Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease
Open accessAbstract
Huntington’s disease is associated with a reactive microglial response and consequent inflammation. To address the role of these cells in disease pathogenesis, we depleted microglia from R6/2 mice, a rapidly progressing model of Huntington’s disease marked by behavioural impairment, mutant huntingtin (mHTT) accumulation, and early death, through colony-stimulating factor 1 receptor inhibition (CSF1Ri) with pexidartinib (PLX3397) for the duration of disease. Although we observed an interferon gene signature in addition to downregulated neuritogenic and synaptic gene pathways with disease, overt inflammation was not evident by microglial morphology or cytokine transcript levels in R6/2 mice. Nonetheless, CSF1Ri-induced microglial elimination reduced or prevented disease-related grip strength and object recognition deficits, mHTT accumulation, astrogliosis, and striatal volume loss, the latter of which was not associated with reductions in cell number but with the extracellular accumulation of chondroitin sulphate proteoglycans (CSPGs)—a primary component of glial scars. A concurrent loss of proteoglycan-containing perineuronal nets was also evident in R6/2 mice, and microglial elimination not only prevented this but also strikingly increased perineuronal nets in the brains of naïve littermates, suggesting a new role for microglia as homeostatic regulators of perineuronal net formation and integrity.
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TL;DR
In R6/2 Huntington’s disease mice, sustained CSF1R inhibition with PLX3397 removed microglia and lessened motor and memory deficits, mutant huntingtin buildup, astrogliosis, and striatal shrinkage. The protection coincided with normalized extracellular CSPG deposition and perineuronal nets, while microglial loss in healthy mice increased PNN density.
Key findings
- CSF1Ri depleted microglia across brain regions in R6/2 and non-transgenic mice. R6/2 mice had higher striatal and motor cortex microglial densities but did not show classical activation; treatment prevented grip strength deficits through Week 11 and improved novel object recognition in the first cohort, with no effect on Rotarod performance.
- Microglial elimination reduced striatal EM48+ nuclear inclusions by about 25% (P ≤ 0.05), lowered soluble monomeric and oligomeric mHTT (P ≤ 0.05 and P ≤ 0.001), reduced insoluble high-molecular-weight mHTT (P ≤ 0.05), and prevented ubiquitinated protein accumulation, without changing mHTT transcript levels.
- R6/2 striatum showed increased CD44 and widespread CSPG accumulation, plus PNN loss in motor and somatosensory cortex. CSF1Ri reduced CSPG in striatum, somatosensory cortex, and dentate gyrus and restored PNNs; in naive mice, CSF1Ri increased PNN density in every region examined.
- Microglial depletion prevented R6/2 striatal volume loss and astrogliosis, despite increased NeuN+ density and altered MAP2/tau signal. RNA-seq revealed an interferon signature resembling human Huntington’s disease caudate that was partially resolved with treatment.
Methods
- Five-week-old male R6/2 mice and non-transgenic littermates received AIN-76A chow containing PLX3397 at 275 mg/kg or vehicle from Week 6 until sacrifice at Week 11; the first cohort had 5–6 mice/group, with a replication cohort of 8–10/group. CAG repeats were confirmed at 126–130.
- Behavioral testing included Rotarod, forelimb grip strength, open field, and novel object recognition. Tissue was analyzed by immunohistochemistry and confocal microscopy, stereology of the anterior caudoputamen, Western blot fractionation, qPCR, NanoString immune profiling, and RNA-seq.
- Additional wild-type C57BL/6J mice were treated for 10 weeks with PLX5622 at 1200 mg/kg for PNN analysis. Statistics used t-tests, two-way ANOVA with Tukey post hoc, and MIXED procedures for repeated measures, with blinding for behavioral and histological assays.
Limitations
- Stated: the R6/2 model is aggressive and short-lived, so the authors call for validation in longer-lived models such as BACHD or zQ175; peripheral PLX3397 effects on skeletal muscle macrophages could contribute to grip strength changes; the second cohort’s novel object recognition result was not significant, possibly due to immobility and exclusions; and R6/2 lacks the broad neuroinflammation seen in end-stage human Huntington’s disease.
- Evident: transcriptomic comparisons used only three mice per group, and several findings rely on trends rather than significant differences, such as piriform cortex CSPG (P = 0.08) and some PNN measures. Treatment began presymptomatically at Week 6, so postsymptomatic benefit was not tested.
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- Findingown data§ Figure 2 Continued · p. 10
In the detergent-soluble fraction, CSF1Ri and microglial depletion significantly lowered monomeric (P≤0.05) and oligomeric (P≤0.001) mHTT.
“CSF1Ri and microglial depletion significantly reduced both monomeric ( P 5 0.05) and oligomeric ( P 5 0.001) mHTT in the detergent-soluble fraction”
Quote in the paperSubstantial claim - Findingown data§ Figure 2 Continued · p. 10
RNAseq showed no significant group differences in Kit or Flt3 transcript levels.
“no significant differences were detected in their transcript levels ( Kit , Flt3 ) by RNAseq across groups”
Quote in the paperSubstantial claim - Findingown data§ Microglial depletion reduces mHTT accumulation and disease-related protein clearance pathway dysregulation · p. 10
EM48+ signal in microglia was confined to cytoplasmic CD68+ lysosomal granules.
“when we found EM48 + staining in microglia it was localized to cytoplasmic CD68 + lysosomal granules”
Quote in the paperNot a substantial claim - Findingown data§ Figure 2 Continued · p. 13
CSF1Ri left mHTT expression unchanged.
“that CSF1Ri did not alter mHTT expression”
Quote in the paperSubstantial claim - Findingown data§ Figure 2 Continued · p. 13
CSF1Ri fully prevented the rise in ubiquitination in R6/2 mice.
“CSF1Ri completely prevented this phenotype”
Quote in the paperSubstantial claim
- Findingown data§ Figure 1 Continued · p. 8
Microglial elimination was followed by loss of microglial gene expression in control and R6/2 mice.
“Microglial elimination was followed by tell-tale loss of microglial gene expression in control (not shown) and R6/2 mice (Fig. 3C).”
Quote in the paperSubstantial claim - Findingown data§ Figure 1 Continued · p. 8
Pathway analysis of R6/2 versus control brain predicted IFN as the primary cytokine regulator of disease DEGs.
“Thus, pathway analysis of the R6/2 versus control brain predicted IFN as the”
- Also stated in: § Figure 2 Continued · p. 11 · plain
“IPA predicted IFN as the major cytokine upstream regulator in the R6/2 striatum”
Quote in the paperNot a substantial claim - Also stated in: § Figure 2 Continued · p. 11 · plain
- Findingown data§ Figure 1 Continued · p. 10
In R6/2, the inflammatory transcripts Il6 and Il1b were below detection limits.
“inflammatory transcripts such as Il6 and Il1b were in fact below detection limits”
Quote in the paperSubstantial claim - Findingown data§ CSF1Ri via PLX3397 ameliorates grip strength and novel object recognition deficits in R6/2 mice · p. 6
Treatment did not affect Huntington's disease-related Rotarod performance deficits.
“We did not observe any effect of treatment on Huntington's disease-related Rotarod performance deficits (Fig. 1E).”
Quote in the paperNot a substantial claim - Findingown data§ Figure 2 Continued · p. 10
c-Kit and Flt3 staining did not co-localize with neurons or microglia.
“Staining for c-Kit and Flt3 revealed no co-localization with neurons or microglia”
Quote in the paperSubstantial claim - Findingown data§ R6/2 striatal mRNA expression reveals dysregulated interferon signalling that is mitigated by CSF1Ri · p. 8
Even at FDR < 0.1, few inflammation-related DEGs were found in R6/2 striatal tissue.
“However, even at FDR 5 0.1, few inflammation-related DEGs were found in R6/2 striatal tissue (Fig. 2G).”
Quote in the paperNot a substantial claim - Findingown data§ R6/2 striatal mRNA expression reveals dysregulated interferon signalling that is mitigated by CSF1Ri · p. 8
No evidence of disease-related inflammation in terms of cytokine transcript expression (Il6, Il1b, Ifng, Tnfa) was found at the 11-week time point using the NanoString panel.
“Surprisingly, we found no evidence of diseaserelated inflammation in terms of cytokine transcript expression ( Il6 , Il1b , Ifng , Tnfa ) at the 11-week time point using this panel.”
Quote in the paperNot a substantial claim - Findingown data§ Figure 1 Continued · p. 8
Comparison of activation z-scores of significantly overrepresented pathways in human control versus Huntington's disease caudate to those in control versus R6/2 striatal tissue found concordance between the mouse model and the human disease.
“We compared the activation z -scores of significantly overrepresented pathways in human control versus Huntington's disease caudate [ z -score overall = 41.23; gene expression data taken from Hodges et al. , (2006)] to those in control versus R6/2 striatal tissue and found concordance between the mouse model and the human disease (Fig. 3D).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Hodges et al., 2006 source
Not checked in the free run.
- Findingown data§ CSF1Ri via PLX3397 ameliorates grip strength and novel object recognition deficits in R6/2 mice · p. 6
A second cohort replicated the behavioural tasks, producing similar results.
“Finally, to verify cognitive and motor improvements with CSF1Ri in this model, these behavioural tasks were replicated in a second cohort of n = 10/group (Fig. 1F-I), producing similar results.”
Quote in the paperSubstantial claim - Findingown data§ R6/2 microglia display regional differences but are ubiquitously depleted with CSF1Ri · p. 6
Microglial cell body area and IBA1 intensity were significantly increased only in the motor and somatosensory cortices.
“Microglial cell body area (Fig. 2D) and IBA1 intensity (Fig. 2E) were significantly increased only in the motor ( P 5 0.01, P 5 0.01) and somatosensory cortices ( P 5 0.05, P 5 0.05).”
Quote in the paperNot a substantial claim - Findingown data§ Figure 1 Continued · p. 8
CSF1Ri prevented the disease-associated suppression of Isl1 and Cacna2d2.
“Among other genes, CSF1Ri prevented the disease-associated suppression of Isl1 , a gene involved in motor neuron development (Liang et al. , 2011) the conditional deletion of which results in striatal cholinergic interneuron loss (Elshatory and Gan, 2008), as well as Cacna2d2 , mutations in which decrease Ca 2+ channel subunit expression and drive epileptic seizures (Barclay et al. , 2001; Pipp”
Quote in the paperNot a substantial claim0 of 3 sources checked - Findingown data§ Figure 1 Continued · p. 10
These impairments occurred without a broad inflammatory transcriptional signature.
“These impairments occurred in the absence of an extensive inflammatory transcriptional signature.”
Quote in the paperSubstantial claim - Findingown data§ Figure 1 Continued · p. 8
Differential expression occurred in the absence of detectable changes in endogenous wild-type Htt transcript levels across groups.
“Importantly, this differential expression occurred in the absence of detectable changes in endogenous wild-type Htt transcript levels across groups.”
Quote in the paperNot a substantial claim - Findingown data§ Figure 1 Continued · p. 10
Usp18 expression was markedly increased in Huntington's disease.
“Interestingly, Usp18 was markedly increased in Huntington's disease”
Quote in the paperNot a substantial claim - Findingown data§ R6/2 striatal mRNA expression reveals dysregulated interferon signalling that is mitigated by CSF1Ri · p. 8
PCA of normalized gene counts revealed separate clustering of control and R6/2 tissue both prior to and following CSF1Ri.
“PCA of normalized gene counts revealed separate clustering of control and R6/2 tissue both prior to and following CSF1Ri (Fig. 2F).”
Quote in the paperNot a substantial claim - Findingown data§ Figure 6 Continued · p. 17
This increase coincided with IBA1+ microglial depletion (P≤0.001).
“this was accompanied by the depletion of IBA1 + microglia ( P 5 0.001”
Quote in the paperSubstantial claim - Findingown data§ CSF1Ri-driven microglial elimination ubiquitously increases the density of ECM PNNs, which are degraded in the R6/2 brain · p. 17
CSF1Ri microglial elimination prevented disease-associated PNN loss in somatosensory and motor cortices (P≤0.001 and 0.05, respectively).
“Microglial elimination with CSF1Ri prevented the disease-associated PNN loss observed in the somatosensory and motor cortices ( P 5 0.001 and 0.05, respectively)”
Quote in the paperSubstantial claim - Findingown data§ Figure 4 Continued · p. 13
MBP staining showed higher striatal white matter density in disease (P≤0.01).
“Staining for MBP revealed increased striatal white matter density with disease ( P 5 0.01)”
Quote in the paperNot a substantial claim - Findingown data§ Figure 4 Continued · p. 13
CSF1Ri and microglial depletion prevented this astrogliosis.
“This was prevented with CSF1Ri and microglial depletion”
Quote in the paperSubstantial claim - Findingown data§ Figure 5 Continued · p. 15
Extracellular CSPG accumulated strikingly and widely throughout the R6/2 brain.
“we observed a striking and ubiquitous accumulation of extracellular CSPG throughout the R6/2 brain”
Quote in the paperSubstantial claim - Findingown data§ Figure 4 Continued · p. 13
This prevention occurred without changes in neuronal density.
“independent of changes in neuronal density”
Quote in the paperSubstantial claim - Findingown data§ CSF1Ri-driven microglial elimination ubiquitously increases the density of ECM PNNs, which are degraded in the R6/2 brain · p. 17
In these regions, R6/2 microglia showed a more activated phenotype by cell size and IBA1+ intensity.
“regions where microglia had adopted a more activated phenotype in R6/2 mice as measured by cell size and IBA1 + intensity”
Quote in the paperSubstantial claim - Findingown data§ Figure 4 Continued · p. 13
Striatal astrocyte analysis showed marked disease-related astrogliosis by integrated S100β signal density (P≤0.0001).
“analysis of striatal astrocytes revealed marked disease-related astrogliosis as measured by integrated S100 b signal density ( P 5 0.0001”
Quote in the paperSubstantial claim - Findingown data§ CSF1Ri-driven microglial elimination ubiquitously increases the density of ECM PNNs, which are degraded in the R6/2 brain · p. 17
In Huntington's disease striatum, parvalbumin-expressing interneurons showed significantly lower mean WFA+ co-staining intensity (P≤0.01).
“parvalbumin-expressing interneurons in the Huntington's disease striatum displayed a significant reduction ( P 5 0.01) in mean WFA + co-staining intensity”
Quote in the paperSubstantial claim - Findingown data§ Figure 6 Continued · p. 17
Compared with vehicle, PLX5622 significantly increased WFA+ PNNs in somatosensory cortex (P≤0.0001).
“WFA + PNNs in the somatosensory cortex were significantly enhanced with PLX5622 treatment compared to vehicle ( P 5 0.0001”
Quote in the paperSubstantial claim - Findingown data§ Figure 4 Continued · p. 13
CSF1Ri microglial elimination fully prevented the striatal volume loss seen in R6/2 mice.
“microglial elimination via CSF1Ri completely prevented the decrease in striatal volume observed in R6/2 mice”
Quote in the paperSubstantial claim - Findingown data§ Figure 2 Continued · p. 13
In control mice, microglial removal increased ubiquitination (P≤0.05).
“the removal of microglia from control mice enhanced ubiquitination ( P 5 0.05)”
Quote in the paperNot a substantial claim - Findingown data§ Figure 2 Continued · p. 13
In CSF1Ri-treated R6/2 mice, striatal p62 was significantly lower (P≤0.05).
“Striatal p62 was significantly reduced in CSF1Ri-treated R6/2 mice ( P 5 0.05)”
Quote in the paperSubstantial claim - Findingown data§ Figure 4 Continued · p. 13
In R6/2 striatum, integrated MAP2 (P≤0.0001) and tau (P≤0.0001) fluorescent signal densities were significantly higher.
“We found significant elevations in the integrated densities of MAP2 ( P 5 0.0001) and tau ( P 5 0.0001) fluorescent signal in the R6/2 striatum”
Quote in the paperSubstantial claim - Findingown data§ CSF1Ri-driven microglial elimination ubiquitously increases the density of ECM PNNs, which are degraded in the R6/2 brain · p. 17
PNN reductions trended in striatum and piriform cortex.
“with trends to reduction seen in regions of lower PNN density and intensity (striatum, piriform cortex”
Quote in the paperNot a substantial claim - Findingown data§ Figure 4 Continued · p. 13
Huntington's disease genotype significantly affected Olig2+ oligodendrocyte lineage cell counts (P≤0.01).
“a significant effect of the Huntington's disease genotype on Olig2 + oligodendrocyte lineage cell number ( P 5 0.01”
Quote in the paperNot a substantial claim - Findingown data§ Figure 5 Continued · p. 15
Across all samples, global CSPG signal correlated directly with CD44 expression (Pearson r=0.8505, P≤0.0001).
“global CSPG signal varied directly with CD44 expression, regardless of experimental group (Pearson correlation coefficient r = 0.8505, P 5 0.0001”
Quote in the paperNot a substantial claim - Findingown data§ Figure 2 Continued · p. 13
R6/2 striatal p62 levels were not statistically higher than control levels.
“although levels were not statistically higher in these compared to controls”
Quote in the paperNot a substantial claim - Findingown data§ CSF1Ri-driven microglial elimination ubiquitously increases the density of ECM PNNs, which are degraded in the R6/2 brain · p. 17
Microglial depletion in naïve non-transgenic mice markedly and significantly raised PNN densities in all brain regions examined.
“the depletion of microglia from naı ¨ve non-transgenic mice significantly and dramatically elevated PNN densities in every brain region examined”
Quote in the paperSubstantial claim - Findingown data§ CSF1Ri-driven microglial elimination ubiquitously increases the density of ECM PNNs, which are degraded in the R6/2 brain · p. 17
IBA1+ microglial processes often lay near and touched PNN surfaces in both control and R6/2 brains.
“IBA1 + microglial processes were frequently observed proximal to and in contact with the surface of PNNs in both control and R6/2 brains”
Quote in the paperSubstantial claim - Findingown data§ CSF1Ri-driven microglial elimination ubiquitously increases the density of ECM PNNs, which are degraded in the R6/2 brain · p. 17
Among regions examined, PNNs were consistently most abundant in somatosensory cortex.
“PNNs were always most abundant in the somatosensory cortex”
Quote in the paperNot a substantial claim - Findingown data§ Figure 7 Continued · p. 20
In our dataset, the homeostatic microglial gene P2ry12 was lost from R6/2 striatum (FDR 5 0.1, LogFC = -0.7083 versus control).
“The loss of the homeostatic microglial gene P2ry12 (Bennett et al. , 2018) from the R6/2 striatum in our dataset (FDR 5 0.1, LogFC = -0.7083 versus control)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Bennett et al. , 2018 source
Not checked in the free run.
- Findingown data§ Figure 7 Continued · p. 20
In contrast to CS-56 staining, WFA+ PNN density was lost with disease in motor and somatosensory cortices.
“and in stark contrast to CS-56 staining, we found a loss of WFA + PNN density with disease in motor and somatosensory cortices.”
Quote in the paperNot a substantial claim- Rests on an assumption: CSPGs are core structural elements of conventional PNNs.
- Findingown data§ Figure 7 Continued · p. 20
The PNN, a distinct CSPG-containing structure related to those above, shows region-specific disruption in disease.
“Finally, we show that a related but distinct CSPG-containing structure, the PNN, is disrupted in a region-specific manner with disease”
Quote in the paperNot a substantial claim- Rests on an assumption: CSPGs are core structural elements of conventional PNNs.
- Findingown data§ Figure 7 Continued · p. 20
Depleting microglia from healthy non-transgenic mice produced a dramatic and widespread accumulation of PNNs.
“Surprisingly, the depletion of microglia from healthy, non-transgenic mice produced a dramatic and ubiquitous accumulation of PNNs”
Quote in the paperSubstantial claim - Findingown data§ Figure 7 Continued · p. 20
Microglial depletion was accompanied by reduced striatal mHTT accumulation.
“Microglial depletion was accompanied by a reduction in striatal mHTT accumulation”
Quote in the paperNot a substantial claim - Findingown data§ Figure 7 Continued · p. 20
There was massive accumulation of extracellular CSPG with disease.
“Furthermore, we report a massive accumulation of extracellular CSPG with disease”
Quote in the paperSubstantial claim - Findingown data§ Figure 7 Continued · p. 20
In R6/2 brain, this CSPG buildup tracked with loss of striatal volume, astrogliosis, and neuropil changes.
“which is associated with striatal volume loss, astrogliosis, and neuropil alterations in the R6/2 brain”
Quote in the paperSubstantial claim - Findingown data§ Figure 7 Continued · p. 20
CSF1Ri-induced microglial depletion prevented all of these phenotypes in part or in full.
“and microglial depletion with CSF1Ri partially or completely prevented each of these phenotypes.”
Quote in the paperSubstantial claim - Findingown data§ Figure 7 Continued · p. 20
In R6/2 Huntington's disease mice, long-term CSF1R inhibition reduced deficits in grip strength and object memory.
“In conclusion, we show that sustained CSF1R inhibition in the R6/2 mouse model of Huntington's disease, which exhibited elevated microglial numbers but not broad inflammation at the transcriptional or morphological level, mitigated grip strength and object memory deficits.”
Quote in the paperSubstantial claim - Premisecitation§ Introduction · p. 3
A pharmacological method based on CSF1R inhibition can eliminate virtually all (>99%) microglia from the murine brain for several months.
“Previously, we developed a pharmacological method to eliminate virtually all ( 99%) microglia from the murine brain for several months at a time (Elmore et al. , 2014; Dagher et al. , 2015), based on inhibition of colony-stimulating factor 1 receptor (CSF1Ri).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data§ Figure 2 Continued · p. 10
The observed effects are attributable specifically to microglial CSF1R inhibition and the resulting microglial depletion.
“supporting the notion that the effects seen here are due specifically to the inhibition of microglial CSF1R and subsequent microglial depletion”
Quote in the paperSubstantial claim - Interpretationreasoning§ Figure 1 Continued · p. 10
The increase in Usp18 suggests mobilization of compensatory mechanisms in R6/2 striatum.
“suggesting the mobilization of relevant compensatory mechanisms in the R6/2 striatum”
Quote in the paperNot a substantial claim - Interpretationreasoning§ Figure 2 Continued · p. 13
The mHTT protein changes did not track transcript abundance.
“thus suggesting that changes in protein level were independent of transcript abundance”
Quote in the paperSubstantial claim - Interpretationreasoning§ Figure 2 Continued · p. 10
Removing microglia lowers neuronal mHTT buildup.
“suggests that elimination of microglia reduces neuronal mHTT accumulation”
Quote in the paperSubstantial claim - Interpretationown data§ Figure 1 Continued · p. 10
The R6/2 model probably does not reproduce all neuroinflammatory features seen in end-stage human Huntington's disease.
“indicating that this model likely does not fully recapitulate the neuroinflammation observed in endstage human Huntington's disease”
Quote in the paperSubstantial claim0 of 3 sources checked - Interpretationreasoning§ CSF1Ri via PLX3397 ameliorates grip strength and novel object recognition deficits in R6/2 mice · p. 6
The failure to achieve statistical significance in novel object recognition with the second cohort may be attributed to the rapid progression of the model, as many R6/2 mice were largely immobile/lethargic at Week 11 just prior to sacrifice, increasing the number of animals excluded during novel object training and consequently decreasing statistical power.
“The failure to achieve statistical significance in novel object recognition with this second cohort may be attributed to the rapid progression of the model, as many R6/2 mice were largely immobile/lethargic at Week 11 just prior to sacrifice, increasing the number of animals excluded during novel object training and consequently decreasing statistical power.”
Quote in the paperNot a substantial claim - Interpretationown data§ R6/2 microglia display regional differences but are ubiquitously depleted with CSF1Ri · p. 6
'Classical' microglial activation is not an overt feature of the R6/2 brain.
“Together, this suggests that 'classical' microglial activation is not an overt feature of the R6/2 brain.”
Quote in the paperNot a substantial claim - Premisecitation§ Figure 7 Continued · p. 20
Human striatal samples analyzed for pathways showed higher astrocyte and CSPG mRNA in disease.
“Importantly, the same human striatal samples used for pathway analysis also displayed elevated astrocyte and CSPG mRNA with disease (Hodges et al. , 2006).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Hodges et al. , 2006 source
Not checked in the free run.
- Premisecitation§ CSF1Ri-driven microglial elimination ubiquitously increases the density of ECM PNNs, which are degraded in the R6/2 brain · p. 17
In the anterior caudate of Huntington's disease patients, parvalbumin interneurons are reduced by roughly 75%.
“Parvalbumin interneurons are reduced in number by 75% in the anterior caudate of patients with Huntington's disease”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Reiner et al., 2013 source
Not checked in the free run.
- Interpretationown data§ Figure 2 Continued · p. 13
Myeloid cells might contribute to homeostatic clearance of non-microglial proteins.
“suggesting a potential role for these myeloid cells in homeostatic non-microglial protein clearance”
Quote in the paperNot a substantial claim - Interpretationown data§ Figure 2 Continued · p. 13
CSF1Ri-driven microglial depletion slows buildup of several mHTT species in R6/2 striatum, at least partly by reversing defective protein clearance.
“Together, these data suggest that microglial depletion via CSF1Ri slows the accumulation of multiple species of mHTT in the R6/2 striatum by at least partially reversing dysfunctional protein clearance systems.”
Quote in the paperSubstantial claim - Premisecitation§ Microglial depletion with CSF1Ri prevents R6/2 striatal atrophy · p. 13
R6/2 mice show pronounced striatal atrophy resembling that in humans.
“R6/2 mice display marked striatal atrophy (Hansson et al. , 1999; Li et al. , 2005) similar to humans”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Hansson et al., 1999 source
Not checked in the free run.
- cites Li et al., 2005
Not checked in the free run.
- Interpretationown data§ CSF1Ri-driven microglial elimination ubiquitously increases the density of ECM PNNs, which are degraded in the R6/2 brain · p. 17
This indicates degradation of the PNNs surrounding these interneurons.
“suggesting degradation of encapsulating PNNs”
Quote in the paperSubstantial claim - Interpretationreasoning§ Figure 7 Continued · p. 20
Loss of PNNs may further contribute to the excitatory/inhibitory imbalance seen in the R6/2 brain.
“As such, their loss may further contribute to the excitatory/inhibitory imbalance observed in the R6/2 brain.”
Quote in the paperNot a substantial claim- Rests on an assumption: PNNs enhance GABAergic electrical transmission in a manner similar to a myelin sheath.
- Interpretationcitation§ Figure 7 Continued · p. 20
Astrocytes directly contribute to neurodegeneration.
“In light of the current study, these reports suggest that astrocytes directly contribute to neurodegeneration”
Quote in the paperNot a substantial claim - Interpretationown data§ Figure 7 Continued · p. 20
This loss suggests microglial dysfunction in Huntington's disease.
“further suggests microglial dysfunction in the context of Huntington's disease.”
Quote in the paperNot a substantial claim
- Classified as probably not a substantial claim. 38
- May combine two claims. 55
- The quote only partly states this claim. 5
Probably not a substantial claim: may not pass S3 (load-bearing).
Findingcitation§ Microglial depletion reduces mHTT accumulation and disease-related protein clearance pathway dysregulation · p. 10Microglia seldom contained nuclear inclusion bodies.
“Nuclear inclusion bodies were rarely seen in microglia”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingcitation§ R6/2 striatal mRNA expression reveals dysregulated interferon signalling that is mitigated by CSF1Ri · p. 8CSF1Ri treatment in non-transgenic mice induced the expected loss of microglial gene signature from the brain transcriptome.
“As before (Najafi et al. , 2018), CSF1Ri treatment in non-transgenic mice induced the expected loss of microglial gene signature from the brain transcriptome (data not shown).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Najafi et al., 2018 source
Not checked in the free run.
May combine two claims.
Findingown data§ CSF1Ri via PLX3397 depletes microglia in R6/2 mice · p. 6IHC with IBA1 revealed a significant increase in striatal R6/2 microglial densities at 7 weeks of age (P<0.001) that was not seen in the diseased somatosensory cortex at this time point.
“IHC with the myeloid marker IBA1 revealed a significant increase in striatal R6/2 microglial densities at 7 weeks of age ( P 5 0.001) that was not seen in the diseased somatosensory cortex at this time point (Supplementary Fig. 1).”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
Findingown data§ Figure 2 Continued · p. 10After CSF1Ri, EM48 intensity in the somatosensory cortex was significantly lower (P≤0.05).
“EM48 intensity was significantly reduced in the somatosensory cortex ( P 5 0.05)”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
Findingown data§ Figure 2 Continued · p. 13Immunoblotting showed significantly more ubiquitination in the detergent-soluble striatal fraction of R6/2 mice (P≤0.05).
“confirmed significantly greater ubiquitination in R6/2 mice ( P 5 0.05)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Figure 1 Continued · p. 10In human Huntington's disease caudate, the pro-inflammatory NFkB pathway was upregulated, but not in R6/2.
“the pro-inflammatory NF b pathway was upregulated in the human Huntington's disease caudate, but not R6/2”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingcitation§ Figure 2 Continued · p. 10In R6/2 mice, the autophagic protein p62 co-localized with EM48+ inclusion bodies.
“co-localization of the autophagic protein p62 with EM48 + inclusion bodies in R6/2 mice”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Kurosawa et al., 2015 source
Not checked in the free run.
May combine two claims.
Findingown data§ R6/2 striatal mRNA expression reveals dysregulated interferon signalling that is mitigated by CSF1Ri · p. 8DEGs in CSF1Ri-treated R6/2 mice largely reflected microglial depletion, in addition to partial reversals in T-cell transcript levels (Tal1, Ccl25).
“DEGs in CSF1Ri-treated R6/2 mice largely reflected microglial depletion, in addition to partial reversals in T-cell transcript levels ( Tal1 , Ccl25 ) (Fig. 2H).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Figure 1 Continued · p. 8A dysregulated IFN signature was found in both the murine and human manifestation of disease, facets of which were ameliorated with CSF1Ri-mediated microglial elimination.
“A dysregulated IFN signature was found in both the murine and human manifestation of disease (Fig. 3D), facets of which were ameliorated with CSF1Ri-mediated microglial elimination as indicated by a resolution of IFN and IFN , but not IFN b , gene enrichment in control versus R6/2 + PLX3397 samples.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ R6/2 microglia display regional differences but are ubiquitously depleted with CSF1Ri · p. 6R6/2 mice displayed elevated microglial densities in the striatum and motor cortex, in addition to a trending increase in the somatosensory cortex.
“R6/2 mice displayed elevated microglial densities in the striatum ( P 5 0.01) and motor cortex ( P 5 0.05), in addition to a trending increase in the somatosensory cortex ( P = 0.06; Fig. 2B and C).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Figure 1 Continued · p. 8Pathway enrichment predicted HTT as the most significant upstream regulator of R6/2 DEGs, in addition to IFN, L-DOPA, and IRF7.
“Pathway enrichment predicted HTT as the most significant upstream regulator of R6/2 DEGs ( z -score: 2.151, P 5 8.31 -10 -22 ), in addition to IFN ( z -score: 3.727, P 5 1.01 -10 -15 ), L-DOPA ( z -score: -5.654, P 5 1.19 -10 -20 ), the type I IFN regulator IRF7 ( z”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Figure 1 Continued · p. 10Microglial removal restored several other overrepresented pathways in human/murine Huntington's disease, including impaired neuronal development, neuritogenesis, contextual conditioning, and coordination.
“Microglial elimination normalized several additional overrepresented human/murine Huntington's disease pathways, i.e. impaired neuronal development, neuritogenesis, contextual conditioning, and coordination.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ R6/2 microglia display regional differences but are ubiquitously depleted with CSF1Ri · p. 6Striatal microglia, although at greater densities, did not appear activated morphologically or by IBA1+ intensity, and were negative for the activation marker IB4.
“Striatal microglia, although at greater densities, did not appear activated morphologically or by IBA1 + intensity, and were negative for the activation marker IB4 (data not shown).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ R6/2 striatal mRNA expression reveals dysregulated interferon signalling that is mitigated by CSF1Ri · p. 8RNA-seq on the same striatal extracts revealed distinct clustering of genotypes, but divergent effects of CSF1Ri on the R6/2 transcriptome were detected.
“We again observed distinct clustering of genotypes, but this time divergent effects of CSF1Ri on the R6/2 transcriptome were detected (Fig. 3A).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Figure 1 Continued · p. 8Resolution of IFN signature was accompanied by a concurrent loss of IFN-involved toll-like receptor signalling (Tlr4, Tlr7, Tlr9) as well as downstream IFN effector pathway deactivation (Stat1).
“This resolution was accompanied by a concurrent loss of IFN-involved toll-like receptor signalling ( Tlr4 , Tlr7 , Tlr9 ) as well as downstream IFN effector pathway deactivation ( Stat1 ).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Figure 2 Continued · p. 10In the detergent-insoluble fraction, CSF1R lowered HMW mHTT (P≤0.05) but not fibrillar mHTT species.
“we found that CSF1R reduced HMW ( P 5 0.05) but not fibrillar mHTT species”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Figure 5 Continued · p. 15CSF1Ri microglial depletion significantly lowered CSPG accumulation to control levels in striatum (P≤0.01), somatosensory cortex (P≤0.05), and dentate gyrus (P≤0.01).
“The depletion of microglia with CSF1Ri significantly reduced CSPG accumulation to control levels in the striatum ( P 5 0.01), somatosensory cortex ( P 5 0.05), and dentate gyrus ( P 5 0.01)”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.
Findingcitation§ Figure 5 Continued · p. 15Elevated CS-56 staining often appeared as diffuse patches resembling DACS, CSPG lattices reported around neurons at the end of the developmental critical period and after kainic acid seizures.
“the diffuse patches of elevated CS-56 staining often resembled 'dandelion clock-like structure' (DACS), extracellular CSPG lattices reported to form around neurons at the end of the developmental critical period”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Hayashi et al., 2007 source
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- cites Yutsudo and Kitagawa, 2015
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May combine two claims.
Findingown data§ CSF1Ri reduces global ECM proteoglycan deposition in the R6/2 brain · p. 15CD44 immunoreactivity was strongly increased in R6/2 striatum (P≤0.01), and treatment prevented this.
“CD44 immunoreactivity was robustly enhanced in the R6/2 striatum ( P 5 0.01) and this was prevented with treatment”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Figure 7 Continued · p. 20Analysis of transcriptomic pathways in the R6/2 model indicated deficits in striatal neuritogenesis and neuronal development, which were reversed along with CSPG levels after microglia were depleted.
“Consistent with this, transcriptomic pathway analysis confirmed impairments in striatal neuritogenesis and neuronal development, which were restored alongside CSPG levels following microglial depletion.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Figure 4 Continued · p. 13Huntington's disease striatum had significantly higher NeuN+ cell density (P≤0.05), which treatment did not alter.
“we found significantly greater NeuN + cell density in the Huntington's disease striatum ( P 5 0.05) that did not change with treatment”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Figure 7 Continued · p. 20In R6/2 striatum after CSF1Ri, Tgfb1 expression was significantly lower (LogFC = -2.0535, FDR 0.01) alongside astrogliosis.
“which was significantly reduced in R6/2 striatum following CSF1Ri ( Tgfb1 , LogFC = -2.0535, FDR 5 0.01) alongside astrogliosis.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown data§ Figure 5 Continued · p. 15These CSPG deposits sometimes appeared in MAP2-negative striatal fibre tracts.
“these deposits sometimes localized to MAP2-negative striatal fibre tracts”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Figure 4 Continued · p. 13CSF1Ri restored white matter density to control levels in R6/2 mice without reducing oligodendrocyte lineage numbers.
“While oligodendrocyte lineage numbers were not attenuated, CSF1Ri returned white matter densities to control levels in R6/2 mice”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ CSF1Ri-driven microglial elimination ubiquitously increases the density of ECM PNNs, which are degraded in the R6/2 brain · p. 17In R6/2 mice, PNNs were significantly lower in motor cortex (P≤0.001) and somatosensory cortex (P≤0.01).
“they were significantly decreased in R6/2 mice ( P 5 0.01 and 0.001, respectively”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Figure 5 Continued · p. 15CSPG signal was significantly higher in R6/2 striatum, motor cortex, somatosensory cortex, and dentate gyrus (P≤0.01), and trended higher in piriform cortex (P=0.08).
“There was a significant ( P 5 0.01; striatum, motor cortex, somatosensory cortex, dentate gyrus) or trending increase ( P = 0.08; piriform cortex) in CSPG signal in every region examined.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Figure 4 Continued · p. 13CSF1Ri partially normalized MAP2 changes and fully normalized tau changes.
“alterations that were either partially (MAP2) or entirely (tau) normalized with CSF1Ri”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Figure 7 Continued · p. 20R6/2 mice had more microglia, but no widespread inflammation by transcript or morphology.
“In conclusion, we show that sustained CSF1R inhibition in the R6/2 mouse model of Huntington's disease, which exhibited elevated microglial numbers but not broad inflammation at the transcriptional or morphological level, mitigated grip strength and object memory deficits.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ Figure 7 Continued · p. 20Microglial depletion was accompanied by partial or full reversal of dysregulated interferon signalling, neuritogenesis, and neuronal development pathways.
“and partial or full reversals of dysregulated interferon signalling, neuritogenesis, and neuronal development pathways.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Figure 7 Continued · p. 20R6/2 parvalbumin striatal interneurons showed reduced WFA+ intensity and apparent loss of PNN structural integrity.
“R6/2 parvalbumin striatal interneurons also displayed a reduction in WFA + intensity and an apparent loss of PNN structural integrity”
Quote in the paperSubstantial claim- Rests on an assumption: CSPGs are core structural elements of conventional PNNs.
Classified as probably not a substantial claim.
Findingown data§ Figure 7 Continued · p. 20We confirmed this in brain tissue from adult wild-type mice given the selective CSF1R inhibitor PLX5622.
“which we verified in brain tissue from adult wild-type mice treated with the selective CSF1R inhibitor PLX5622”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ Figure 7 Continued · p. 20Removing microglia both lessens this PNN disruption and markedly raises PNN density in the naïve adult brain.
“and that the elimination of microglial not only ameliorates this, but greatly enhances PNN density in the naı ¨ve adult brain.”
Quote in the paperNot a substantial claim- Rests on an assumption: CSPGs are core structural elements of conventional PNNs.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Introduction · p. 3Unaffected individuals have on average 16-20 CAG repeats at the HTT locus, while affected patients have more than 40 CAGs, and age of symptom onset generally inversely correlates with repeat length.
“While the unaffected population ranges on average 16-20 triplet repeats at this locus, affected patients contain 5 40 CAGs, with the age of symptom onset in general inversely correlating with repeat length (Duyao et al. , 1993; Labbadia and Morimoto, 2013).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Duyao et al., 1993 source
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- cites Labbadia and Morimoto, 2013
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Premisecitation§ Introduction · p. 3Microglial CSF1R signalling is essential for their survival and has become a thoroughly tested and highly replicated model for targeted elimination of microglia.
“Microglial CSF1R signalling is essential to their survival and has become a thoroughly tested and highly replicated model for targeted elimination of microglia (Elmore et al. , 2014; Asai et al. , 2015; Dagher et al. , 2015; Rice et al. , 2015; Acharya et al. , 2016; Feng et al. , 2016; Spangenberg et al. , 2016; Stafford et al. , 2016; Szalay et al. , 2016; Li et al. , 2017; Bennett et al. , 2018”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Introduction · p. 3Huntington's disease symptoms include progressive movement abnormalities (chorea, dystonia) and cognitive-behavioural impairments, accompanied by selective striatal medium spiny neuron death and cortical atrophy.
“Disease symptoms include progressive movement abnormalities (chorea, dystonia) and cognitivebehavioural impairments, accompanied by selective striatal medium spiny neuron death and cortical atrophy (Ross and Tabrizi, 2011).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Ross and Tabrizi, 2011
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Premisecitation§ Introduction · p. 3The cause of Huntington's disease is an abnormal expansion of CAG triplet repeats in exon 1 of the HTT gene, resulting in an elongated polyglutamine tract in mutant huntingtin protein.
“The cause of Huntington's disease, an autosomal dominant neurological disorder, is well established as an abnormal expansion of CAG triplet repeats in exon 1 of the ubiquitously expressed huntingtin ( HTT ) gene, resulting in an elongated polyglutamine (Q) tract in the mutant huntingtin protein (mHTT) (MacDonald et al. , 1993).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites MacDonald et al., 1993 source
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Premisecitation§ Introduction · p. 3Microglia are resident myeloid phagocytes comprising about 12% of cells in the brain and sample the entire parenchymal milieu every 24 hours for deviations from homeostasis.
“Microglia, resident myeloid phagocytes comprising 12% of cells in the brain, sample the entire parenchymal milieu every 24 h for deviations from homeostasis (Nimmerjahn et al. , 2005).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Nimmerjahn et al., 2005 source
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Premisecitation§ Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease · p. 2Huntington's disease involves a reactive microglial response and inflammation.
“Huntington's disease is associated with a reactive microglial response and consequent inflammation.”
- Also stated in: § Introduction · p. 3 · plain
“In Huntington's disease, microglial activation is detected years before the onset of clinical symptoms and correlates with striatal neuron dysfunction in subclinical (Tai et al. , 2007) as well as clinical stages of the disease (Pavese et al. , 2006; Politis et al. , 2011).”
Quote in the paperSubstantial claim0 of 3 sources checked- Also stated in: § Introduction · p. 3 · plain
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Introduction · p. 3Mutant huntingtin accumulates in many cell types and in multiple forms, due at least in part to failure of protein quality control networks, as reflected by accumulation of ubiquitin and other post-translationally-modified proteins and disruptions in autophagy.
“Pathologically, mHTT accumulates in many cells types, and in multiple forms, due at least in part to the failure of protein quality control networks, as reflected by an accumulation of ubiquitin and other post-translationally-modified proteins (Ochaba et al. , 2016) and disruptions in autophagy (Kurosawa et al. , 2015).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Premisecitation§ Introduction · p. 3In Huntington's disease, microglial activation is detected years before clinical symptom onset and correlates with striatal neuron dysfunction in subclinical and clinical stages.
“In Huntington's disease, microglial activation is detected years before the onset of clinical symptoms and correlates with striatal neuron dysfunction in subclinical (Tai et al. , 2007) as well as clinical stages of the disease (Pavese et al. , 2006; Politis et al. , 2011).”
Quote in the paperSubstantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given§ Animals · p. 4Researchers were blinded to genotype and treatment group for behavioural tasks and in the analysis of behavioural, histological, stereological, and biochemical assays.
“Researchers were blinded to genotype and treatment group for behavioural tasks and in the analysis of behavioural, histological, stereological, and biochemical assays.”
- Also stated in: § Behavioural testing · p. 4 · plain
“All behavioural tests were conducted and analysed in a blinded fashion.”
Quote in the paperNot a substantial claim- Also stated in: § Behavioural testing · p. 4 · plain
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Study design and conductnone given§ Animals · p. 4Assignment of animals to treatment groups was conducted in a random fashion.
“Assignment of animals to treatment groups was conducted in a random fashion.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductreasoning§ Behavioural testing · p. 4Exclusionary criteria for novel object recognition were applied: if mice did not spend time investigating both objects during training, or either object during testing, the testing data were excluded from analysis.
“Exclusionary criteria were as follows: if mice did not spend time investigating both objects during training, or either object during testing, the testing data were excluded from analysis, as it cannot be confirmed they spent enough time exploring to learn/discriminate.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Figure 1 Continued · p. 8A growing number of non-viral diseases are characterized by the presence of a similar IFN transcriptional signature, evident within the microglial transcriptome itself as upregulated interferon signalling gene sets in cells isolated from both an Alzheimer's disease-like model of neurodegeneration as well as ageing humans.
“A growing number of non-viral diseases are characterized by the presence of a similar IFN transcriptional signature (Mostafavi et al. , 2016) evident within the microglial transcriptome itself as upregulated interferon signalling gene sets in cells isolated from both an Alzheimer's disease-like model of neurodegeneration as well as ageing humans (Galatro et al. , 2017; Mathys et al. , 2017).”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given§ Animals · p. 4All animal experiments were performed in accordance with animal protocols approved by IACUC at UC Irvine, an AAALAC-accredited institution.
“All animal experiments were performed in accordance with animal protocols approved by the Institutional Animal Care and Use Committee (IACUC) at the University of California, Irvine, an American Association for Accreditation of Laboratory Animal Care (AAALAC)-accredited institution.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationreasoning§ CSF1Ri via PLX3397 ameliorates grip strength and novel object recognition deficits in R6/2 mice · p. 6Similar cognitive and grip strength effects observed between cohorts suggest that PLX3397 may have therapeutic potential in Huntington's disease, particularly in the case of grip strength.
“Nonetheless, the similar cognitive and grip strength effects observed between cohorts suggests that PLX3397 may have therapeutic potential in Huntington's disease, particularly in the case of grip strength.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone given§ Figure 1 Continued · p. 8RNAseq DEGs were validated by and mirrored in the prior results from the more sensitive NanoString assay covering a subset of immune genes.
“RNAseq DEGs were validated by and mirrored in the prior results from the more sensitive NanoString assay covering a subset of immune genes.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Introduction · p. 3The R6/2 mouse line is a short-lived, rapidly progressing model of Huntington's disease that displays motor and behavioural deficits beginning around 7 weeks of age and progressing until early death at 11-13 weeks.
“The R6/2 line is a short-lived and rapidly progressing mouse model of Huntington's disease that displays motor and behavioural deficits beginning around 7 weeks of age and progressing until an early death at 11-13 weeks (Mangiarini et al. , 1996).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Mangiarini et al., 1996 source
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Premisecitation§ Figure 2 Continued · p. 10PLX3397 also inhibits c-Kit and, at higher doses, Flt3 receptor tyrosine kinases.
“it can also inhibit c-Kit and, at higher concentrations, Flt3 receptor tyrosine kinases”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Tap et al., 2015 source
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Premisecitation§ Introduction · p. 3Intrastriatal engraftment of mHTT-expressing human glial progenitor cells in immunodeficient mice results in neuronal hyperexcitability in the striatum along with motor impairments.
“Furthermore, intrastriatal engraftment of mHTT-expressing human glial progenitor cells in immunodeficient mice results in neuronal hyperexcitability in the striatum along with motor impairments (Benraiss et al. , 2016; Osipovitch et al. , 2019).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Premisecitation§ Figure 2 Continued · p. 13Protein clearance by ubiquitin and autophagy is severely impaired in Huntington's disease, shown by accumulated ubiquitinated species in patient and mouse brain and increased p62.
“Ubiquitinand autophagy-based protein clearance systems are highly impaired in Huntington's disease, as evidenced by a striking build-up of ubiquitinated species in patient brain and mouse models”
Quote in the paperSubstantial claim0 of 3 sources checkedMay combine two claims.
Premisecitation§ Introduction · p. 3Endogenous mutant huntingtin alone alters the microglial transcriptional landscape through increased expression of Pu.1, resulting in enhanced production of Il6 and Tnf transcripts and increased neurotoxicity in the context of a secondary immune challenge.
“While microglia conventionally react to stress signals and exogenous toxins in neurodegeneration, the presence of endogenous mHTT alone alters their transcriptional landscape through increased expression of the myeloid lineage-determining factor Pu.1 (Crotti et al. , 2014), resulting in enhanced production of Il6 and Tnf transcripts as well as increased neurotoxicity in the context of a secondary”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Crotti et al., 2014 source
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Premisecitation§ Figure 1 Continued · p. 10Usp18 inhibits microglial activation by specifically blocking IFN-induced transcription.
“which inhibits microglial activation by specifically blocking IFN-induced transcription”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Goldmann et al., 2015 source
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Premisecitation§ CSF1Ri-driven microglial elimination ubiquitously increases the density of ECM PNNs, which are degraded in the R6/2 brain · p. 17Microglia are postulated to degrade PNNs in some disease states, probably via increased extracellular proteases.
“it has been postulated that microglia mediate the degradation of PNNs in certain disease states, likely through enhanced production of extracellular proteases”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ CSF1Ri reduces global ECM proteoglycan deposition in the R6/2 brain · p. 15CD44 binds hyaluronan plus other matrix components including glycoproteins and proteoglycans.
“which binds the primary component of parenchymal ECM, the glycosaminoglycan (GAG; polysaccharides consisting of a repeating disaccharide unit) hyaluronan, as well as other matrix constituents such as glycoproteins and proteoglycans”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Dzwonek and Wilczynski, 2015
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Premisecitation§ CSF1Ri reduces global ECM proteoglycan deposition in the R6/2 brain · p. 15Microglia regulate CD44 expression in astrocytes.
“microglia have been shown to regulate astrocytic expression of the receptor”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Liddelow et al., 2017 source
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims. The quote only partly states this claim.
Interpretationcitation§ Figure 4 Continued · p. 15The increased white matter and neuropil density alongside striatal volume loss in R6/2 mice might arise from impaired neurite outgrowth or disrupted synapses in Huntington's disease.
“the enhanced white matter and neuropil density coincident with striatal volume loss in R6/2 mice may stem from impaired neurite outgrowth”
Quote in the paperNot a substantial claim0 of 3 sources checkedMay combine two claims.
Premisecitation§ Figure 4 Continued · p. 13Aberrant splicing in Huntington's disease raises total tau and juvenile MAP2; MAP2 withdraws from dendrites toward the cell body in patients, and together these changes promote dendritic and striatal atrophy.
“faulty splicing in Huntington's disease increases total tau and the juvenile form of MAP2”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Fernandez-Nogales et al., 2016 source
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- cites Cabrera and Lucas, 2017
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Premisecitation§ CSF1Ri reduces global ECM proteoglycan deposition in the R6/2 brain · p. 15CSPGs have a core protein covalently linked to one or more sulphated GAG sidechains, related to unsulphated hyaluronan, and are mainly made by reactive astrocytes.
“CSPGs consist of a core protein covalently bound to one or more sulphated GAG sidechains”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Silver and Miller, 2004
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- cites Yu et al., 2012
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Interpretationown data§ Figure 5 Continued · p. 15Microglia may directly or indirectly, via astrocyte reactivity, drive abnormal CSPG deposition into the extracellular space.
“supporting the idea that microglia can directly or indirectly (i.e. through regulation of astrocyte reactivity) mediate the aberrant deposition of CSPGs into the extracellular space”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ Figure 7 Continued · p. 20TGFβ is produced mainly by microglia and by disease astrocytes.
“which is primarily produced by microglia (Zhang et al. , 2014) and disease astrocytes (Endo et al. , 2015)”
Quote in the paperSubstantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Figure 4 Continued · p. 13MAP2 and tau stabilize microtubules needed for autophagosome transport, particularly in neurons.
“Both proteins stabilize microtubules critical for autophagosome transport”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Kast and Dominguez, 2017
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- cites La Spada and Taylor, 2010
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Premisecitation§ Figure 4 Continued · p. 13Oligodendrocyte lineage cells are reported to proliferate uniquely in R6/2 striatum.
“which are reported to be uniquely proliferative in the R6/2 striatum”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites McCollum et al., 2013 source
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Premisecitation§ CSF1Ri-driven microglial elimination ubiquitously increases the density of ECM PNNs, which are degraded in the R6/2 brain · p. 15PNNs form a reticular dendrosomatic structure around mostly parvalbumin-expressing interneurons, thought to lock synapses during development.
“where they form a reticular dendrosomatic structure around largely parvalbumin-expressing interneurons”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites Miyata et al., 2012 source
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- cites Yutsudo and Kitagawa, 2015
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Premisecitation§ CSF1Ri-driven microglial elimination ubiquitously increases the density of ECM PNNs, which are degraded in the R6/2 brain · p. 17PNN breakdown impairs inhibitory firing of GABAergic interneurons, contributing to tumour-associated seizures similar to those in R6/2 mice.
“PNN degradation impairs the inhibitory firing of GABAergic interneurons, thus contributing to tumour-associated seizures”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Tewari et al., 2018 source
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Premisecitation§ Microglial depletion with CSF1Ri prevents R6/2 striatal atrophy · p. 13In R6/2 microglia, mutant HTT primes the cells by raising Pu.1, a myeloid transcription factor that promotes phagocytosis.
“Mutant HTT expression in R6/2 microglia effectively 'primes' the cell by increasing expression of the myeloid transcription factor Pu.1”
Quote in the paperSubstantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
Premisecitation§ Figure 6 Continued · p. 17Unlike glia-secreted CSPGs, PNNs and their proteoglycans are made by neurons.
“Unlike CSPGs secreted by glia, PNNs and their proteoglycan constituents are synthesized by neurons”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Miyata et al., 2005 source
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Premisecitation§ CSF1Ri-driven microglial elimination ubiquitously increases the density of ECM PNNs, which are degraded in the R6/2 brain · p. 15CSPGs can be preferentially incorporated into conventional PNNs depending on side-chain sulphation.
“Depending on side chain sulphation pattern, CSPGs can also be preferentially incorporated into conventional PNNs”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Fawcett et al., 2019 source
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Interpretationreasoning§ Figure 6 Continued · p. 17Microglia tightly control basal PNN formation via ongoing homeostatic degradation, a function that can change pathologically after brain injury or disease.
“this indicates that microglia tightly regulate basal PNN formation through sustained levels of homeostatic degradation”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ Figure 7 Continued · p. 20TGFβ stimulates astrocyte reactivity and CSPG production.
“Consistent with this, astrocyte reactivity and CSPG production is stimulated by TGF b (Yu et al. , 2012; Ohtake et al. , 2016)”
Quote in the paperSubstantial claim0 of 2 sources checked- cites Yu et al. , 2012
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- cites Ohtake et al. , 2016 source
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Premisecitation§ CSF1Ri reduces global ECM proteoglycan deposition in the R6/2 brain · p. 15In adult brain, CD44 expression is mainly restricted to astrocytes and activated microglia.
“CD44 expression in the adult brain is primarily confined to astrocytes and activated microglia”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Matsumoto et al., 2012 source
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Interpretationcitation§ Figure 7 Continued · p. 20Astrocyte mHTT directly alters reactivity in a way that worsens disease.
“suggesting that astrocyte mHTT directly alters reactivity in a manner detrimental to disease (Stanek et al. , 2019).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Stanek et al. , 2019 source
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Premisecitation§ Figure 7 Continued · p. 20PNNs are constructed autonomously by neurons.
“PNNs are autonomously constructed by neurons (Miyata et al. , 2005; Geissler et al. , 2013; Fowke et al. , 2017)”
Quote in the paperNot a substantial claim0 of 3 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Figure 7 Continued · p. 20PNNs stabilize neuronal circuitry and inhibit plasticity.
“stabilizing the neuronal circuitry and inhibiting plasticity (Wang and Fawcett, 2012; Fawcett et al. , 2019).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Premisecitation§ Figure 7 Continued · p. 20In BACHD mice, removing mHTT only from microglia does not lower mHTT buildup or lessen striatal volume loss.
“Additionally, the depletion of mHTT from astrocytes alone (Wood et al. , 2018), but not microglia (Petkau et al. , 2019), reduces mHTT accumulation and striatal volume loss in the BACHD mouse model.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Petkau et al. , 2019 source
Not checked in the free run.
May combine two claims.
Premisecitation§ Figure 7 Continued · p. 20In BACHD mice, removing mHTT only from astrocytes lowers mHTT buildup and lessens striatal volume loss.
“Additionally, the depletion of mHTT from astrocytes alone (Wood et al. , 2018), but not microglia (Petkau et al. , 2019), reduces mHTT accumulation and striatal volume loss in the BACHD mouse model.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Wood et al. , 2018
Not checked in the free run.
May combine two claims.
Premisecitation§ Figure 7 Continued · p. 20In YAC128 Huntington's disease mice, motor deficits were rescued when HTT-suppressing miRNA was delivered bilaterally into the striatum to neurons plus astrocytes (AAV1), but not when delivered to neurons only (AAV2-HBKO).
“Furthermore, bilateral intrastriatal AAV-RNAi delivery of HTT-suppressing miRNA targeted to neurons and astrocytes (AAV1), but not neurons alone (AAV2-HBKO), rescued motor deficits in the YAC128 mouse model of Huntington's disease”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Stanek et al. , 2019 source
Not checked in the free run.
May combine two claims.
Interpretationreasoning§ Figure 7 Continued · p. 20Microglia drive secondary damage by changing astrocyte reactivity and/or other pathways, which speeds pathogenesis.
“while microglia promote secondary damage through modulation of astrocyte reactivity and/or other pathways, thereby accelerating pathogenesis.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Figure 7 Continued · p. 20Loss of PNN structural integrity has been shown to contribute to tumour-associated seizures through impaired GABAergic inhibitory firing.
“which has before been shown to contribute to tumour-associated seizures (Tewari et al. , 2018) due to impaired GABAergic inhibitory firing”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Tewari et al. , 2018 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Figure 7 Continued · p. 20PNNs are net-like structures laid down on the soma and proximal dendrites of mostly GABAergic parvalbumin interneurons shortly after microglia finish synaptic pruning.
“reticular structures that form along the soma and proximal dendrites of primarily GABAergic parvalbumin interneurons soon after synaptic pruning is completed by microglia (Paolicelli et al. , 2011)”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Paolicelli et al. , 2011 source
Not checked in the free run.
May combine two claims.
Interpretationown data§ Figure 7 Continued · p. 20Microglia act as homeostatic controllers of PNN formation in the healthy brain, a role not previously studied.
“underscoring a yet unstudied role of microglia as homeostatic regulators of PNN formation in the healthy brain.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ Figure 7 Continued · p. 20CSPGs in PNNs are labelled by WFA differently from CS-56, possibly because of differences in CSPG sidechain sulphation or epitope availability.
“CSPGs contained in PNNs are labelled by the plant lectin WFA in a manner distinct from CS-56 (Hayashi et al. , 2007; Pantazopoulos et al. , 2015; Yutsudo and Kitagawa, 2015), potentially due to differences in CSPG sidechain sulphation status (Sorg et al. , 2016) or epitope availability.”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites Hayashi et al. , 2007 source
Not checked in the free run.
- cites Pantazopoulos et al. , 2015 source
Not checked in the free run.
- cites Yutsudo and Kitagawa, 2015
Not checked in the free run.
- Rests on an assumption: CSPGs are core structural elements of conventional PNNs.
The paper relies on this without support.
CSPGs are core structural elements of conventional PNNs.
“CSPGs are also core structural elements of conventional PNNs”
The paper relies on this without support.
PNNs enhance GABAergic electrical transmission in a manner similar to a myelin sheath.
“as PNNs are thought to enhance GABAergic electrical transmission akin to a myelin sheath.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
PNNs are themselves affected in Alzheimer's disease and in Huntington's disease partly through engulfment by activated microglia.
“However, PNNs are themselves affected in Alzheimer’s disease [189] and in Huntington’s disease partly through engulfment by activated microglia [190, 191] (Fig. 3D).”
From The extracellular matrix and perineuronal nets in memory (2022) · cites this paper as [190]
The PNN results section (pp. 16–17) reports PNN loss in the R6/2 Huntington’s disease mouse model and says microglial depletion prevented that loss in two cortical regions. It observes microglial contact with PNNs, but does not show engulfment; it describes extracellular proteases as a possible mechanism instead. The Alzheimer’s disease portion has a separate citation and is not assessed here. (LLM, conf=0.86)
Experimental — accuracy not yet measuredMicroglial elimination in R6/2 mice prevented the loss of PNNs and dramatically increased PNNs in the brains of naïve littermates.
“Microglial elimination in R6/2 mice prevented the loss of PNNs and dramatically increased PNNs in the brains of naïve littermates.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [456]
Microglia-mediated perineuronal net loss occurs in Huntington's disease.
“recent work from our lab identified a role for microglia-mediated PNN loss in Huntington's disease [36].”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [36]
Microglia-mediated perineuronal net loss occurs in the Huntington's disease brain even in the absence of overt microglial activation.
“the occurrence of microglia-mediated PNN loss, which we first reported in the Huntington's disease brain even in the absence of overt microglial activation [36]”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [36]
The consequences of loss of microglial function resemble the enhanced accumulation of extracellular-matrix-composed perineuronal nets that occurs in healthy adult mice following pharmacological loss of microglia.
“and therefore the consequences of this loss of microglial function resemble the enhanced accumulation of ECM-composed PNNs that we have shown occurs in healthy adult mice following the pharmacological loss of microglia themselves [36].”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [36]
Microglia have a homeostatic role in the maintenance of perineuronal nets, such that basal perineuronal net levels in the healthy adult brain are elevated following microglial depletion.
“It is interesting to note that we identified here and elsewhere [36] a homeostatic role for microglia in the maintenance of PNNs, such that basal PNN levels in the healthy adult brain are elevated following microglial depletion.”
From Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain (2020) · cites this paper as [36]
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Self-citation
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- Authors
- Crapser, J. D., Ochaba, J., Soni, N., Reidling, J. C., Thompson, L. M., & Green, K. N.
- Affiliations
- University of California, Irvine (US)
- Corresponding author
- Thompson, Leslie M
- Green, Kim N
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-12-17
- Volume
- 143
- Issue
- 1
- Pages
- 266-288
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC6935750
- OpenAlex
- W2994774911
- Cited by
- 157
- References
- 138
- Citations by year
- 2026: 14 · 2025: 29 · 2024: 30 · 2023: 25 · 2022: 21 · 2021: 25 · 2020: 13
- FWCI
- 6.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Brain (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (R01NS083801, R01AG056768, P50AG016573, R01NS090390, F31NS108611)
- NSF fellowship
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- Huntington's disease, microglial depletion, CSF1R inhibition, pexidartinib, R6/2 mice, mutant huntingtin, extracellular matrix, chondroitin sulfate proteoglycans, glial scar, perineuronal nets, astrocyte activation, microglial inflammation, interferon gene signature, synaptic gene expression
- MeSH terms
- Huntingtin Protein, Aminopyridines, Animals, Astrocytes, Disease Models, Animal, Extracellular Matrix, Humans, Huntington Disease, Inflammation, Mice, Transgenic, Chondroitin Sulfate Proteoglycans, Pyrroles, RNA, Messenger, Synapses, Down-Regulation, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Cytokines, Neurites, Neostriatum, Microglia, Hand Strength, Recognition, Psychology, Mice, Transcriptome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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