Network analysis identifies strain-dependent response to tau and tau seeding-associated genes

Mice with APPswe and PSEN1de9 transgenes backcrossed onto wild-derived backgrounds had higher levels of amyloid-β compared with age-matched mice on a B6 background.

“These mice had higher levels of amyloid-β (Aβ) compared with age-matched mice on a B6 background (Onos et al., 2019).”

• cites Onos et al., 2019 sourcePartly supported

  The Results section, “Evidence of mixed pathologies in wild-derived APP/PS1 strains,” reports higher Aβ42 levels than in B6.APP/PS1 mice for female CAST.APP/PS1 and WSB.APP/PS1 mice at 8 months. It does not establish higher Aβ levels for all wild-derived backgrounds or for males; it also reports fewer cortical plaques in all three wild-derived strains. (LLM, conf=0.90)

  Experimental — accuracy not yet measured

Responses of homeostatic microglia and disease-associated microglia are determined by wild-derived genetic backgrounds.

“Single-cell RNA sequencing (RNA-seq) of sorted microglia further demonstrated that the responses of immune cell subtypes, namely homeostatic microglia and disease-associated microglia (DAMs), are determined by wild-derived genetic backgrounds (Yang et al., 2021).”

• cites Yang et al., 2021 sourceSupported

Neurodegenerative hub-genes were detected by comparing Signature C (darkorange) and wild-derived amyloid response (Fisher's exact test: P = 1.62 × 10−19).

“Neurodegenerative hub-genes (purple) were detected by comparing Signature C (darkorange) and wild-derived amyloid response (Fisher’s exact test: P = 1.62 × 10−19; Onos et al., 2019).”

• cites Onos et al., 2019 sourceSupported

In comparison to the 35-gene module from Onos et al., 19 of their genes were significantly enriched also in the darkorange module (Fisher exact test, P = 1.62 × 10−19).

“In comparison to their 35-gene module, we found that 19 of their genes were significantly enriched also in our darkorange module (Fig. 6 C, highlighted in purple; Fisher exact test, P = 1.62 × 10−19).”

• cites Onos et al., 2019 sourceSupported

Trem2 is present in Signatures A and C.

“For example, Trem2, a known AD risk gene expressed in microglia (Krasemann et al., 2017; Sims et al., 2017), is present in Signatures A and C.”

• cites Krasemann et al., 2017 sourceSupported
• cites Sims et al., 2017 sourceSupported

The output of the mouse neurological disorders RNA-seq portal showed a downregulation of Signature C genes within studies designated "other cell types".

“Notably, the output of this portal showed a downregulation of Signature C genes within studies designated “other cell types” (Fig. S5 C).”

• cites Al-Ouran et al., 2019 sourcePartly supported

  The Results and Discussion section describes this portal and shows downregulated genes in mouse models studying different cell types. Those results concern the paper’s yellow-module gene set, however; our copy does not report an analysis of Signature C genes or a category designated “other cell types.” (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Our list of core genes can be interpreted as robust tau-responsive genes for future study.

“As preclinical studies continue to make direct comparisons between human and mouse transcriptomics (Monzón-Sandoval et al., 2022; Onos et al., 2022), our list of core genes can be interpreted as robust tau-responsive genes for future study.”

• cites Monzón-Sandoval et al., 2022 sourceSupported
• cites Onos et al., 2022 sourceSupported

A similar effect of genetic background was found via WGCNA when modeling Aβ.

“A similar effect of the genetic background was found via WGCNA when modeling Aβ (Onos et al., 2019).”

• cites Onos et al., 2019 sourceSupported

Transcriptomic data from Onos and colleagues showed a compelling effect of these three wild-derived strains on amyloid accumulation.

“Transcriptomic data from Onos and colleagues showed a compelling effect of these three wild-derived strains on amyloid accumulation (Onos et al., 2019; Yang et al., 2021).”

• cites Onos et al., 2019 sourcePartly supported

  The Results section on mixed pathologies reports significantly fewer cortical plaques in all three wild-derived APP/PS1 strains than in B6.APP/PS1, establishing strain differences in amyloid deposition. The transcriptional-profiling Results instead show strain-dependent gene expression and responses to amyloid; they do not themselves establish an effect on amyloid accumulation. Page numbers are not available in the supplied copy. (LLM, conf=0.86)

  Experimental — accuracy not yet measured
• cites Yang et al., 2021 sourcePartly supported

  The Introduction and Results report transcriptomic differences among the wild-derived strains in microglial responses to amyloid. The Results also report higher cerebral amyloid angiopathy in WSB.APP/PS1, but the cited paper does not show that its transcriptomic data establish an effect of all three strains on amyloid accumulation. Page numbers were not supplied in our copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

Using the expression of 11 mouse orthologs of human AD GWAS loci genes, wild-derived mice are transcriptionally distinct from B6 mice regardless of tau genotype.

“Using the expression of these 11 genes, wild-derived mice are transcriptionally distinct from B6 mice regardless of tau genotype (Fig. S5 B).”

• cites Salih et al., 2019 sourcePartly supported

  The Results section (“High-resolution co-expression network using RNA-seq in amyloid-responsive microglia”; page unavailable) identifies 11 mouse orthologues of human Alzheimer’s disease GWAS loci. It does not report that their expression distinguishes wild-derived mice from B6 mice, with or without a tau genotype; its comparisons concern APP/PSEN1 mice and wild-type controls. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

There is a considerable overlap when comparing the tau seeding-associated genes in wild-derived mouse strains to a previous study of amyloid response in wild-derived strains.

“Interestingly, we see a considerable overlap when comparing the tau seeding–associated genes in wild-derived mouse strains to a previous study of amyloid response in wild-derived strains (Onos et al., 2019).”

• cites Onos et al., 2019 sourceSupported

The gene lists can be used with external databases like the mouse neurological disorders RNA-seq portal to probe similar signatures across mouse models.

“We demonstrated the ability to use our gene lists with external databases like the mouse neurological disorders RNA-seq portal (Al-Ouran et al., 2019) to probe similar signatures across mouse models.”

• cites Al-Ouran et al., 2019 sourceSupported

Principal component analysis demonstrates that the largest contribution to transcriptome variation is genetic background.

“Principal component analysis (PCA) demonstrates that the largest contribution to the variation in the transcriptome is genetic background (Fig. 3 B).”

Four modules were significantly correlated to both seeding activity and wild-derived genetic background: darkorange, steelblue, lightsteelblue1, and sienna3.

“Using this approach, we were able to identify four modules that were significantly correlated to both traits of interest: darkorange, steelblue, lightsteelblue1, and sienna3 (Fig. 5 A).”

Across all three wild-derived mice, genotyped variants were found in 401 of the 537 nominated target genes.

“Across all three wild-derived mice in this study, we found genotyped variants in 401 of the total 537 nominated target genes.”

Representative samples demonstrate the presence of high molecular weight and low molecular weight species of phospho-tau Thr231 and total tau.

“Representative samples demonstrate the presence of high molecular weight and low molecular weight species of phospho-tau Thr231 and total tau (DAKO).”

Human MAPT mRNA levels showed no significant effect of genetic background (F3,66 = 0.234, P = 0.87).

“Relative hMAPT expression was calculated relative to GAPDH and showed no effect of genetic background via one-way ANOVA (n = 16–20 per group, technical replicates = 2, F3,66 = 0.234, P = 0.87).”

17 out of 133 DEGs in Signature B were shared by all three wild-derived backgrounds.

“17/133 DEGs in Signature B were shared by all three wild-derived backgrounds.”

168 genes out of the 471 genes in the KEGG pathway 'Pathways of neurodegeneration-multiple diseases' (map05022) follow the genetic background-independent effect.

“A total of 168 genes out of the 471 genes in the pathway (Pathways of neurodegeneration—multiple diseases KEGG map05022) follow this genetic background–independent effect (Fig. S3 F).”

There was no effect of genetic background on pTau231 levels (F3,75 = 1.665, P = 0.189).

“or pTau231 (n= 19–21 per group, F3,75 = 1.665, P = 0.189).”

There was no significant difference in tau seeding activity between B6 and WSB AAV-hTauP301L-injected mice (P > 0.05).

“However, there was no significant difference between B6 and WSB AAV-hTauP301L–injected mice (P > 0.05).”

• AssumptionThe authors state this as an assumption: FRET+ signal in the tau biosensor assay is a valid proxy for tau seeding activity.

Ube2j1, Calm3, and Mapk1 genes were lowly expressed similarly in B6 and all three wild-derived mice injected with AAV-hTauP301L compared with AAV-eGFP-injected controls.

“For example, Ube2j1, Calm3, and Mapk1 genes were lowly expressed similarly in B6 and all three wild-derived mice injected with AAV-hTauP301L compared with the AAV-eGFP–injected control group (Fig. 3 E).”

2,467 genes were commonly expressed across all genetic backgrounds and were identified as DEGs in all genetic backgrounds.

“Of these DEGs, 2,467 genes were commonly expressed across all genetic backgrounds and were identified as DEGs in all genetic backgrounds (yellow highlighted intersection, Fig. 3 C).”

60 modules of co-expressed genes were identified by WGCNA.

“We identified 60 modules of co-expressed genes (Table S1 I and Fig S4, A–C)”

There was no effect of genetic background on total tau levels (F3,75 = 1.439, P = 0.238).

“There was no effect of genetic background on either total tau via one-way ANOVA (n = 19–21 per group, F3,75 = 1.439, P = 0.238)”

Genes within the darkorange module were most positively correlated to tau seeding.

“Gene significance calculation of each gene in the four modules of interest reveals the genes within the darkorange module were most positively correlated to tau seeding (Fig. 5 B).”

• AssumptionThe authors state this as an assumption: FRET+ signal in the tau biosensor assay is a valid proxy for tau seeding activity.

17 genes were shared by CAST, PWK, and WSB that were not differentially expressed in B6 mice.

“There were 17 genes shared by CAST, PWK, and WSB (Fig. 4 B) that were not differentially expressed in B6 mice.”

Tau seeding activity was significantly affected by genetic background (F3,78 = 9.237, P = 2.67 × 10−5).

“Tau seeding activity was significantly affected by genetic backgrounds via one-way ANOVA (n = 19–24 per group, technical replicates =2, F3,78 = 9.237, P = 2.67 × 10−5).”

• AssumptionThe authors state this as an assumption: FRET+ signal in the tau biosensor assay is a valid proxy for tau seeding activity.

A total number of 79 DEGs were identified in CAST, 51 in PWK, and 53 in WSB using genetic background as a covariate.

“A total number of 79 DEGs were identified in CAST (Effect: tau.CAST; Table S1 F), 51 DEGs in PWK (Effect: tau.PWK; Table S1 G), and 53 DEGs in WSB (Effect: tau.WSB; Table S1 H).”

Cilia- and flagella-associated protein 74 was upregulated in wild-derived mice injected with AAV-hTauP301L compared with AAV-GFP-injected mice of the same genetic background.

“As an example, cilia- and flagella-associated protein 74 was upregulated in wild-derived mice injected with AAV-hTauP301L compared with AAV-GFP–injected mice of the same genetic background (Fig. 4 C).”

136 of the 537 AMP-AD target genes did not contain any genotyped variants.

“136 of the 537 AMP-AD target genes did not contain any genotyped variants.”

The 133 genes in Signature B are enriched for several pathways that have not been studied well in the context of tauopathy.

“taken together, these 133 genes in Signature B are enriched for several pathways that have not been studied well in the context of tauopathy (Table S2 K).”

Percent cells with FRET signal were significantly increased in WSB versus B6 in the pilot study (P = 0.0172).

“Percent cells with FRET signal were significantly increased in WSB versus B6 in our pilot study (*P < 0.05; nB6 = 6, nWSB = 5; Welch’s t test P = 0.0172).”

In total, 5,792 variants were found in 537 AMP-AD nominated target genes.

“In total, we found 5,792 variants in 537 nominated target genes (Table S1, A and B).”

133 DEGs were identified in one or more wild-derived backgrounds.

“133 in total DEGs were identified in one or more wild-derived backgrounds.”

KEGG enrichment analysis of the 2,467-gene Signature A was significantly enriched for several neurodegenerative terms.

“Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of this gene set (2,467 genes) was significantly enriched for several neurodegenerative terms (Fig. 3 D, Fig. S3 E, and Table S2 J).”

CAST and PWK genetic background mice had significantly elevated tau seeding activity compared to B6 controls (P < 0.001).

“Tukey honest significant difference post-hoc test revealed elevated tau seeding activity in CAST and PWK relative to B6 (***P < 0.001; B6-CAST p_adj = 0.046, B6-PWK p_adj = 1.12 × 10−4).”

• AssumptionThe authors state this as an assumption: FRET+ signal in the tau biosensor assay is a valid proxy for tau seeding activity.

Of the 60 modules, 21 were significantly associated with either seeding activity or wild-derived genetic background (P < 0.05).

“Of these 60 modules, 21 were significantly associated with either seeding activity or wild-derived genetic background (Fig. S4 D, P < 0.05).”

None of these 21 modules demonstrated a significant effect of sex.

“Importantly, none of these 21 modules demonstrated a significant effect of sex (Fig. S4 D).”

The majority of darkorange module genes on the mouse neuroinflammation panel were annotated as part of the Innate Immune Response and/or Microglia Function (29 out of 56).

“The majority of darkorange module genes on the mouse neuroinflammation panel were annotated as being a part of the Innate Immune Response and/or Microglia Function (29 out of 56; Fig. 8 B and Table S2 R).”

The core transcriptional response to tau across different genetic backgrounds is enriched for pathways of neurodegeneration.

“Importantly, our study shows that the core transcriptional response to tau across different genetic backgrounds is enriched for pathways of neurodegeneration (Fig. 3).”

The darkorange module contains 666 genes associated with the effect of genetic background on tau seeding activity.

“The darkorange module contains a total of 666 genes that we found to be associated with the effect of genetic background on tau seeding activity (Fig. 6 C, highlighted in orange).”

Analysis of publicly available data collected from mouse models of tauopathy reveals a modest overlap between our AAV approach and similar tau models at 6 mo.

“Analysis of publicly available data collected from mouse models of tauopathy (GSE114910, GSE125957) reveals a modest overlap between our AAV approach and similar tau models at 6 mo.”

The Microglia Function pathway was decreased in both PWK and CAST mice.

“The “Innate Immune Response” pathway was concordantly increased in PWK and CAST mice, while the “Microglia Function” pathway was decreased in both genetic backgrounds.”

Bayesian module selection found that the darkorange module is most likely to act through complete mediation between genetic background, seeding activity, and the darkorange module.

“Of these three possible relationships between genetic background, seeding activity, and the darkorange as a mediator, we found that the darkorange module is most likely to act through complete mediation.”

There is a clear shift in homeostatic and disease-associated marker genes across the genetic background when hTauP301L is expressed.

“Although we are inferring the microglial transcriptional state from bulk transcriptomic data, there is a clear shift in homeostatic and disease-associated marker genes across the genetic background when hTauP301L is expressed.”

There are 18 disease-associated marker genes within the darkorange module (Fisher's exact test: P = 2.31 × 10−5).

“We found 21 homeostatic marker genes (Fisher’s exact test: P = 2.33 × 10−7) and 18 disease-associated marker genes (Fisher’s exact test: P = 2.31 × 10−5) within the darkorange module.”

Approximately 8% (56/666) of the genes in the darkorange module were selected as part of the mouse neuroinflammation panel curated list.

“We found that ∼8% (56/666) of the genes in the darkorange module were selected as part of this curated list (Table S2 R).”

28 out of 56 darkorange module genes on the mouse neuroinflammation panel were significantly upregulated in AAV-hTauP301L-injected mice versus AAV-eGFP-injected controls across all genetic backgrounds.

“We found that 28 out of 56 darkorange module genes on the mouse neuroinflammation panel were significantly upregulated in AAV-hTauP301L–injected mice versus AAV-eGFP–injected controls across all genetic backgrounds, validating the involvement of these darkorange module genes in the immune response to tau (Fig. 7, A–D).”

Bayesian model selection suggests that the relationship between the darkorange module and tau seeding is most probabilistically via complete mediation.

“Furthermore, Bayesian model selection suggests that the relationship between the darkorange module and tau seeding is most probabilistically via complete mediation (dark green arrows).”

• AssumptionThe authors state this as an assumption: FRET+ signal in the tau biosensor assay is a valid proxy for tau seeding activity.

Of the 28 shared upregulated genes, the highest fold change was observed in CAST and PWK mice.

“Of these 28 genes, the highest fold change was observed in CAST and PWK mice (Fig. 7 E).”

The darkorange module was identified as a significantly associated mediator of the relationship between genetic background and tau seeding in high-dimensional mediation analysis (α = 0.0833, β = 35.7258, P = 0.0349).

“The darkorange module was identified as a significantly associated mediator (α = 0.0833, β = 35.7258, P = 0.0349).”

Global significance score shows several pathways that were similarly modulated in PWK and CAST mice.

“Global significance score shows several pathways that were similarly modulated in PWK and CAST mice.”

Normalized expression of the 29 genes of interest as measured by the nCounter platform identifies the largest effect in CAST and PWK mice compared to B6 and WSB mice.

“Strikingly, the normalized expression of these genes as measured by the nCounter platform identifies the largest effect in CAST and PWK mice compared to B6 and WSB mice (Fig. 8 C).”

The eigenvalue of expression of genes in the darkorange module is increased in AAV-hTauP301L-injected mice relative to AAV-eGFP-injected controls.

“The eigenvalue of the expression of genes in the darkorange module is increased in AAV-hTauP301L–injected mice relative to AAV-eGFP–injected controls (Fig. 6 A).”

There is an overlap of 310 genes shared between our viral model and either of the two selected transgenic tauopathy models.

“There is an overlap of 310 genes shared between our viral model and either of the two selected transgenic models (Fig. S5 A).”

There are 21 homeostatic marker genes within the darkorange module (Fisher's exact test: P = 2.33 × 10−7).

“We found 21 homeostatic marker genes (Fisher’s exact test: P = 2.33 × 10−7) and 18 disease-associated marker genes (Fisher’s exact test: P = 2.31 × 10−5) within the darkorange module.”

Key microglial genes (Trem2, Tyrobp, Tgfbr2) and complement cascade genes (C1qa, C1qb, Pros1) were affected by genetic background in both amyloid and tau studies.

“Interestingly, key microglial genes (Trem2, Tyrobp, Tgfbr2) and the complement cascade genes (C1qa, C1qb, Pros1) were affected by genetic background in both amyloid and tau studies (Fig. 5 C).”

The cortex of wild-derived CAST and PWK mice permits significantly higher prion-like proteopathic seeding activity of tau compared to that of B6 controls.

“We report that the cortex of wild-derived CAST and PWK mice permits significantly higher prion-like proteopathic seeding activity of tau compared to that of B6 controls.”

Darkorange is a significant mediator of the relationship between genetic background and tau seeding (joint significance via HIMA, P = 0.0349).

“Two steps of mediation analysis identified that darkorange is a significant mediator of the relationship between genetic background and tau seeding (joint significance calculated via HIMA, P = 0.0349).”

• AssumptionThe authors state this as an assumption: FRET+ signal in the tau biosensor assay is a valid proxy for tau seeding activity.

KEGG enrichment of Signature C reveals microglia-related terms, calculated in gprofiler2 via Fisher's one-tailed test, with all terms P < 0.05.

“KEGG enrichment of Signature C reveals microglia-related terms calculated in gprofiler2 via Fisher’s one-tailed test (all terms P < 0.05).”

Using a genotyping array, gigaMUGA, the three wild-derived strains contain many variants in the nominated targets from the AMP-AD database.

“Using a genotyping array, gigaMUGA, we report that these three wild-derived strains contain many variants in the nominated targets from the AMP-AD database (Fig. 1).”

PWK and CAST were the two genetic backgrounds susceptible to tau seeding.

“This subset of pathways was of interest to us since PWK and CAST were the two genetic backgrounds susceptible to tau seeding (Fig. 2 G).”

KEGG enrichment of Signature C identified multiple immune responses.

“Multiple immune responses (Fig. 6 B) were identified using KEGG.”

The expression score of each signature via PCA of raw reads demonstrated similar shifts in PWK and CAST, concordant with changes observed in tau seeding activity.

“The expression score of each signature via PCA of raw reads demonstrated similar shifts in PWK and CAST, which were concordant with the changes observed in tau seeding activity (Fig. 6 D).”

The Innate Immune Response pathway was concordantly increased in PWK and CAST mice.

“The “Innate Immune Response” pathway was concordantly increased in PWK and CAST mice, while the “Microglia Function” pathway was decreased in both genetic backgrounds.”

There is a core tau-responsive transcriptional signature that is not affected by genetic background (Signature A).

“First, a core tau-responsive transcriptional signature that is not affected by genetic background (Signature A).”

WSB mice appear to have a unique downregulation in two genes involved in motor transport, Kif14 and Myl1.

“For example, WSB mice appear to have a unique downregulation in two genes involved in motor transport, Kif14 and Myl1 (Fig. 3 D).”

Analysis of the effect of genetic background on hTauP301L expressing mice further supported the role of Signature C (darkorange module) in the innate immune response and microglial function.

“Analysis of the effect of genetic background on hTauP301L expressing mice further supported the role of Signature C (darkorange module) in the innate immune response and microglial function (Fig. 8).”

There is a unique transcriptional response to tau (Signature B).

“Second, a unique transcriptional response to tau that may indicate wild-derived mice should be used to study certain risk genes (Signature B).”

21 of the 60 WGCNA modules were significantly associated with FRET+ seeding activity or wild-derived genetic background (Pearson's correlation, P < 0.05).

“21 of them were significantly associated with FRET+ seeding activity or wild-derived genetic background (Fig. S4 D; Pearson’s correlation, P < 0.05).”

There is a tau seeding activity-associated transcriptional signature that implicates microglia (Signature C).

“Third, a tau seeding activity–associated transcriptional signature that implicates microglia (Signature C).”

There is an increase in tau seeding activity in the cortex of CAST and PWK mice.

“We found an increase in tau seeding activity in the cortex of CAST and PWK mice (Fig. 2).”

We report a unique or "segregating" response to tau in wild-derived mice.

“We report a unique or “segregating” response to tau in wild-derived mice (Fig. 4).”

Our network analysis identified a module of genes associated with the increase of tau seeding activity in CAST and PWK mice.

“Importantly, our network analysis identified a module of genes associated with this increase of tau seeding activity in CAST and PWK mice (Fig. 5).”

The overlapping genes include Trem2, Tyrobp, Tgfbr2, and Cd68.

“These include Trem2, Tyrobp, Tgfbr2, and Cd68.”

The viral approach preserves each genetic background without genetic drift or unwanted variants over a multiyear backcrossing experiment.

“we ensure that each genetic background is preserved without any possible genetic drift or the addition of unwanted variants over a multiyear backcrossing experiment.”

Genetic variation across genetic backgrounds is the greatest driver of gene expression.

“These data suggest that genetic variation across genetic backgrounds is the greatest driver of gene expression.”

The genetic heterogeneity across wild-derived mice exacerbates the prion-like action of tau in the brain cortex.

“Taken together, our data suggest that the genetic heterogeneity across wild-derived mice exacerbates the prion-like action of tau in the brain cortex.”

• AssumptionThe authors state this as an assumption: FRET+ signal in the tau biosensor assay is a valid proxy for tau seeding activity.

At least eight mice per group are needed to properly power the main study.

“This analysis indicates that at least eight mice per group are needed to properly power the main study.”

Little is known about the effect of wild-derived mouse backgrounds on modeling tauopathy.

“Even though wild-derived backgrounds have been shown to have a large effect on modeling Aβ pathology, little is known about their effect on modeling tauopathy.”

The core tau signature includes many targets that are already implicated in neurodegenerative diseases.

“These data demonstrate that the core tau signature includes many targets that are already implicated in neurodegenerative diseases.”

The genetic heterogeneity of the wild-derived mouse genetic backgrounds could modulate many genes of interest for the study of AD and related dementias.

“these data suggest that the genetic heterogeneity of the wild-derived mouse genetic backgrounds could modulate many genes of interest for the study of AD and related dementias.”

• AssumptionRests on an assumption: The AMP-AD nominated target genes are relevant to AD and related dementias.

There exist some novel responses to tau present only in wild-derived mice.

“These data suggest that there exist some novel responses to tau present only in wild-derived mice.”

The influence of genetic diversity on tau pathology and seeding has not been thoroughly investigated.

“Therefore, the influence of genetic diversity on tau pathology and seeding has not been thoroughly investigated.”

• AssumptionRests on an assumption: Most studies use the same monogenic mouse models, unlike genetically diverse human patients.

A large part (2,467 genes) of the Signature A core tau signature is resistant to the variation between genetic backgrounds.

“These data suggest a large part (2,467 genes) of what we call the “Signature A: core tau signature” is resistant to the variation between genetic backgrounds.”

The genetic variations across different mouse genetic backgrounds do not influence the ability to express tau using AAV-hTauP301L injection.

“These data suggest that the genetic variations across different mouse genetic backgrounds do not influence our ability to express tau using AAV-hTauP301L injection.”

The immune system may be implicated in the increase in seed-competent tau observed in CAST and PWK mice.

“These data suggest that the immune system may be implicated in the increase in seed-competent tau observed in CAST and PWK mice.”

The genetic backgrounds most susceptible to tau seeding had the most increase in markers of inflammation.

“Taken together, this suggests the genetic backgrounds that were most susceptible to tau seeding had the most increase in markers of inflammation.”

Both pathways are sensitive to genetic context when modeling both hallmarks of AD.

“This finding suggests that both pathways are sensitive to genetic context when modeling both hallmarks of AD.”

There is a core response to TauP301L/S expression that is shared between these three models.

“This example meta-analysis suggests that there is a core response to TauP301L/S expression that is shared between these three models.”

Mouse genetic background is an important factor when studying immune responses to pathological tau species.

“Our data suggest that mouse genetic background is an important factor when studying immune responses to pathological tau species.”

The upregulation of 28 darkorange module genes validates the involvement of these genes in the immune response to tau.

“We found that 28 out of 56 darkorange module genes on the mouse neuroinflammation panel were significantly upregulated in AAV-hTauP301L–injected mice versus AAV-eGFP–injected controls across all genetic backgrounds, validating the involvement of these darkorange module genes in the immune response to tau (Fig. 7, A–D).”

In the cross-study comparison, it was not possible to match for sex, exact region, the promoter used by the model, or the genetic background of the mice in each study.

“However, it was not possible to match for sex, exact region, the promoter used by the model, or the genetic background of the mice in each study.”

The fundamental pathways involved in studying mouse models of dementia do not change across genetic backgrounds.

“This finding suggests that the fundamental pathways involved in studying mouse models of dementia do not change across genetic backgrounds.”

Our enrichment analysis and comparison to previously published microglial contextual states suggest the importance of microglia in tau seeding.

“Our enrichment analysis and comparison to previously published microglial contextual states suggest the importance of microglia in tau seeding (Fig. 6).”

This study provides compelling evidence that microglia within PWK and CAST mice contribute to an increased susceptibility to tau seeding.

“However, we believe that this study provides compelling evidence that microglia within PWK and CAST mice contribute to an increased susceptibility to tau seeding.”

By combining unbiased whole transcriptomic analyses with targeted RNA probing, we have identified a subset of genes involved with tau seeding and increased inflammatory response.

“By combining unbiased whole transcriptomic analyses with targeted RNA probing, we have identified this subset of genes involved with tau seeding and increased inflammatory response.”