Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy

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

Soluble factors secreted by activated microglia under chronic inflammation are thought to mediate aberrant synaptic phagocytosis inducing synapse loss and cognitive impairment.

“Soluble factors secreted by activated microglia under conditions of chronic inflammation have been thought to mediate aberrant synaptic phagocytosis inducing synapse loss and cognitive impairment (Butler et al., 2021; Dejanovic et al., 2018).”

• cites Butler et al., 2021 sourceNot checked — no full text of the source
• cites Dejanovic et al., 2018 sourceDisputed

  The Results report increased microglial synapse engulfment and synapse loss in Tau-P301S mice. But the co-culture experiment points to close neuron–microglia interaction rather than secreted soluble factors as the mechanism of synapse removal. The cited passages do not establish the claimed link to cognitive impairment. (LLM, conf=0.88)

  Checked by a reasoning model — may be wrong.

  Experimental — accuracy not yet measured

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

Deficiency of Apoe or Trem2 attenuates tau-dependent neuroinflammation and neurodegeneration in PS19 mice.

“Deficiency of Apoe or Trem2 attenuates tau-dependent neuroinflammation and neurodegeneration in mice expressing human P301S mutant tau (PS19 mice) (Shi et al., 2017; Leyns et al., 2017; Sayed et al., 2018).”

• cites Shi et al., 2017 sourcePartly supported

  The paper reports that ApoE knockout in P301S mice largely attenuated neuronal loss and brain atrophy (Abstract, Fig. 1) and that their microglia showed reduced activation (Abstract, Fig. 3). It does not report that Trem2 deficiency attenuates either outcome in PS19 mice; its TREM2 mentions are in references to work on amyloid. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Leyns et al., 2017Not matched

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

• cites Sayed et al., 2018 sourcePartly supported

  The Results section on atrophy and microgliosis reports that complete TREM2 deficiency protected PS19 mice against hippocampal atrophy; it also reports only a trend toward reduced microglial density. The Discussion describes lower proinflammatory markers in mice completely lacking TREM2. This paper does not establish the claim for Apoe deficiency, and its Results show that partial TREM2 deficiency increased inflammatory markers rather than attenuating them. Page numbers are unavailable 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.

Mice lacking Ch25h have normal cholesterol metabolism.

“Mice lacking Ch25h appear to have a normal phenotype, show no changes in serum cytokine levels (Bauman et al., 2009), and have normal cholesterol metabolism (Reboldi et al., 2014).”

• cites Reboldi et al., 2014 sourceSupported

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

In PS19 mice, early intracellular aggregation of tau can impair long-term potentiation, a mechanism related to synaptic plasticity and consolidation of memory.

“In PS19 mice, early intracellular aggregation of tau can impair long-term potentiation, a mechanism related to synaptic plasticity and consolidation of memory (Yoshiyama et al., 2007).”

• cites Yoshiyama et al., 2007 sourcePartly supported

  The Results (page unavailable) report significantly impaired hippocampal long-term potentiation in six-month-old PS19 mice and describe it as a measure related to learning, memory, and synaptic plasticity. The paper also reports tau aggregates at synapses, but does not establish that intracellular tau aggregation caused the LTP impairment or specifically discuss memory consolidation. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

CH25H is upregulated in Alzheimer's disease brain as well as in mouse models of amyloid and tau pathology.

“We previously reported that CH25H is upregulated in AD brain as well as mouse models of amyloid and tau pathology (Wong et al., 2020).”

• cites Wong et al., 2020 sourceSupported

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

Progression of tau pathology correlates with memory dysfunction and cognitive impairments in Alzheimer's disease.

“The progression of tau pathology has been correlated with memory dysfunction and cognitive impairments in AD (DeVos et al., 2018; Giannakopoulos et al., 2003).”

• cites DeVos et al., 2018 sourcePartly supported

  The Introduction states that accumulation of tau pathology correlates with cognitive decline, and the Discussion reports a similar correlation in PET studies of people with AD. Neither passage specifically establishes a correlation with memory dysfunction, so that part of the attributed claim is not supported by our copy. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites Giannakopoulos et al., 2003 sourceNot checked — no full text of the source

Probably not a substantial claim.

More than half of the reported genetic risk factors of Alzheimer's disease are related to microglia-mediated immune response and cholesterol metabolism.

“More than half of the reported genetic risk factors of AD are related to microglia-mediated immune response and cholesterol metabolism (Karch and Goate, 2015).”

• cites Karch and Goate, 2015 sourcePartly supported

  The Immune Response and Cholesterol Metabolism sections identify several late-onset AD risk genes associated with those pathways, and the CD33 section describes a microglial mechanism. The paper does not establish that more than half of reported AD genetic risk factors belong to those categories, nor does it characterize all of the listed immune-response genes as microglia-mediated. Section labels are available in our copy, but page numbers are not. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

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

Activated microglia may secrete one or more factors leading to neurodegeneration.

“Data also suggest that activated microglia may also secrete one or more factors leading to neurodegeneration (Leyns and Holtzman, 2017; Colonna and Butovsky, 2017).”

• cites Leyns and Holtzman, 2017Not matched

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

• cites Colonna and Butovsky, 2017 sourceSupported

Probably not a substantial claim.

Pharmacological depletion of microglia in PS19 mice decreases the age-dependent progression of tau pathology.

“In addition, pharmacological depletion of microglia in the same transgenic mice decreased the age-dependent progression of tau pathology, indicating that tau-dependent neurodegeneration may occur primarily as a result of microglial activation leading to a state of chronic neuroinflammation and subsequent neuronal cell death (Shi et al., 2019).”

• cites Shi et al., 2019 sourceSupported

It may state two separate claims as one.

25-HC disrupts synaptic plasticity and learning in mice treated with LPS.

“Related to this, we recently demonstrated that 25-HC disrupts synaptic plasticity and learning in mice treated with LPS (Izumi et al., 2021), suggesting the possibility that 25-HC may trigger tau-induced impairment of synaptic plasticity in addition to neuronal loss.”

• cites Izumi et al., 2021 sourcePartly supported

  The Results show that 25-HC inhibits long-term potentiation in hippocampal slices, and that LPS impairs both potentiation and learning in wild-type mice but not Ch25h knockout mice. The Introduction interprets the knockout findings as suggesting that 25-HC mediates or contributes to LPS-impaired learning; the paper does not directly demonstrate that 25-HC itself disrupts learning in LPS-treated mice. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

PS19 mice develop profound loss of neurons in the hippocampus and entorhinal cortex by 9 months of age, accompanied by tau hyperphosphorylation and aggregation, neurofibrillary tangle formation, and gliosis.

“PS19 mice develop a profound loss of neurons in the hippocampus and entorhinal cortex by 9 mo of age, accompanied by tau hyperphosphorylation and aggregation, neurofibrillary tangle formation, and gliosis (Yoshiyama et al., 2007).”

• cites Yoshiyama et al., 2007 sourcePartly supported

  The Results report hippocampal neuron loss by 8 months and marked hippocampal atrophy at 9 months, alongside tau pathology, neurofibrillary tangles, and gliosis. They describe neuron loss extending to the entorhinal cortex by 12 months, however, not by 9 months as the citing sentence claims. Page numbers are unavailable 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.

In the central nervous system, Ch25h is upregulated in various mouse models of neuroinflammation.

“In the central nervous system (CNS), Ch25h is upregulated in various mouse models of neuroinflammation (reviewed in The Myeloid Landscape 2 database reported in Friedman et al. [2018]).”

• cites Friedman et al., 2018 sourcePartly supported

  The Results section, under “Resources for Further Data Mining and Visualization” (page unavailable), confirms that Friedman et al. provide a searchable database of gene-expression results across mouse CNS disease models. Our copy does not state that Ch25h is upregulated in any of those models; searches for Ch25h and cholesterol 25-hydroxylase found no such passage. The citation supports identification of the database, but not the specific expression claim. (LLM, conf=0.78)

  Experimental — accuracy not yet measured

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

25-HC is believed to mediate the antiviral properties of interferon in response to infection with viral pathogens.

“Ch25h is an important interferon (IFN)-inducible gene, and 25-HC is believed to mediate the antiviral properties of IFN in response to infection with a variety of viral pathogens (Liu et al., 2013; Zu et al., 2020).”

• cites Liu et al., 2013 sourceSupported
• cites Zu et al., 2020Not 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.

Mice lacking Ch25h show no changes in serum cytokine levels.

“Mice lacking Ch25h appear to have a normal phenotype, show no changes in serum cytokine levels (Bauman et al., 2009), and have normal cholesterol metabolism (Reboldi et al., 2014).”

• cites Bauman et al., 2009 sourceSupported

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

Ch25h is an interferon-inducible gene.

“Ch25h is an important interferon (IFN)-inducible gene, and 25-HC is believed to mediate the antiviral properties of IFN in response to infection with a variety of viral pathogens (Liu et al., 2013; Zu et al., 2020).”

• cites Liu et al., 2013 sourceSupported
• cites Zu et al., 2020Not 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.

Microglial phenotype activation switches from a homeostatic state to DAM in a two-stage process that is Apoe and Trem2 dependent.

“A two-stage activation of microglial phenotype, switching from a homeostatic state to DAM, has been shown to be Apoe and Trem2 dependent (Krasemann et al., 2017; Deczkowska et al., 2018; Keren-Shaul et al., 2017).”

• cites Krasemann et al., 2017 sourcePartly supported

  The Introduction and Discussion describe a switch from homeostatic microglia to a disease-associated phenotype driven by the TREM2–APOE pathway. The Results also show that disrupting Trem2 suppresses Apoe and restores homeostatic genes. However, this paper calls the phenotype MGnD and does not describe the switch as a two-stage process to DAM; that specific characterization is not supported by this source. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Deczkowska et al., 2018 sourcePartly supported

  The Introduction describes a two-stage transition from homeostatic microglia to DAM and says that progression from stage 1 to stage 2 requires TREM2. It explicitly says the first transition is TREM2-independent and its mediating factors are unknown. It reports Apoe upregulation during that transition, but does not establish that the two-stage process is Apoe-dependent. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Keren-Shaul et al., 2017 sourcePartly supported

  The Results and Discussion (page not provided) describe a two-stage transition from homeostatic microglia to DAM: the first stage is Trem2-independent, and progression to fully activated DAM is Trem2-dependent. They report Apoe upregulation in the first stage, but do not show that activation depends on Apoe. Thus the claim’s Apoe-dependence is not supported by this paper. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

25-HC has both anti-inflammatory and proinflammatory actions depending on the model system and context.

“25-HC has also been reported to have both anti- (Reboldi et al., 2014; Dang et al., 2017) and proinflammatory (Gold et al., 2014; Fu et al., 2014) actions depending on the model system and context.”

• cites Reboldi et al., 2014 sourceSupported
• cites Dang et al., 2017 sourceSupported
• cites Gold et al., 2014 sourceNot checked yet

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

25-HC can regulate lipid metabolism in astrocytes.

“We have recently shown that 25-HC acts as an amplifier of the microglial inflammatory response (Wong et al., 2020) and can also regulate lipid metabolism in astrocytes (Cashikar et al., 2023).”

• cites Cashikar 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.

APOE and TREM2 are two major genetic risk factors for late-onset Alzheimer's disease and are highly expressed in disease-associated microglia (DAM).

“Two of the major genetic risk factors for late-onset AD, apolipoprotein E (APOE) and the triggering receptor expressed on myeloid cells 2 (TREM2), are both highly expressed in a unique subset of microglia, termed disease-associated microglia (DAM) (Keren-Shaul et al., 2017).”

• cites Keren-Shaul et al., 2017 sourcePartly supported

  The Results say that Trem2 is strongly induced in DAM, and the Discussion identifies Apoe upregulation as part of DAM activation. The Results also link Trem2 mutations to AD risk. Our copy does not establish that both genes are major genetic risk factors specifically for late-onset AD; it links Apoe to AD progression and lists a reference concerning the APOE4 allele in late-onset families. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

Only wild-type microglia produce and secrete high levels of 25-HC upon stimulation with an inflammatory challenge such as LPS; Ch25h-deficient microglia do not.

“Our previous studies with primary microglia isolated from WT and Ch25h-deficient mice show that only WT microglia produce and secrete high levels of 25-HC upon stimulation with an inflammatory challenge, such as LPS (Wong et al., 2020).”

• cites Wong et al., 2020 sourceSupported

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

Hyperphosphorylation of tau induces conformational changes that promote protein aggregation.

“Hyperphosphorylation of tau induces conformational changes that promote protein aggregation (Alonso et al., 2001).”

• cites Alonso et al., 2001 sourcePartly supported

  The Results show that hyperphosphorylation promotes tau self-assembly into filaments and tangles. The Discussion proposes that phosphorylation neutralizes inhibitory charges, allowing assembly, but does not establish the claimed conformational changes as the mechanism. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

It may state two separate claims as one.

Administration of 25-HC into the corpus callosum of mice induces potent proinflammatory activation of microglia, NLRP3 inflammasome-mediated neuroinflammation, IL-1β secretion, and cell death.

“Ch25h was reported to be upregulated in patient-derived cells of X-linked adrenoleukodystrophy, and administration of 25-HC into the corpus callosum of mice induced potent proinflammatory activation of microglia, NLRP3 inflammasome-mediated neuroinflammation, interleukin 1 beta (IL-1β) secretion, and cell death (Jang et al., 2016).”

• cites Jang et al., 2016 sourceSupported

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

p-tau induces IL-1β expression through activation of the MyD88-NF-κB pathway and NLRP3 inflammasome in a similar tauopathy mouse model.

“In a recent study by Jiang et al. (2021), p-tau was shown to induce IL-1β expression through activation of the MyD88-NF-κB pathway and NLRP3 inflammasome in a similar tauopathy mouse model (Jiang et al., 2021).”

• cites Jiang et al., 2021 sourceSupported

Probably not a substantial claim.

The proinflammatory cytokine IL-1β is a downstream target of NF-κB.

“Since the proinflammatory cytokine IL-1β is a downstream target of NF-κB (Greten et al., 2007)”

• cites Greten et al., 2007 sourceSupported

Probably not a substantial claim.

Single-cell transcriptomic analysis in AD human and AD mouse model brain tissue identified unique signatures of gene expression in microglia in physical proximity to amyloid plaques and tau aggregates, termed DAM.

“Single-cell transcriptomic analysis carried out in AD human and AD mouse model brain tissue have identified unique signatures of gene expression in microglia in physical proximity to amyloid plaques and tau aggregates, termed DAM (Keren-Shaul et al., 2017; Krasemann et al., 2017; Zhou et al., 2020).”

• cites Keren-Shaul et al., 2017 sourcePartly supported

  The Results describe single-cell RNA-seq of AD-model mouse brains identifying disease-associated microglia (DAM), with spatial analyses locating them near Aβ plaques. The Results also report Lpl-positive microglia around Aβ plaques in human AD tissue, but those human samples were examined by staining, not single-cell transcriptomics. The paper does not locate DAM near tau aggregates. (LLM, conf=0.89)

  Experimental — accuracy not yet measured
• cites Krasemann et al., 2017 sourcePartly supported

  The Results section reports distinct microglial gene-expression signatures in AD mouse models and identifies plaque-associated microglia in both APP-PS1 mice and human AD. It calls this phenotype MGnD, however, and the passages describe RNA sequencing of sorted microglial subsets rather than single-cell transcriptomic analysis. They do not establish proximity to tau aggregates. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Zhou et al., 2020 sourcePartly supported

  The Results section, “DAM signature is Trem2-dependent at early and late stages of Aβ accumulation,” identifies a DAM-expressing microglial subcluster in the 5XFAD mouse model. But “Human brain AD gene signatures are distinct from those of the 5XFAD model” says the human AD microglial signature is quite distinct from mouse DAM. The cited passages also do not establish that the sequenced microglia were physically near both amyloid plaques and tau aggregates. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

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

Recent reports have indicated that the NF-κB in activated microglia exacerbates neurodegeneration in PS19 mice.

“Recent reports have indicated that the NF-κB in activated microglia exacerbates neurodegeneration in PS19 mice (Wang et al., 2022).”

• cites Wang et al., 2022 sourceSupported

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

A previous report showed that Stat3 is highly phosphorylated in activated microglia and exacerbates neurodegeneration in PS19 mice.

“A previous report showed that Stat3 is highly phosphorylated in activated microglia and exacerbates neurodegeneration in PS19 mice (Litvinchuk et al., 2018).”

• cites Litvinchuk et al., 2018 sourcePartly supported

  The Results section on STAT3 signaling reports increased phospho-STAT3 in PS19 mice, including nuclear staining in microglia. The Results on pharmacological inhibition show that blocking STAT3 phosphorylation reduced tau pathology and neuroinflammation, but do not establish that microglial STAT3 phosphorylation itself exacerbated neuronal loss. Neuronal loss was rescued by C3aR deletion, a different intervention (Results, “C3aR inactivation rescues synapse and neuronal loss”; page unavailable). (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.

Inactivation of NF-κB in microglia of PS19 mice partially restored microglial homeostasis, decreased tau seeding and spreading, and protected against spatial learning and memory deficits.

“In another recent report, inactivation of NF-κB in microglia of PS19 mice partially restored microglial homeostasis, decreased tau seeding and spreading, and protected against spatial learning and memory deficits (Wang et al., 2022).”

• cites Wang et al., 2022 sourceSupported

It may state two separate claims as one.

The DAM microglial subset is characterized by reduced expression of homeostatic genes (e.g., Tmem119, P2ry12, Cx3cr1) and increased expression of inflammatory genes (e.g., Clec7a, Apoe, Trem2) including Ch25h.

“This microglial subset is characterized by reduced expression of homeostatic genes (e.g., Tmem119, P2ry12, Cx3cr1) and increased expression of inflammatory genes (e.g., Clec7a, Apoe, Trem2) including Ch25h (Chen and Colonna, 2021).”

• cites Chen and Colonna, 2021 sourceSupported

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

Tau-mediated neuroinflammation coincides with a marked decrease in homeostatic microglia.

“Tau-mediated neuroinflammation also coincides with a marked decrease in homeostatic microglia (Sobue et al., 2021).”

• cites Sobue et al., 2021 sourceSupported

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

Downregulation of genes necessary for cholesterol biosynthesis in 7- and 9-mo-old PS19 mice has been recently reported.

“Downregulation of genes necessary for cholesterol biosynthesis in 7- and 9-mo-old PS19 mice has been recently reported (Tsumagari et al., 2022).”

• cites Tsumagari et al., 2022 sourcePartly supported

  The Results section reports downregulation of cholesterol-biosynthesis proteins and of SREBP2 at 7 and 9 months. However, the Methods identify the mice as hTau-Tg line 2541, not PS19, and the study measured protein abundance rather than downregulation of genes. The cited paper therefore supports the pathway finding but not the specified mouse line or gene-level wording. (LLM, conf=0.89)

  Experimental — accuracy not yet measured

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

Contamination of cell-free RNA for each sample group was removed using SoupX.

“Contamination of cell-free RNA for each sample group was removed using SoupX.”

• cites Young and Behjati, 2020 sourceSupported

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

Cxcl10 is a key IFN-γ-inducible chemokine that has been previously reported to be stimulated by tau fibrils in mouse primary microglia, as well as in PS19 mice, where it may facilitate T cell infiltration into the brain.

“Cxcl10 is a key IFN-γ–inducible chemokine that has been previously reported to be stimulated by tau fibrils in mouse primary microglia (Udeochu et al., 2023), as well as in PS19 mice, where it may facilitate T cell infiltration into the brain (Chen et al., 2023).”

• cites Udeochu et al., 2023 sourceSupported
• cites Chen et al., 2023 sourceSupported

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

Decreased expression of the cholesterol biosynthetic enzymes and the cholesterol biosynthetic intermediate lanosterol, without significant changes in free cholesterol levels, has been recently reported in AD brain tissue.

“Decreased expression of the cholesterol biosynthetic enzymes and the cholesterol biosynthetic intermediate, lanosterol, without significant changes in free cholesterol levels, has also been recently reported in AD brain tissue (Varma et al., 2021).”

• cites Varma et al., 2021 sourceSupported

It may state two separate claims as one.

25-HC inhibits cholesterol synthesis and promotes cholesterol esterification in primary mouse astrocytes.

“We have recently shown that 25-HC inhibits cholesterol synthesis and promotes cholesterol esterification in primary mouse astrocytes (Cashikar et al., 2023).”

• cites Cashikar 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.

Abnormal cholesterol metabolism has been implicated in AD; both increased and decreased levels of cholesterol and its metabolites have been reported.

“Abnormal cholesterol metabolism has also been implicated in AD; however, both increased and decreased levels of cholesterol and its metabolites have been reported (Feringa and van der Kant, 2021; Sun et al., 2015; Di Paolo and Kim, 2011).”

• cites Feringa and van der Kant, 2021 sourceSupported
• cites Sun et al., 2015 sourceNot checked — no full text of the source
• cites Di Paolo and Kim, 2011 sourcePartly supported

  The introductory passage under Abstract links altered lipid metabolism and cholesterol regulation to AD. The section on cholesterol metabolism and transport describes changes in cholesterol and a metabolite in experimental AD models, but does not report both increased and decreased levels of cholesterol and its metabolites in people with AD. (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.

Exhausted activation of microglia is crucial to promoting T cell infiltration into the brain, which exacerbates neuroinflammation and neurodegeneration and impairs cognition, in two different mouse models of tauopathy (THY-tau22 and PS19 mice).

“Recent reports in two different mouse models of tauopathy (THY-tau22 and PS19 mice) suggest that exhausted activation of microglia is crucial to promoting the T cell infiltration into the brain, which exacerbates neuroinflammation and neurodegeneration and impairs cognition (Laurent et al., 2017; Chen et al., 2023).”

• cites Laurent et al., 2017 sourcePartly supported

  The Discussion (page unavailable) reports microglial CCL3 production before T-cell infiltration in THY-Tau22 mice, but says it *could* contribute to recruitment; it does not establish that exhausted microglial activation is crucial. The Results, “T cell depletion restrains cognitive deficits in THY-Tau22 mice” (page unavailable), support a role for infiltrating T cells in neuroinflammation and cognitive decline. This paper studies THY-Tau22, not PS19, and its Discussion describes T-cell recruitment in the absence of neuronal death rather than showing that infiltration exacerbates neurodegeneration. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Chen et al., 2023 sourcePartly supported

  Split into 2 atoms — 1 confirmed, 1 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.

In a mouse model of experimental autoimmune encephalomyelitis, expression of Gpr183 was demonstrated in a variety of T cells and was shown to be required for the encephalitogenic T cell infiltration into the brain.

“In a mouse model of experimental autoimmune encephalomyelitis, expression of Gpr183 was demonstrated in a variety of T cells and was shown to be required for the encephalitogenic T cell infiltration into the brain (Wanke et al., 2017).”

• cites Wanke et al., 2017 sourcePartly supported

  The ‘EBI2 Expression in T Cells Regulates Their Migration’ section reports Gpr183/EBI2 expression across several T-cell subsets. The ‘EBI2 Expression Confers Pathogenicity to Myelin-Specific Th17 Cells’ section reports reduced CNS entry by EBI2-deficient encephalitogenic T cells, but also finds that those cells can infiltrate the tissue. The paper supports a role in promoting or accelerating infiltration, not that Gpr183 is required for it. (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.

Accumulation of ceramides in the brain can be stimulated by cytokines and oxidative stress, and ceramides can amplify neuroinflammation and promote apoptosis.

“Accumulation of ceramides in the brain can be stimulated by cytokines and oxidative stress, and ceramides can amplify neuroinflammation and promote apoptosis (Alessenko and Albi, 2020).”

• cites Alessenko and Albi, 2020 sourceSupported

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

Elevated levels of ceramides and galactosyl-ceramides have been reported in the middle frontal gyrus of AD patients.

“Elevated levels of ceramides and galactosyl-ceramides have been reported in the middle frontal gyrus of AD patients (Cutler et al., 2004).”

• cites Cutler et al., 2004 sourceSupported

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

T-lymphocyte infiltration into the brain has been previously reported in AD patients and has been associated with impaired cognition.

“T-lymphocyte infiltration into the brain has been previously reported in AD patients and has been associated with impaired cognition (Gate et al., 2020; Jorfi et al., 2023).”

• cites Gate et al., 2020 sourcePartly supported

  The paper reports CD8+ T cells in AD-affected hippocampi, supporting the brain-infiltration part of the claim (Abstract; page not provided). It also reports a negative correlation between cognition and CD8+ TEMRA cells in people with MCI or AD, but that analysis concerns peripheral T cells, not the cells found in the brain. It therefore does not establish an association between brain infiltration and impaired cognition. (LLM, conf=0.87)

  Experimental — accuracy not yet measured
• cites Jorfi et al., 2023 sourcePartly supported

  The Discussion reports increased extravascular T cells in the brains of patients with AD, supporting the infiltration claim. It also says a prior finding of increased CD8+ T cells in patients’ cerebrospinal fluid suggests an impact on cognitive impairment, but it does not report an observed association between brain infiltration and impaired cognition. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

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

Abnormal levels of various phospholipids and sphingolipids have been reported in AD.

“Abnormal levels of various phospholipids and sphingolipids have also been reported in AD (Chew et al., 2020; Di Paolo and Kim, 2011; Wood, 2012; Akyol et al., 2021).”

• cites Chew et al., 2020 sourceSupported
• cites Di Paolo and Kim, 2011 sourceSupported
• cites Wood, 2012 sourceSupported

It may state two separate claims as one.

In an in vitro model of tau entry into neurons, depletion of cholesterol from the plasma membrane or addition of 24(S)-HC promoted tau entry into the cytosol whereas 25-HC reduced it.

“A recent study using an in vitro model of tau entry into neurons showed that depletion of cholesterol from the plasma membrane or addition of 24(S)-HC promoted tau entry into the cytosol whereas 25-HC reduced it (Tuck et al., 2022).”

• cites Tuck et al., 2022 sourceSupported

Probably not a substantial claim.

Astrocyte-specific deletion of SREBP2 has been reported to markedly impair brain development, neuronal function, and behavior in mice.

“Interestingly, astrocyte-specific deletion of SREBP2 has been reported to markedly impair brain development, neuronal function, and behavior in mice (Ferris et al., 2017).”

• cites Ferris et al., 2017 sourceSupported

It may state two separate claims as one.

p-tau is undetectable in WT and CKO mice and detected only in T and TCKO mice.

“As expected, p-tau was undetectable in WT and CKO mice and detected only in T and TCKO, which overexpressed human-mutant tau (Fig. 3 A).”

It may state two separate claims as one.

Percentage area covered by GFAP in TCKO mice is greater than in non-tau mice (WT and CKO) but the differences are not significant (P < 0.1348 and P < 0.1460).

“Although, the percentage of area covered by GFAP in TCKO mice was greater than that of non-tau mice (WT and CKO), the differences were not significant (P < 0.1348 and P < 0.1460).”

It may state two separate claims as one.

The percent reduction in neuronal loss is 55% for the dentate gyrus granular layer and 80% for the piriform cortex pyramidal layer.

“The percent reduction in neuronal loss observed for the DG granular layer and the pyramidal layer of the piriform cortex was 55% (Fig. S2 B) and 80%, respectively (Fig. S2 E).”

It may state two separate claims as one.

Area of GFAP immunoreactivity in TCKO brain tissue is significantly lower than in T mice in hippocampus (P < 0.01) and entorhinal/piriform cortex (P < 0.01).

“However, the area of GFAP immunoreactivity in TCKO brain tissue was significantly lower than that in T mice in the hippocampus (P < 0.01; Fig. 4 C) as well as entorhinal/piriform cortex (P < 0.01; Fig. 4 D).”

It may state two separate claims as one.

In 9.5-month-old female PS19 mice, Ch25h mRNA expression in hippocampus is increased three to fourfold compared with controls (P < 0.0001), and is absent in Ch25h knockout mice.

“By 9.5 mo of age, a stage when T mice show marked neuroinflammation and neurodegeneration, we identified a three to fourfold increase in Ch25h expression in T mice compared with controls (P < 0.0001), as well as the absence of Ch25h expression in KO mice.”

It may state two separate claims as one.

Neuronal loss in TCKO mice is markedly reduced (≥80%) and is similar to the non-transgenic control group.

“Neuronal loss in TCKO mice was markedly reduced (≥80%) and was similar to the non-transgenic control group.”

It may state two separate claims as one.

AD-tau injection induces abundant tau phosphorylation mainly in the ipsilateral hippocampus, where almost 60% of the area covered by AT8 immunoreactivity is detected, and this is similar in T and TCKO mice.

“AD-tau injection induced abundant tau phosphorylation mainly in the ipsilateral hippocampus, where almost 60% of the area covered by AT8 immunoreactivity was detected and was similar in T and TCKO mice (Fig. 3 H).”

The quote only partly states this claim.

Levels of 24S-hydroxycholesterol and 27-hydroxycholesterol in hippocampus are unaffected by tau pathology at 9.5 and 6 months.

“Although both 24S-HC and 27-HC are produced in the CNS, they were unaffected by tau pathology.”

It may state two separate claims as one.

Percentage surface area covered by Iba1 immunoreactivity is markedly reduced in TCKO mice compared with T mice in hippocampus (P < 0.05) and entorhinal/piriform cortex (P < 0.0001).

“The percentage of surface area covered by Iba1 immunoreactivity was markedly reduced in TCKO mice in comparison with T mice in the hippocampus (P < 0.05; Fig. 4 I) as well as in entorhinal/piriform cortex (P < 0.0001; Fig. 4 J).”

It may state two separate claims as one.

Microglia from TCKO mice present significant reduction in number of branches per cell compared with non-tau mice, but processes are significantly longer (P < 0.05) than microglia from T mice.

“We found that microglia from TCKO mice also present a significant reduction in the number of branches per cell compared with the non-tau mice (Fig. 4 N), but the processes were in fact significantly longer (P < 0.05) than microglia from T mice (Fig. 4 M), which suggests microglia in TCKO”

It may state two separate claims as one.

Only 8% of the ipsilateral frontal cortex area is covered by AT8 immunoreactivity, with no significant changes between T and TCKO mice.

“Only 8% of the ipsilateral frontal cortex area was covered by AT8 immunoreactivity and no significant changes between T and TCKO mice were observed (Fig. 3 J).”

It may state two separate claims as one.

Area covered by CD68 immunoreactivity is significantly reduced in hippocampus (P < 0.05) and entorhinal cortex (P < 0.0001) of TCKO mice.

“The area covered by CD68 immunoreactivity was also significantly reduced in the hippocampus (P < 0.05; Fig. 4 K) and entorhinal cortex (P < 0.0001; Fig. 4 L) of TCKO mice.”

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

T mice show a trend for increased ventricular volume that is not statistically significant (P = 0.226).

“As expected, T mice developed marked brain atrophy primarily of the hippocampus and entorhinal/piriform cortex compared with WT and CKO mice (Fig. 2, B and C), while there was a trend for increased ventricular volume that was not statistically significant (P = 0.226) (Fig. 2 D).”

It may state two separate claims as one.

Reactive astrocytes in T mice show significant reduction in length of processes and number of branches per cell (P < 0.00001).

“In the astrocyte morphology analysis (Fig. 4 B), we identified numerous reactive astrocytes in T mice, characterized by a significant reduction (P < 0.00001) in the length of the processes (Fig. 4 E) and the number of branches per cell (Fig. 4 F).”

It may state two separate claims as one.

Astrocytes from TCKO mice display significant reduction in process length and branch number compared with WT mice, and their processes are more ramified than astrocytes in T mice (P < 0.00001).

“Astrocytes from TCKO mice displayed a significant reduction in both parameters in comparison with WT mice, and the processes were more ramified than astrocytes in T mice (P < 0.00001), which is consistent with the reduction in GFAP immunoreactivity.”

It may state two separate claims as one.

About 90% of Ch25h immunoreactivity in Alzheimer's disease frontal cortex is within IBA1-positive microglia and less than 1% is in GFAP-positive astrocytes.

“About 90% of Ch25h immunoreactivity was observed within IBA1-positive microglia (Fig. 1, A, B, and D) and <1% in GFAP-positive astrocytes (Fig. 1, A and E).”

It may state two separate claims as one.

In T versus WT comparison, 2,477 genes were upregulated and 831 were downregulated.

“In T versus WT comparison, 2,477 genes were upregulated and 831 were downregulated (Fig. S4, B and C).”

It may state two separate claims as one.

In TCKO mice, P2ry12 area also remained low and did not revert to control (WT and CKO) levels.

“In TCKO mice, P2ry12 area also remained low and did not revert to control (WT and CKO) levels.”

It may state two separate claims as one.

The area covered by Tmem119 immunoreactivity remained reduced in TCKO mice in the hippocampus (P < 0.0749) and entorhinal/piriform cortex (P < 0.9999).

“Interestingly, the area covered by Tmem119 immunoreactivity remained reduced in TCKO mice in the hippocampus (Fig. 5 F; P < 0.0749) and entorhinal/piriform cortex (Fig. 5 G; P < 0.9999).”

It may state two separate claims as one.

In T mice, important DAM signature genes including Apoe, Trem2, Cst7, Clec7a, Tyrobp, Axl, C1q, Csf1, Cstd, and Cstb were among those upregulated, while in TCKO mice, a marked reduction of DAM gene expression was observed.

“As expected, in T mice, important DAM signature genes including Apoe, Trem2, Cst7, Clec7a, Tyrobp, Axl, C1q, Csf1, Cstd, and Cstb were among those upregulated, while in TCKO mice, a marked reduction of DAM gene expression was observed (Fig. S4 H and Table S3).”

It may state two separate claims as one.

Levels of desmosterol and free cholesterol in the cortex were unaffected (T versus WT: desmosterol, P < 0.6691; free cholesterol, P < 0.0794).

“Although the bulk RNA-seq analysis in the hippocampus showed the downregulation of cholesterol biosynthetic enzymes in T mice respect WT mice that were restored in TCKO mice, levels of desmosterol (Fig. S5 A) and free cholesterol (Fig. S5 B) in the cortex were unaffected (T versus WT: desmosterol, P < 0.6691; free cholesterol, P < 0.0794).”

It may state two separate claims as one.

Genes related to NF-κB and Jak/Stat pathways are highly expressed in microglia nuclei and genes related to sterol biosynthesis were highly expressed in astrocyte nuclei.

“Genes related to NF-κB and Jak/Stat pathways are highly expressed in microglia nuclei and genes related to sterol biosynthesis were highly expressed in astrocyte nuclei.”

It may state two separate claims as one.

p-Stat3 immunoreactivity was significantly increased in the microglia of T mice (P < 0.0007) and decreased in the microglia of TCKO mice (P < 0.0176).

“Consistent with previous findings, p-Stat3 immunoreactivity was significantly increased in the microglia of T mice (P < 0.0007) and decreased in the microglia of TCKO mice (P < 0.0176) (Fig. 7 G).”

It may state two separate claims as one.

Only 770 genes were upregulated and 275 were downregulated in TCKO compared with CKO mice.

“However, only 770 genes were upregulated and 275 were downregulated in TCKO compared with CKO mice”

It may state two separate claims as one.

Ch25h deficiency not only promoted an increase in the homeostatic microglia nuclei proportion but also decreased the DAM and the IFN subclusters.

“Ch25h deficiency not only promoted an increase in the homeostatic microglia nuclei proportion but also decreased the DAM and the IFN subclusters (Fig. 8 E and Table S10).”

It may state two separate claims as one.

The presence of tau pathology at 9.5 mo of age promoted a decrease in the percentage of nuclei of the homeostatic microglia (cluster 0) and an increase of DAM (cluster 1) and IFN (cluster 3) genes.

“Nuclei proportion analysis for each experimental group showed that the presence of tau pathology at 9.5 mo of age promoted a decrease in the percentage of nuclei of the homeostatic microglia (cluster 0) and an increase of DAM (cluster 1) and IFN (cluster 3) genes (Fig. 8 E and Table S10).”

It may state two separate claims as one.

Levels of lipids from cluster c were significantly elevated in T mice compared with WT mice and strikingly downregulated in TCKO mice.

“Levels of lipids from this cluster were found significantly elevated in T mice compared with WT mice and strikingly downregulated in TCKO mice”

It may state two separate claims as one.

Tau fibrils induced the expression of Il1b (P < 0.01) in WT microglia, while a negligible increase was detected in CKO microglia.

“While tau fibrils induced the expression of Il1b (gene for IL-1β; P < 0.01) in WT microglia, a negligible increase was detected in CKO microglia (Fig. 9 E).”

It may state two separate claims as one.

Tau fibrils elicited increased expression of Cxcl10 (P < 0.01) that was markedly reduced (P < 0.05) in CKO microglia treated with tau fibrils.

“Furthermore, tau fibrils elicited increased expression of Cxcl10 (P < 0.01) that was markedly reduced (P < 0.05) in CKO microglia treated with tau fibrils (Fig. 9 G).”

It may state two separate claims as one.

Genes in the GO term "regulation of cytokine production" were upregulated in a tau-specific manner in comparison to non-tau WT mice and were all downregulated in Ch25h-deficient PS19 mice.

“Analysis of the GO term “regulation of cytokine production” showed genes that were upregulated in a tau-specific manner in comparison to non-tau WT mice and were all downregulated in Ch25h-deficient PS19 mice (Fig. 6 C and Table S5).”

It may state two separate claims as one.

Reduced phosphorylation of p65 NF-κB subunit and IL-1β expression was observed in Ch25h-deficient PS19 mice.

“Consistently, reduced phosphorylation of p65 NF-κB subunit and lL-1β expression was observed in Ch25h-deficient PS19 mice.”

It may state two separate claims as one.

Secretion of IL-1β was augmented by 25-HC treatment of primary microglia and reduced in Ch25h-deficient microglia.

“Secretion of IL-1β was augmented by 25-HC treatment of primary microglia and reduced in Ch25h-deficient microglia.”

It may state two separate claims as one.

Expression of the tau transgene results in increased expression of a large number of genes whereas only a smaller number of genes are downregulated in a tau-specific manner.

“It is apparent that expression of the tau transgene results in increased expression of a large number of genes whereas only a smaller number of genes are downregulated in a tau-specific manner (Fig. S4 D).”

It may state two separate claims as one.

Our snRNA-seq analysis shows that the cholesterol biosynthetic enzymes are expressed mainly in astrocytes, which are critical for cholesterol biosynthesis in the brain.

“Our snRNA-seq analysis shows however that the cholesterol biosynthetic enzymes are expressed mainly in astrocytes which are critical for cholesterol biosynthesis in the brain.”

It may state two separate claims as one.

Ch25h-deficient microglia express increased levels of the anti-inflammatory protein IL-10, but decreased levels of the chemokine Cxcl10.

“Moreover, Ch25h-deficient microglia express increased levels of the anti-inflammatory protein, IL-10, but decreased levels of the chemokine, Cxcl10.”

It may state two separate claims as one.

Among the genes expressed in astrocytes, loss of Ch25h restored the expression of sterol biosynthesis genes, which were significantly downregulated by tau pathology in PS19 mice.

“Among the genes expressed in astrocytes, loss of Ch25h restored the expression of sterol biosynthesis genes, which were significantly downregulated by tau pathology in PS19 mice.”

It may state two separate claims as one.

Ch25h expression and 25-HC synthesis in microglia in the brains of P301S mice increase after the onset of tau pathology and are associated with neuroinflammation and neurodegeneration.

“Taken together, our results indicate that Ch25h expression and 25-HC synthesis in microglia in the brains of P301S mice increase after the onset of tau pathology and are associated with neuroinflammation and neurodegeneration.”

Probably not a substantial claim.

Ch25h converts cholesterol to 25-hydroxycholesterol (25-HC).

“Ch25h converts cholesterol to 25-hydroxycholesterol (25-HC) (Lund et al., 1998).”

• cites Lund et al., 1998 sourceNot checked — no full text of the source

It may state two separate claims as one.

Ch25h deficiency reduces tau phosphorylation and aggregation.

“Our results suggest that Ch25h deficiency reduces tau phosphorylation and aggregation.”

Probably not a substantial claim.

Neuroinflammation is a prominent neuropathological feature of Alzheimer's disease.

“Neuroinflammation is a prominent neuropathological feature of AD, and considerable genetic and experimental evidence have implicated microglia, the brain’s resident immune cell, as major drivers of innate immunity-induced neurodegeneration (Leyns and Holtzman, 2017).”

• cites Leyns and Holtzman, 2017Not matched

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

It may state two separate claims as one. The quote only partly states this claim.

The specificity of the Ch25h RNAscope probe was validated by comparing Ch25h mRNA signal in brain sections from WT and Ch25h-deficient (CKO) mice, with low background in CKO similar to negative control.

“The specificity of the Ch25h probe for RNAscope was validated by comparing the Ch25h mRNA signal in brain sections from WT and mice deficient for Ch25h (CKO).”

It may state two separate claims as one.

Microglia in TCKO mice are less activated, possibly in an intermediate state of activation.

“which suggests microglia in TCKO mice are less activated, possibly in an intermediate state of activation.”

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

Mice lacking Ch25h appear to have a normal phenotype.

“Mice lacking Ch25h appear to have a normal phenotype, show no changes in serum cytokine levels (Bauman et al., 2009), and have normal cholesterol metabolism (Reboldi et al., 2014).”

• cites Bauman et al., 2009 sourceNot checked yet

It may state two separate claims as one.

By 9.5 months of age, PS19 mice manifest marked microgliosis and astrogliosis, which have been associated with tau phosphorylation and neurodegeneration.

“By 9.5 mo of age, PS19 mice manifested marked microgliosis and astrogliosis, which have been associated with tau phosphorylation and neurodegeneration (Yoshiyama et al., 2007; Shi et al., 2017).”

• cites Yoshiyama et al., 2007 sourceNot checked yet

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

• cites Shi et al., 2017 sourceNot checked yet

Probably not a substantial claim.

Tau-dependent neurodegeneration may occur primarily as a result of microglial activation leading to chronic neuroinflammation and subsequent neuronal cell death.

“In addition, pharmacological depletion of microglia in the same transgenic mice decreased the age-dependent progression of tau pathology, indicating that tau-dependent neurodegeneration may occur primarily as a result of microglial activation leading to a state of chronic neuroinflammation and subsequent neuronal cell death (Shi et al., 2019).”

• cites Shi et al., 2019 sourceNot checked yet

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

25-HC has a protective role in blocking tau entry into neurons in vitro.

“A protective role for 25-HC in blocking tau entry into neurons has been reported in a recent in vitro study (Tuck et al., 2022).”

• cites Tuck 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.

Ch25h has several important immune-related functions involving both innate and adaptive immunity.

“Ch25h is primarily expressed in myeloid cells under inflammatory conditions and has been shown to have several important immune-related functions involving both innate and adaptive immunity (Griffiths and Wang, 2022).”

• cites Griffiths and Wang, 2022 sourceNot checked yet

It may state two separate claims as one.

Some genes show increased or decreased expression in CKO and TCKO but not in WT and T mice, suggesting that these DEGs are specifically changing due to the absence of Ch25h.

“Some genes show increased or decreased expression in CKO and TCKO but not in WT and T mice (Fig. S4 D), suggesting that these DEGs are specifically changing due to the absence of Ch25h.”

It may state two separate claims as one.

Deletion of MyD88 or the inflammasome adaptor protein ASC in these mice blocked neuroinflammation, reduced p-tau levels, and improved cognition.

“Deletion of MyD88 or the inflammasome adaptor protein ASC in these mice blocked neuroinflammation, reduced p-tau levels, and improved cognition.”

• cites Jiang et al., 2021 sourceNot checked yet

It may state two separate claims as one.

Ch25h deficiency in T mice appears to strongly decrease the progression of reactive microglia to a DAM state, but without fully reverting to a resting (homeostatic) microglial state.

“Overall, Ch25h deficiency in T mice appears to strongly decrease the progression of reactive microglia to a DAM state, but without fully reverting to a resting (homeostatic) microglial state.”

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

Conversion of homeostatic microglia into DAM is a progressive change that occurs through a TREM2-independent stage (DAM1) followed by a Trem2-dependent stage (DAM2), characterized by increased expression of genes related to microglial phagocytic activity as well as lipid metabolism (e.g., Ch25h).

“Conversion of homeostatic microglia into DAM is a progressive change that occurs through a TREM2-independent stage (DAM1) followed by a Trem2-dependent stage (DAM2), characterized by increased expression of genes related to microglial phagocytic activity as well as lipid metabolism (e.g., Ch25h) (Keren-Shaul et al., 2017).”

• cites Keren-Shaul et al., 2017 sourceNot checked yet

It may state two separate claims as one.

The elevated levels of these lipids observed in T mice with or without Ch25h suggests that this is a tau-mediated phenomenon specific to PS19 mice which may not fully replicate all the lipid changes associated with AD.

“The elevated levels of these lipids observed in T mice with or without Ch25h suggests that this is a tau-mediated phenomenon specific to PS19 mice which may not fully replicate all the lipid changes associated with AD.”

It may state two separate claims as one.

By eliminating Ch25h, much of the neurodegeneration observed in aged PS19 mice was prevented, similar to the effect observed by deleting Trem2, Apoe, or depleting microglia in PS19 mice.

“Thus, by simply eliminating one non-essential DAM gene, Ch25h, much of the neurodegeneration observed in aged PS19 mice was prevented similar to the effect observed by deleting Trem2, Apoe, or depleting microglia in PS19 mice (Leyns et al., 2017; Shi et al., 2017, 2019).”

• cites Leyns et al., 2017Not matched

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

• cites Shi et al., 2017, 2019Not matched

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

• AssumptionRests on an assumption: Ch25h is a non-essential gene.

It may state two separate claims as one.

Treatment of primary mouse microglia with the TLR4 agonist LPS markedly upregulates Ch25h expression and 25-HC secretion in addition to cytokine overproduction.

“We have previously shown that treatment of primary mouse microglia with the TLR4 agonist LPS markedly upregulates Ch25h expression and 25-HC secretion in addition to cytokine overproduction (Wong et al., 2020).”

• cites Wong et al., 2020 sourceNot checked yet

It may state two separate claims as one.

25-HC is a lipid effector that can modulate inflammatory functions of microglia.

“suggesting that 25-HC is a lipid effector that can modulate inflammatory functions of microglia.”

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

Elevated levels of oxysterols including 25-HC were detected in late-stage AD brains.

“Interestingly, elevated levels of oxysterols including 25-HC were detected in late-stage AD brains (Testa et al., 2016).”

• cites Testa et al., 2016 sourceNot checked yet

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

It may state two separate claims as one.

Ch25h triggers neuroinflammation through 25-HC secreted by microglia, leading to age-dependent neurodegeneration.

“The absence of Ch25h in PS19 mice strikingly attenuated DEGs related to these same inflammatory pathways supporting a role for Ch25h in triggering neuroinflammation through 25-HC secreted by microglia, leading to age-dependent neurodegeneration.”

It may state two separate claims as one.

Ch25h is not highly expressed under non-inflammatory conditions and thus deleting it did not cause major transcriptional changes under normal conditions.

“highlighting the fact that Ch25h is not highly expressed under non-inflammatory conditions and thus deleting it did not cause major transcriptional changes under normal conditions (Table S2).”

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

Two independent experiments were conducted for tau uptake assay and microglia gene expression.

“Two independent experiments were conducted for tau uptake assay and microglia gene expression.”

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

Gaussian distribution was evaluated using the D'Agostino & Pearson normality test.

“Gaussian distribution was evaluated using the D’Agostino & Pearson normality test.”

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

All animal procedures and experiments were performed under guidelines approved by the animal studies committee at Washington University School of Medicine.

“All animal procedures and experiments were performed under guidelines approved by the animal studies committee at Washington University School of Medicine.”

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

Clusters containing high levels of marker gene expression for non-immune cell types were removed and data were reclustered.

“Clusters containing high levels of marker gene expression for non-immune cell types were removed and data were reclustered.”

It may state two separate claims as one.

The increased sphingolipid levels in PS19 mice suggest a dysregulation of sphingolipid metabolism mediated by tau accumulation, which was restored by the loss of Ch25h.

“In our study, increased levels of sphingomyelins, cerebrosides (glucosyl- and galactosyl-ceramides) and ceramide were observed in PS19 mice suggesting a dysregulation of sphingolipid metabolism mediated by tau accumulation which was restored by the loss of Ch25h.”

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.

It is likely that 25-HC exerts synergistic effects with other cytokines and (or) chemokines as well as lipid mediators, resulting in age-dependent proinflammatory actions as well as recruitment of other immune cells into the brain.

“It is likely that 25-HC exerts synergistic effects with other cytokines and (or) chemokines as well as lipid mediators, resulting in age-dependent proinflammatory actions as well as recruitment of other immune cells into the brain.”

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

Hippocampus, posterior lateral ventricle, and entorhinal/piriform cortex areas were blinded to genotype during measurement.

“Hippocampus, posterior lateral ventricle, and entorhinal/piriform cortex areas were blinded to genotype and measured using the NDPview.2 software (Hamamatsu Photonics).”

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

Clusters containing high mitochondrial-genome content or marker genes for more than one coarse cell type were removed and data were reclustered using the first 15 PCs and a resolution of 0.2.

“Clusters containing high mitochondrial-genome content or marker genes for more than one coarse cell type (i.e., microglia and excitatory neurons) were removed and data were reclustered using the first 15 PCs and a resolution of 0.2.”

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

Nuclei with mitochondria content >5% or total UMI < 300 or > 6,000 were removed in Seurat.

“Nuclei with mitochondria content >5% or total UMI < 300 or > 6,000 were then removed in Seurat.”

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

The thickness of the CA1 pyramidal cell layer, DG granular cell layer, and pyramidal layer from the piriform cortex were blinded to genotype during measurement.

“The thickness of the CA1 pyramidal cell layer, DG granular cell layer, and pyramidal layer from the piriform cortex were blinded to genotype and measured by drawing a scale perpendicular to the cell layer at two spots in all three slices and taking the average value for each mouse using the Zen lite software (Zeiss).”