLA upregulation can attenuate synaptic uptake in vivo, SORLA upregulation can also enhance uptake of tau oligomers in vitro.

“This suggests that while SORLA upregulation can attenuate synaptic uptake in vivo, SORLA upregulation can also enhance uptake of tau oligomers in vitro.”

It may state two separate claims as one.

These results together indicate that SORLA upregulation can reduce AT8 ptau and seed-competent tau in PS19 brain.

“These results together indicate that SORLA upregulation can reduce AT8 ptau and seed-competent tau in PS19 brain.”

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

Deletion of a neuron-specific VPS26 isoform (VPS26b) in mouse brain is associated with decreased total and cell-surface SORLA levels, as well as increased murine brain Aβ and CSF tau.

“Interestingly, deletion of a neuron-specific VPS26 isoform (VPS26b) in mouse brain is associated with decreased total and cell-surface SORLA levels, as well as increased murine brain Aβ and CSF tau (Simoes, Guo et al. 2021), implicating interdependent roles for retromer, SORLA and AD pathology.”

• cites Simoes, Guo et al. 2021 sourceNot checked yet

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

It may state two separate claims as one.

Together, these results demonstrate that SORLA upregulation reverses pathological changes in synaptic structure, function and plasticity in tau-burdened hippocampus and implicates enhanced SORLA expression as an upstream driver for global neuroprotective effects in a tauopathy mouse model.

“Together, these results demonstrate that SORLA upregulation reverses pathological changes in synaptic structure, function and plasticity in tau-burdened hippocampus and implicates enhanced SORLA expression as an upstream driver for global neuroprotective effects in a tauopathy mouse model.”

Probably not a substantial claim.

Expression of retromer components have been shown to be downregulated in AD.

“Expression of retromer components have been shown to be downregulated in AD (Small, Kent et al. 2005).”

• cites Small, Kent et al. 2005 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.

VPS26 haploinsufficiency in mice have been shown to elevate amyloidogenic APP processing, Aβ accumulation, and induce synaptic defects.

“VPS26 haploinsufficiency in mice have been shown to elevate amyloidogenic APP processing, Aβ accumulation, and induce synaptic defects (Muhammad, Flores et al. 2008), and pharmacological stabilization of the retromer complex can attenuate amyloidogenic APP processing in primary cultured mouse neurons (Mecozzi, Berman et al. 2014).”

• cites Muhammad, Flores et al. 2008 sourceNot checked — no full text of the source

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

Transgenic expression of human SORLA reduces Aβ accumulation and pathology in APP/PS1 AD mice.

“In contrast, transgenic expression of human SORLA reduces Aβ accumulation and pathology in APP/PS1 AD mice (Caglayan, Takagi-Niidome et al. 2014).”

• cites Caglayan, Takagi-Niidome et al. 2014 sourceNot checked — no full text of the source

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

p-value correction for multiple testing using the Bonferroni method was performed for differential expression analysis.

“p-value correction for multiple testing using the Bonferroni method was performed using Seurat under default settings.”

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

Multiple testing correction was performed with the Benjamini and Hochberg approach using MSstats.

“multiple testing correction was performed with the Benjamini and Hochberg approach using MSstats.”

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

SORLA can interact directly with tau through interactions with the N-terminal SORLA VSP10 domain, and SORLA can promote tau aggregation and seeding from tau-enriched fractions in AD brain samples in an HEK293 tau-RD FRET biosensor model.

“recent evidence suggests that SORLA can interact directly with tau through interactions with the N-terminal SORLA VSP10 domain, and SORLA can promote tau aggregation and seeding from tau-enriched fractions in AD brain samples in an HEK293 tau-RD FRET biosensor model (Cooper, Lathuiliere et al. 2024)”

• cites Cooper, Lathuiliere et al. 2024 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.

Microglia and astrocytes feature overlapping transcriptomic signatures that coincide with activation in Aβ or tau mouse models of neurodegeneration and proteotoxicity.

“Together, these results indicate that microglia and astrocytes feature overlapping transcriptomic signatures that coincide with activation in Aβ or tau mouse models of neurodegeneration and proteotoxicity.”

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

All procedures involving animals were performed under the guidelines of SBMRI Institutional Animal Care and Use Committee.

“All procedures involving animals were performed under the guidelines of Sanford-Burnham Medical Research Institute (SBMRI) Institutional Animal Care and Use Committee.”

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

APOE can bind to activated C1q and inhibit activation of the classical complement cascade.

“APOE can bind to activated C1q and inhibit activation of the classical complement cascade (Yin, Ackermann et al. 2019).”

• cites Yin, Ackermann et al. 2019 sourceNot checked yet

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

Use of the PS19 tauopathy model only features tau pathology in the absence of Aβ pathology; transgenic or humanized APP models may be needed to better recapitulate neurodegenerative effects associated with SORLA modulation in AD.

“We also note that use of the PS19 tauopathy model only features tau pathology in the absence of Aβ pathology; transgenic or humanized APP models may be needed to better recapitulate neurodegenerative effects associated with SORLA modulation in AD.”

• AssumptionRests on an assumption: The PS19 tauopathy model features tau pathology in the absence of Aβ pathology.

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

APOE/C1q complexes correlate with cognitive impairment and atherosclerosis in the choroid plexus in mouse and human AD brain, implicating that disease pathogenesis may involve direct interactions between APOE and C1q.

“APOE/C1q complexes also correlated with cognitive impairment and atherosclerosis in the choroid plexus in mouse and human AD brain, implicating that disease pathogenesis may involve in direct interactions between APOE and C1q (Yin, Ackermann et al. 2019).”

• cites Yin, Ackermann et al. 2019 sourceNot checked yet

It may state two separate claims as one.

SORLA upregulation can attenuate, while SORLA deletion can aggravate pathological tau phosphorylation and seeding in aged PS19 mouse brain, where tau pathology resides mostly within neurons.

“Our results here indicate that SORLA upregulation can attenuate, while SORLA deletion can aggravate pathological tau phosphorylation and seeding in aged PS19 mouse brain, where tau pathology resides mostly within neurons.”

• AssumptionRests on an assumption: Tau pathology in PS19 mouse brain resides mostly within neurons.

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

All samples in RNAscope analysis were stained concurrently and imaged with the same confocal microscope settings.

“All samples were stained concurrently and images were acquired using a Zeiss 880 Confocal Microscope at 63x magnification.”

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

Humanized tau models such as hTau feature age-dependent tau pathology, neuronal loss and memory deficits.

“humanized tau models such as the hTau model comprising a P1-derived artificial chromosome (PAC) copy of the human MAPT gene locus in a murine Mapt KO background (Duff, Knight et al. 2000, Tucker, Meyer et al. 2001, Andorfer, Kress et al. 2003) also feature age-dependent tau pathology, neuronal loss and memory deficits (Andorfer, Kress et al. 2003, Andorfer, Acker et al. 2005, Polydoro, Acker et al”

• cites Duff, Knight et al. 2000 sourceNot checked — no full text of the source
• cites Tucker, Meyer et al. 2001 sourceNot checked — no full text of the source
• cites Andorfer, Kress et al. 2003 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.

Signatures associated with microglia DAM states as well as MHC-related transcripts are also observed in PS19 mouse models.

“Signatures associated with microglia DAM states as well as MHC-related transcripts are also observed in PS19 mouse models (Udeochu, Amin et al. 2023, Wang, Martini-Stoica et al. 2024).”

• cites Udeochu, Amin et al. 2023 sourceNot checked yet
• cites Wang, Martini-Stoica et al. 2024Not 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.

We avoided imputation of missing values prior to statistical testing using MSstats; instead we calculated pseudo Log2 fold-change, adj.pvalue and pvalue of proteins completely missing in one condition.

“We avoided imputation of missing values prior to statistical testing using MSstats; instead we calculated pseudo Log2 fold-change (L2FC), adj.pvalue and pvalue of proteins completely missing in one condition in proteins with missing values.”

It may state two separate claims as one.

APOE is a mediator of both Aβ and tau pathogenesis.

“indicating that APOE is a mediator of both Aβ and tau pathogenesis.”

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

Apoe deletion in mice results in synaptic loss and cognitive impairment, which could be restored by peripheral Apoe expression.

“Apoe deletion in mice results in synaptic loss and cognitive impairment, which could be restored by peripheral Apoe expression (Lane-Donovan, Wong et al. 2016).”

• cites Lane-Donovan, Wong et al. 2016 sourceNot checked yet

Probably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.

SORLA is expressed in a variety of CNS cell types, and pathological effects due to AD stop-gain variants are likely derived from combined effects from glia, neurons and functional cross-talk between various CNS cell types.

“SORLA is expressed in a variety of CNS cell types, and pathological effects due to AD stop-gain variants are likely derived from combined effects from glia, neurons and functional cross-talk between various CNS cell types.”

• AssumptionRests on an assumption: SORLA is expressed in a variety of CNS cell types.

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

For each comparison, all groups within a replicate experiment were stained simultaneously to avoid batch variation and imaged at the same fluorescent intensity.

“For each comparison, all groups within a replicate experiment were stained simultaneously to avoid batch variation and imaged at the same fluorescent intensity.”

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

Sema4d is a potential driver of astrogliosis in AD mouse brain.

“Sema4d is a potential driver of astrogliosis in AD mouse brain (Evans, Mishra et al. 2022).”

• cites Evans, Mishra et al. 2022 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.

Lower quality cells with >10% mitochondrial reads and top 2% quantile of nFeature_RNA were removed from the snRNAseq dataset.

“Lower quality cells with >10% mitochondrial reads and top 2% quantile of nFeature_RNA (number of detected genes) were removed.”

It may state two separate claims as one.

While SORLA upregulation can suppress PlxnB1/B2 levels, SORLA deletion can exacerbate PlxnB1/B2 expression.

“This suggests that while SORLA upregulation can suppress PlxnB1/B2 levels, SORLA deletion can exacerbate PlxnB1/B2 expression.”

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

Plxnb1 levels are associated with increased Aβ load and clinical degenerative features by targeted proteomic analysis in human AD brain.

“Plxnb1 levels are also associated with increased Aβ load and clinical degenerative features by targeted proteomic analysis in human AD brain (Yu, Petyuk et al. 2018)”

• cites Yu, Petyuk et al. 2018 sourceNot checked yet

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

SORLA haploinsufficiency in minipigs results in elevated Aβ and tau CSF levels with little change in brain Aβ/tau pathology.

“Interestingly, SORLA haploinsufficiency in minipigs results in elevated Aβ and tau CSF levels with little change in brain Aβ/tau pathology (Andersen, Bogh et al. 2022).”

• cites Andersen, Bogh et al. 2022Not 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.

The P301S tauopathy model used here features varied, yet strong pathological effects and is widely characterized in the AD/tauopathy field.

“Although the P301S tauopathy model used here features varied, yet strong pathological effects and is widely characterized in the AD/tauopathy field”

• AssumptionRests on an assumption: The P301S tauopathy model features varied, yet strong pathological effects and is widely characterized in the AD/tauopathy field.

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

SORLA deletion results in endosomal and lysosomal defects in iPSC-derived neurons.

“Previous groups have reported that SORLA deletion results in endosomal (Knupp, Mishra et al. 2020, Hung, Tuck et al. 2021), as well as lysosomal defects (Hung, Tuck et al. 2021) in iPSC-derived neurons.”

• cites Knupp, Mishra et al. 2020 sourceNot checked yet

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

• cites Hung, Tuck et al. 2021 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.

Expression of human APOE4 exacerbates pathological features including tau pathology, ventricle dilation and glial activation.

“expression of human APOE4 is seen to exacerbate pathological features including tau pathology, ventricle dilation and glial activation (Shi, Yamada et al. 2017).”

• cites Shi, Yamada et al. 2017Not 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.

Samples were integrated using Harmony with sample as the variable to remove batch effects.

“RunPCA was used to perform PCA on the scaled data and subsequently the samples were integrated using Harmony’s RunHarmony function with samples as the variable to remove.”

• cites Korsunsky, Millard et al. 2019 sourceNot checked yet

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

APOE and C1q are key drivers of tau pathogenesis in PS19 brain and important mediators of synaptic function.

“In addition to being key drivers of tau pathogenesis in PS19 brain, APOE and C1q have been shown to be important mediators of synaptic function.”

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

Dysregulation of AD risk factors such as APOE affects both Aβ and tau pathogenesis in various mouse models.

“In the case of APOE, dysregulation of these AD risk factors affect both Aβ and tau pathogenesis in various mouse models.”

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

It is not possible to specifically determine how cell-specific modulation of SORLA can affect tau using the global transgenic overexpression/deletion models used here.

“While it is not possible to specifically determine how cell-specific modulation of SORLA can affect tau using the global transgenic overexpression/deletion models used here”

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

Murine Apoe deletion reduced Aβ deposition in various transgenic APP mouse models.

“Murine Apoe deletion reduced Aβ deposition in various transgenic APP mouse models (Bales, Verina et al. 1997, Bales, Verina et al. 1999, Holtzman, Fagan et al. 2000, Irizarry, Cheung et al. 2000, Ulrich, Ulland et al. 2018)”

• cites Bales, Verina et al. 1997 sourceNot checked — no full text of the source
• cites Bales, Verina et al. 1999 sourceNot checked — no full text of the source
• cites Holtzman, Fagan et al. 2000Not 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.

Sequencing depth (nCount_RNA) and percent mitochondrial reads were regressed out during the ScaleData step in the snRNAseq analysis.

“Sequencing depth (nCount_RNA) and percent mitochondrial reads were regressed out during the ScaleData step.”

• Also stated in: § METHOD DETAILS · plain

  “Data was scaled using ScaleData and the effects of sequencing depth (nCount_RNA) and mitochondrial percentage were regressed out.”

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

The false identification rate was set to 1%.

“The false identification rate was set to 1%.”

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

Twelve images per condition from biological triplicate were taken for tau biosensor quantification.

“Twelve images per condition from biological triplicate were taken for quantification using ImageJ.”

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

All experiments in figures (including supplemental figures) were repeated at least three times (independent experiments) unless specified otherwise in the figure legends.

“All experiments in figures (including supplemental figures) were repeated at least three times (independent experiments) unless specified otherwise in the figure legends.”

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

Segments that failed GeoMx QC metrics were removed from downstream analysis.

“Segments that failed the QC metrics were removed from downstream analysis.”

Probably not a substantial claim.

Reducing tau levels can attenuate synaptic impairment in hAPP and APP23 mouse models.

“reducing tau levels can attenuate synaptic impairment in hAPP (Roberson, Scearce-Levie et al. 2007) and APP23 (Ittner, Ke et al. 2010) mouse models”

• cites Roberson, Scearce-Levie et al. 2007 sourceNot checked — no full text of the source
• cites Ittner, Ke et al. 2010 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.

For mRNA dot quantification, an optimal threshold was established for each stain and all samples were quantified using the same settings.

“For the number of mRNA dots, an optimal threshold was established for each stain in Fiji ImageJ and all the samples were quantified utilizing the same settings.”

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

Removal of the neuronal APOE4 transgene in APOE4/PS19 mice attenuates tau pathology, ventricle dilation, gliosis and neuronal hyperexcitability.

“Removal of the neuronal APOE4 transgene in APOE4/PS19 mice attenuates tau pathology, ventricle dilation, gliosis and neuronal hyperexcitability (Koutsodendris, Blumenfeld et al. 2023)”

• cites Koutsodendris, Blumenfeld et al. 2023 sourceNot checked yet

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

To quantify percent area covered, an optimal threshold was established for each stain in Fiji ImageJ and all samples were quantified using matched threshold settings.

“To quantify percent area covered, an optimal threshold was established for each stain in Fiji ImageJ and all the samples were quantified using matched threshold settings.”

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

PlxnB1/B2 and Sema4D levels have been shown to be upregulated in aged thy-TAU22 mice by bulk RNAseq analysis and PlxnB1 in human GRN-FTD astrocytes.

“Interestingly, PlxnB1/B2 and Sema4D levels have been shown to be upregulated in aged thy-TAU22 mice by bulk RNAseq analysis (Sierksma, Lu et al. 2020) and in PlxnB1 in human GRN-FTD astrocytes (Gerrits, Giannini et al. 2022) (Figure S8E).”

• cites Sierksma, Lu et al. 2020 sourceNot checked yet
• cites Gerrits, Giannini et al. 2022 sourceNot checked yet

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