Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the Aβ42:Aβ40 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer's Mouse Model

May combine two claims. The quote only partly states this claim.

PS2APP;Trem2ko mice at 12 months of age have ApoE-laden microglia, with marked accumulation of ApoE in Trem2-deficient microglia.

“Trem2-deficient microglia showing compromised expression of proliferation/Wnt-related genes and marked accumulation of ApoE.”

• Also stated in: § Introduction · plain

  “Additional analyses of PS2APP;Trem2ko mice at 12 months of age revealed ApoE-laden microglia”

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Other GO biological processes downregulated in PS2APP;Trem2ko microglia included positive regulation of bone resorption (fold enrichment = 24.6, FDR = 0.030), protein kinase B signaling (16.2, 0.047), negative regulation of tumor necrosis factor production (14.1, 0.026), positive regulation of smooth muscle cell migration (13.9, 0.025), transmembrane receptor protein tyrosine kinase signaling (5.9

“Other GO biological processes implicated as being downregulated in PS2APP;Trem2ko microglia included positive regulation of bone resorption (fold enrichment = 24.6, FDR = 0.030), protein kinase B signaling (fold enrichment = 16.2, FDR = 0.047), negative regulation of tumor necrosis factor production (fold enrichment = 14.1, FDR = 0.026), positive regulation of smooth muscle cell migration (fold”

May combine two claims.

In PS2APP compared with nontransgenic microglia, the Neurodegeneration-related, Interferon-related, Proliferation, and LPS-related modules were upregulated, whereas the Microglia and Brain Myeloid modules were modestly but significantly downregulated.

“In PS2APP compared with nontransgenic microglia, several of these gene sets were upregulated, including the Neurodegeneration-related, Interferon-related, Proliferation, and LPS-related modules, whereas the Microglia and Brain Myeloid modules that typify microglia in their “homeostatic” or “resting” state were modestly but significantly downregulated (Fig. 2D; Fig. 2-3.”

May combine two claims.

Even though only 5 of 82 genes in the Proliferation module were upregulated strongly enough in PS2APP microglia to reach genome-wide significance (adjusted p ≤ 0.05), the overall expression of the module was clearly enriched compared with microglia from nontransgenic mice.

“For instance, even though only 5 of 82 genes in the Proliferation module were upregulated strongly enough in PS2APP microglia to reach genome-wide significance (adjusted p ≤ 0.05), the overall expression of the module was clearly enriched compared with microglia from nontransgenic mice (Fig. 2D; Fig. 2-3.”

May combine two claims.

Despite only 2 of 82 genes (Ccna2 and Aspm) showing significant reduction in transcript abundance after correction for genome-wide analysis, the overall induction of the Proliferation module was compromised in PS2APP;Trem2ko microglia.

“Again, despite only 2 of 82 genes (Ccna2 and Aspm) showing significant reduction in transcript abundance after correction for genome-wide analysis, the overall induction of the Proliferation module was compromised in PS2APP;Trem2ko microglia (Fig. 2D; Fig. 2-3).”

May combine two claims.

Consistent changes in plaque compaction and composition were observed across ages and sexes in PS2APP;Trem2ko brains, in contrast to total plaque burden which varied with age or sex.

“In contrast to the effects of Trem2 deletion on total plaque burden that varied with age or sex, we observed consistent changes in plaque compaction and composition across ages and sexes.”

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Plaque load was reduced in 12 month PS2APP;Trem2ko females and in 19-22 month PS2APP;Trem2ko males compared with PS2APP;Trem2wt mice.

“We expected to see further exacerbation of amyloid plaque load in Trem2-deficient brains at more advanced ages, but, to our surprise, plaque load was reduced in 12 month PS2APP;Trem2ko females and in 19–22 month PS2APP;Trem2ko males compared with PS2APP;Trem2wt mice (Fig. 3A,B).”

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When using the pan-reactive 6E10 Aβ antibody to detect total Aβ species in the soluble fraction, abundance trended slightly downward in PS2APP;Trem2ko mice and correlated negatively with Aβ42:Aβ40 ratio.

“In contrast, when we used the pan-reactive 6E10 Aβ antibody to detect total Aβ species in this fraction, the abundance trended slightly downward in PS2APP;Trem2ko mice and correlated negatively with Aβ42:Aβ40 ratio (Fig. 5F–H).”

May combine two claims.

Using Campbell-Switzer silver stain, plaque burden was increased in 6-7 month PS2APP;Trem2ko females, and trending upward but not reaching significance in 6-7 month PS2APP;Trem2ko males.

“Indeed, using the Campbell-Switzer silver stain to label amyloid plaque (Campbell et al., 1987; Switzer, 2000), we observed that plaque burden was increased in 6–7 month PS2APP;Trem2ko females, and trending upward but not reaching significance in 6–7 month PS2APP;Trem2ko males (Fig. 3A,B).”

• cites Campbell et al., 1987Not checked yet

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• cites Switzer, 2000Not checked yet

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The downregulation of the Microglia and Brain Myeloid modules that normally occurs during CNS challenge was not prevented by Trem2 deletion; expression of these modules was similar in PS2APP;Trem2wt and PS2APP;Trem2ko microglia.

“Unlike the clear requirement of Trem2 for induction of many genes in the Neurodegeneration-related gene set, the downregulation of the Microglia and Brain Myeloid modules that normally occurs during any CNS challenge (Friedman et al., 2018) was not prevented by Trem2 deletion since expression of these modules was similar in PS2APP;Trem2wt and PS2APP;Trem2ko microglia (Fig. 2D; Fig. 2-3).”

• cites Friedman et al., 2018Not checked yet

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The elevated Aβ42:Aβ40 ratio in PS2APP;Trem2ko brains resulted more from reduced abundance of Aβ40 than from increased abundance of Aβ42, although Aβ42 abundance was elevated in the 6-7 month females, coinciding with the increased plaque deposition in that group.

“The elevated Aβ42:Aβ40 ratio in PS2APP;Trem2ko brains resulted more from reduced abundance of Aβ40 than from increased abundance of Aβ42 (Fig. 5-1), although Aβ42 abundance was elevated in the 6–7 month females, coinciding with the increased plaque deposition we observed in that group (Fig. 3A).”

May combine two claims.

Quantification of plaque-associated ApoE in whole-brain sections found a significant increase in female PS2APP;Trem2ko mice at 6-7 and 12 months of age, but no significant changes in male cohorts at any age tested.

“In contrast to the findings of Parhizkar et al. (2019), quantification of plaque-associated ApoE in whole-brain sections found a significant increase in female PS2APP;Trem2ko mice at 6–7 and 12 months of age, but no significant changes in male cohorts at any age tested (Fig. 6A).”

May combine two claims.

Using the conformation-specific OC antibody, significantly higher levels of soluble fibrillar Aβ oligomers were detected in the soluble fraction from PS2APP;Trem2ko mice, and a positive correlation was observed between OC+ fibrillar oligomers and the Aβ42:Aβ40 ratio.

“Using the conformation-specific OC antibody (Tomic et al., 2009), we detected significantly higher levels of soluble fibrillar Aβ oligomers in the soluble fraction from PS2APP;Trem2ko mice (Fig. 5C,D), and we observed a positive correlation between the amount of OC+ fibrillar oligomers in this fraction and the Aβ42:Aβ40 ratio (Fig. 5E).”

• cites Tomic et al., 2009Not checked yet

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Of the 134 genes in the Neurodegeneration-related set, 80 showed upregulation in PS2APP versus normal microglia, and approximately half of these showed impaired induction in PS2APP;Trem2ko microglia (adjusted p ≤ 0.05).

“Of the 134 genes in this set, 80 showed upregulation in PS2APP versus normal microglia (Friedman et al., 2018), and approximately half of these showed impaired induction in PS2APP;Trem2ko microglia (adjusted p values ≤ 0.05) (Fig. 2E).”

• cites Friedman et al., 2018Not checked yet

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In a recent dataset of bulk microglia RNA-Seq profiles from 5xFAD mice, a twofold decrease in the extent of Apoe induction was seen in Trem2-deficient microglia, but the gene was still highly induced relative to nontransgenic microglia.

“In a very recent dataset of bulk microglia RNA-Seq profiles from 5xFAD mice (Griciuc et al., 2019), we did see a twofold decrease in the extent of Apoe induction in Trem2-deficient microglia, but the gene was still highly induced relative to the expression level in microglia from nontransgenic mice (Fig. 6F).”

• cites Griciuc et al., 2019Not checked yet

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The abundance of Aβ peptides rose markedly with age while the Aβ42:Aβ40 ratio declined, particularly in the GuHCl fraction.

“The abundance of Aβ peptides rose markedly with age while the Aβ42:Aβ40 ratio declined, particularly in the GuHCl fraction (Fig. 5).”

May combine two claims.

Amino-cupric-silver staining showed "bouquets" of argyrophilic structures presumably surrounding plaques throughout the cortex and hippocampus, and staining in white matter tracts such as corpus callosum, perforant path, and fornix.

“Overall, the staining pattern appeared very similar to the Lamp1 stain, with “bouquets” of argyrophilic structures presumably surrounding plaques throughout the cortex and hippocampus. Staining was also observed in relevant white matter tracts, such as the corpus callosum, perforant path, and fornix, suggesting that degenerating axonal processes are not restricted to dystrophic neurites around”

May combine two claims.

Amber cores were reduced in PS2APP;Trem2het and nearly absent in PS2APP;Trem2ko brains.

“These amber cores were reduced in PS2APP;Trem2het and nearly absent in PS2APP;Trem2ko brains, indicating that Trem2-dependent microglial activity is essential for the formation of these particular amyloid structures.”

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Plaques in Trem2-deficient mice are more injurious to adjacent neurites but show weaker labeling with molecular probes (Thioflavin S, methoxy-X04 and X-34) related to those used in the clinic (11C-PiB, 18F-Florbetapir).

“The fact that plaques in Trem2-deficient mice are more injurious to adjacent neurites but show weaker labeling with molecular probes (Thioflavin S, methoxy-X04 and X-34) related to those used in the clinic (11C-PiB, 18F-Florbetapir)”

May combine two claims.

Preventing the microglial response to Aβ pathology via Trem2 deletion reversed neither axonal dystrophy nor dendritic spine loss around plaque and indeed made both of these pathologies worse.

“preventing the microglial response to Aβ pathology via Trem2 deletion reversed neither axonal dystrophy nor dendritic spine loss around plaque and indeed made both of these pathologies worse.”

May combine two claims.

At all ages examined, and in both sexes, microglial clustering around plaque and other measurements of microglial activation were sharply reduced in PS2APP;Trem2ko mice.

“At all ages examined, and in both sexes, microglial clustering around plaque and other measurements of microglial activation were sharply reduced in PS2APP;Trem2ko mice.”

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From 6-7 months onward, axonal injury was magnified in PS2APP;Trem2ko mice, even at later ages when the abundance of argyrophilic amyloid plaques was diminished.

“From 6–7 months onward, axonal injury was magnified in PS2APP;Trem2ko mice, even at later ages when the abundance of argyrophilic amyloid plaques was diminished.”

May combine two claims.

Trem2 deletion has age- and sex-dependent effects on plaque abundance assessed using the Campbell-Switzer silver stain in PS2APP mice, with slightly more plaque in PS2APP;Trem2ko females at 6-7 months of age but markedly less plaque in both female and male PS2APP;Trem2ko mice at later ages.

“We observed both age- and sex-dependent effects of Trem2 deletion on plaque abundance assessed using the Campbell-Switzer silver stain, with slightly more plaque in PS2APP;Trem2ko females at 6–7 months of age but markedly less plaque in both female and male PS2APP;Trem2ko mice at later ages.”

May combine two claims.

In 6-month-old female PS2APP mice, plaque-proximal dendritic spine density was not rescued by Trem2 deletion but was further reduced in PS2APP;Trem2ko mice compared with PS2APP;Trem2wt or PS2APP;Trem2het mice.

“Spine density loss in the proximity of plaques was not rescued by Trem2 deletion, but was actually further exacerbated in PS2APP;Trem2ko mice compared with PS2APP;Trem2wt or PS2APP;Trem2het groups (Fig. 9).”

• Also stated in: § Axonal dystrophy, dendritic spine loss, and CSF NfL detection are exacerbated in PS2APP;Trem2ko mice · plain

  “Spine density near plaque was lower in PS2APP;Trem2ko mice than in PS2APP;Trem2wt or PS2APP;Trem2het mice.”

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Trem2 deletion in amyloidosis models has been reported to either increase or decrease phosphorylation of the endogenous tau protein.

“Trem2 deletion in amyloidosis models has also been reported to either increase or decrease phosphorylation of the endogenous tau protein (Jay et al., 2015; Wang et al., 2016).”

• cites Jay et al., 2015Not checked yet

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• cites Wang et al., 2016Not checked yet

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Whether Trem2 exerts protective or detrimental functions in mouse models of AD-related neuropathology has been rather unclear.

“However, whether Trem2 exerts protective or detrimental functions in mouse models of AD-related neuropathology has been rather unclear (Gratuze et al., 2018; Hansen et al., 2018; Ulland and Colonna, 2018).”

• cites Gratuze et al., 2018Not checked yet

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• cites Hansen et al., 2018Not checked yet

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• cites Ulland and Colonna, 2018Not checked yet

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In transgenic models of cerebral β-amyloidosis, plaque load has been reported to be increased, decreased, or unchanged in mice that lack Trem2, depending on the model, age, and brain region analyzed.

“In transgenic models of cerebral β-amyloidosis, plaque load has been reportedly increased, decreased, or unchanged in mice that lack Trem2, depending on the model, age, and brain region being analyzed (Jay et al., 2015, 2017a; Wang et al., 2015, 2016; Yuan et al., 2016; Parhizkar et al., 2019).”

• cites Jay et al., 2015, 2017aNot checked yet

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• cites Wang et al., 2015, 2016Not checked yet

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• cites Yuan et al., 2016Not checked yet

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TREM2 is an Alzheimer's disease risk gene expressed in microglia.

“TREM2 is an Alzheimer's disease (AD) risk gene expressed in microglia.”

• cites Guerreiro et al., 2013Not checked yet

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• cites Jonsson et al., 2013Not checked yet

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Asb11 is important for maintaining progenitor cell activity in multiple cell types.

“Dkk2, Wif1, and Ctnna3 can all negatively regulate Wnt activity (Hsieh et al., 1999; Busby et al., 2004; Gage et al., 2008), whereas Asb11 is important for maintaining progenitor cell activity in multiple cell types (Diks et al., 2006; Tee et al., 2012).”

• cites Diks et al., 2006Not checked yet

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• cites Tee et al., 2012Not checked yet

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Gene expression modules defined by Friedman et al. (2018) can be used to characterize the diverse ways that microglia respond to environmental and genetic perturbations.

“We recently defined a number of gene expression modules that can be used to characterize the diverse ways that microglia respond to environmental and genetic perturbations (Friedman et al., 2018).”

• cites Friedman et al., 2018Not checked yet

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All animal care and handling procedures were reviewed and approved by the Genentech Institutional Animal Care and Use Committee and were conducted in full compliance with regulatory statutes, Institutional Animal Care and Use Committee policies, and National Institutes of Health guidelines.

“All animal care and handling procedures were reviewed and approved by the Genentech Institutional Animal Care and Use Committee and were conducted in full compliance with regulatory statutes, Institutional Animal Care and Use Committee policies, and National Institutes of Health guidelines.”

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Whole-slide image analyses were performed in a blinded manner.

“MATLAB (The MathWorks) running on a high-performance computing cluster was used for all whole-slide image analyses performed in a blinded manner.”

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Images for X-34 stains were collected and processed blind to genotypes.

“Images were collected and processed blind to genotypes.”

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To avoid the presence of peripheral myeloid cells in the flow analysis and FACS collections, Ccr2+ cells and Ly6g+ cells were excluded.

“To avoid the presence of peripheral myeloid cells in the flow analysis and FACS collections, Ccr2+ cells (peripheral monocytes/macrophages) and Ly6g+ cells (neutrophils) were excluded.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

PS2APP mice develop amyloid plaque and attendant gliosis pathologies that increase with age, with female mice accumulating the pathology more rapidly than males.

“PS2APP mice develop amyloid plaque and attendant gliosis pathologies that increase with age, with female mice accumulating the pathology more rapidly than males (Ozmen et al., 2009).”

• cites Ozmen et al., 2009Not checked yet

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All steps in tissue dissociation and cell suspension preparation were performed on ice or at 4°C to prevent artifactual microglial activation.

“All steps were performed on ice or at 4°C to prevent artifactual microglial activation.”

May combine two claims.

The reductions in total Iba1 and Gfap staining indicate reduced extents of microgliosis and astrogliosis, respectively, in PS2APP;Trem2ko mice.

“indicative of reduced extents of microgliosis and astrogliosis, respectively, in PS2APP;Trem2ko mice”

Probably not a substantial claim: may not pass S3 (load-bearing).

Acquisition of the DAM state is Trem2-dependent in mouse models of AD, amyotrophic lateral sclerosis, and demyelinating disease.

“The acquisition of the DAM state is Trem2-dependent in mouse models of AD, amyotrophic lateral sclerosis, and demyelinating disease (Poliani et al., 2015; Wang et al., 2015; Keren-Shaul et al., 2017; Krasemann et al., 2017).”

• cites Poliani et al., 2015Not checked yet

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• cites Wang et al., 2015Not checked yet

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• cites Keren-Shaul et al., 2017Not checked yet

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In the hTau model, Trem2 deletion increased the amounts of tau phosphorylation and aggregation detected.

“In the hTau model (Andorfer et al., 2003), Trem2 deletion increased the amounts of tau phosphorylation and aggregation detected (Bemiller et al., 2017).”

• cites Bemiller et al., 2017Not checked yet

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All images, segmentation overlays, and data were reviewed by a pathologist.

“All images, segmentation overlays, and data were reviewed by a pathologist.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Dkk2, Wif1, and Ctnna3 can all negatively regulate Wnt activity.

“Dkk2, Wif1, and Ctnna3 can all negatively regulate Wnt activity (Hsieh et al., 1999; Busby et al., 2004; Gage et al., 2008), whereas Asb11 is important for maintaining progenitor cell activity in multiple cell types (Diks et al., 2006; Tee et al., 2012).”

• cites Hsieh et al., 1999Not checked yet

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• cites Busby et al., 2004Not checked yet

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• cites Gage et al., 2008Not checked yet

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CD45low and CD45high gates were defined using a nontransgenic animal as a control, and the same gates were transposed onto cells from PS2APP animals sorted on the same day in the same machine to ensure accuracy and consistency.

“CD45low and CD45high gates were defined using a nontransgenic animal as a control to identify microglia in their normal state (CD45low). The same gates were transposed onto cells from PS2APP animals sorted on the same day in the same machine to ensure accuracy and consistency in determining percentages of CD45low and CD45high populations.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Two sections per animal were stained, with all cohorts stained and analyzed simultaneously.

“Two sections per animal were stained, with all cohorts stained and analyzed simultaneously.”

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Trem2-dependent microglial proliferation and activation attenuate the toxic effects of Aβ toward neurons, i.e., the DAM state is mainly protective.

“Collectively, our data indicate that Trem2-dependent microglial proliferation and activation attenuate the toxic effects of Aβ toward neurons (i.e., the DAM state is mainly protective)”

• AssumptionRests on an assumption: The effects of Trem2 deletion in PS2APP mice are mediated specifically by microglial Trem2 rather than by other Trem2-expressing myeloid cells or non-myeloid cells.

Probably not a substantial claim: may not pass S3 (load-bearing).

Imaging and analysis for two-photon microscopy were performed under blinded conditions.

“Imaging and analysis were performed under blinded conditions.”

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Transcriptional profiling studies have defined a disease/damage-associated microglial activation state that is commonly observed in the brains of neurodegeneration models.

“Transcriptional profiling studies have defined a disease/damage-associated microglial (DAM) activation state that is commonly observed in the brains of neurodegeneration models (Deczkowska et al., 2018; Friedman et al., 2018).”

• cites Deczkowska et al., 2018Not checked yet

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• cites Friedman et al., 2018Not checked yet

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Animal pairs, including one PS2APP;Trem2wt and one PS2APP;Trem2ko animal, were generally processed together from perfusion through sorting.

“Generally, animal pairs, including one PS2APP;Trem2wt and one PS2APP;Trem2ko animal, were processed together from perfusion through sorting.”

Classified as probably not a substantial claim. May combine two claims.

The 6-7 month cohort of male and female mice was purposely analyzed separately to determine the effects of Trem2 deficiency in each sex since female mice have accelerated amyloid pathology compared with males, and to avoid confounding by age-dependent differences in pathology between males and females.

“The 6–7 month cohort of male and female mice was purposely analyzed separately to determine the effects of Trem2 deficiency in each sex since female mice have accelerated amyloid pathology compared with males, and we did not want an analysis of interactions between sex and Trem2 genotype to be confounded by the age-dependent differences in pathology between males and females.”

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In the PS19 model, Trem2 deletion had a protective effect, preventing tau-driven synaptic loss and atrophy in the hippocampus and entorhinal cortex, respectively.

“In contrast, in the PS19 model (Yoshiyama et al., 2007), Trem2 deletion had a protective effect, preventing tau-driven synaptic loss and atrophy in the hippocampus and entorhinal cortex, respectively (Leyns et al., 2017).”

• cites Leyns et al., 2017Not checked yet

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As a control, PS2APP;Bace1ko hippocampal TBS homogenate supernatant showed minimal OC antibody detection but substantial 6E10 signal, consistent with the ability of 6E10 to detect both soluble APP and Aβ peptides.

“As a control, we spotted hippocampal TBS homogenate supernatant from a PS2APP;Bace1ko animal (Meilandt et al., 2019), in which soluble APP is still produced by α-cleavage while β-cleavage and thus Aβ production are prevented, and demonstrated that the OC antibody had minimal detection, whereas 6E10 still had substantial signal (compare # symbols in Fig. 5C,F and dotted lines in Fig. 5D,G from a PS”

• cites Meilandt et al., 2019Not checked yet

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The elevated Aβ42:Aβ40 ratio in Trem2-deficient brains may increase plaque seeding at younger ages while reducing the incorporation and compaction of Aβ into existing plaques at older ages.

“Together with our observation that total amyloid plaque is reduced in PS2APP;Trem2ko brains at later ages (Fig. 3A), these results suggest that the elevated Aβ42:Aβ40 ratio in Trem2-deficient brains may increase plaque seeding at younger ages (since Aβ42 is more prone to aggregate and deposit than Aβ40) (Klein, 2002) while reducing the incorporation and compaction of Aβ into existing plaques at”

• cites Klein, 2002Not checked yet

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• cites Condello et al., 2015Not checked yet

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The authors' results are reminiscent of a recent study of APPPS1 mice, which showed that Trem2 deletion produced increased seeding of amyloid plaques at early ages but slower rates of amyloid plaque accumulation at later ages.

“Overall, our results are reminiscent of a recent study of APPPS1 mice, which showed that Trem2 deletion produced increased seeding of amyloid plaques at early ages but slower rates of amyloid plaque accumulation at later ages (Parhizkar et al., 2019).”

• cites Parhizkar et al., 2019Not checked yet

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Microglial Apoe expression is induced by Aβ-driven neuropathology in a largely Trem2-independent manner, and Trem2-deficient microglia accumulate disproportionately large amounts of ApoE compared with normal PS2APP microglia.

“Together, our evidence indicates that microglial Apoe expression is induced by Aβ-driven neuropathology in a largely Trem2-independent manner, and that Trem2-deficient microglia accumulate disproportionately large amounts of ApoE compared with the smaller ApoE puncta observed in normal PS2APP microglia (Fig. 6C).”

May combine two claims.

Trem2 may both restrict the initial seeding of plaques and promote sequestration and compaction of Aβ into existing plaques.

“Thus, Trem2 may both restrict the initial seeding of plaques and promote sequestration and compaction of Aβ into existing plaques.”

May combine two claims.

The form rather than the amount of plaque correlates with neuronal damage, and sufficient microgliosis occurs in PS2APP;Trem2het mice to enable plaque compaction and neuroprotection.

“The intermediate effect of Trem2 heterozygosity on microglial clustering around plaque (Figs. 1A, 7B) and Campbell-Switzer plaque staining (Fig. 3A), but not on plaque diffuseness (Fig. 4B), Aβ42:Aβ40 ratio (Fig. 5A), or neuritic dystrophy (Figs. 7C,D, 8A), suggested that the form rather than the amount of plaque correlates with neuronal damage, and that sufficient microgliosis occurs in PS2APP;T”

Classified as probably not a substantial claim.

Aβ42 oligomers are commonly understood to be the more toxic form of Aβ.

“The elevated Aβ42:Aβ40 ratio and fibrillar Aβ oligomers in PS2APP;Trem2ko brains would seem to be detrimental for neuronal health since Aβ42 oligomers are commonly understood to be the more toxic form of Aβ (Klein, 2002; Haass and Selkoe, 2007).”

• cites Klein, 2002Not checked yet

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• cites Haass and Selkoe, 2007Not checked yet

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Apoe is one of the most highly induced genes in mouse microglia in response to neurodegenerative stimuli.

“Apoe is one of the most highly induced genes in mouse microglia in response to neurodegenerative stimuli (Deczkowska et al., 2018).”

• cites Deczkowska et al., 2018Not checked yet

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NfL measured in CSF or plasma has recently emerged as a potential biomarker of neurodegeneration in human patients and in mouse disease models.

“NfL measured in the CSF or plasma has recently emerged as a potential biomarker of neurodegeneration in human patients and in mouse disease models (Bacioglu et al., 2016; Khalil et al., 2018).”

• cites Bacioglu et al., 2016Not checked yet

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• cites Khalil et al., 2018Not checked yet

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The authors were blinded to Trem2 genotype during plaque morphology assessment.

“Although we were blinded to Trem2 genotype, there was an obvious difference in plaque appearance between PS2APP;Trem2wt and PS2APP;Trem2ko brains, with X-34+ structures in PS2APP;Trem2ko brains looking more splayed and less compact (Fig. 4A), similar to descriptions of Trem2-dependent plaque alterations in other β-amyloid models (Wang et al., 2016; Yuan et al., 2016).”

Probably not a substantial claim: may not pass S3 (load-bearing).

Alternatively, the increased abundance of fibrillar Aβ oligomers in the TBS-soluble fraction could result from reduced incorporation into highly condensed plaques in brains with Trem2-deficient microglia.

“Alternatively, the increased abundance of fibrillar Aβ oligomers in the TBS-soluble fraction could result from reduced incorporation into highly condensed plaques in brains with Trem2-deficient microglia.”

May combine two claims.

Elevated PET signal for ligands of the neuroinflammation marker TSPO have predicted better cognitive measures and slower AD progression in mice with β-amyloid pathology and human patients, respectively.

“elevated PET signal for ligands of the “neuroinflammation marker” TSPO have predicted better cognitive measures and slower AD progression in mice with β-amyloid pathology and human patients, respectively (Hamelin et al., 2016; Focke et al., 2019).”

• cites Hamelin et al., 2016Not checked yet

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• cites Focke et al., 2019Not checked yet

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Reduced synaptic density, particularly near plaque, is a feature of AD tissues and β-amyloid mouse models.

“another feature of neuronal pathology observed in AD tissues and β-amyloid mouse models, reduced synaptic density, particularly near plaque (Spires and Hyman, 2004; Tsai et al., 2004; Spires et al., 2005)”

• cites Spires and Hyman, 2004Not checked yet

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• cites Tsai et al., 2004Not checked yet

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• cites Spires et al., 2005Not checked yet

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Trem2-dependent microglial activity may both restrain the formation/seeding of plaques at an early stage of pathology, conceivably through uptake and degradation of soluble Aβ species, but also enhance the sequestration of Aβ into existing plaque structures, particularly at later stages of pathology.

“Together with a recent similar report (Parhizkar et al., 2019), these results suggest that Trem2-dependent microglial activity may both restrain the formation/seeding of plaques at an early stage of pathology, conceivably through uptake and degradation of soluble Aβ species, but also enhance the sequestration of Aβ into existing plaque structures, particularly at later stages of pathology.”

• cites Parhizkar et al., 2019Not checked yet

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May combine two claims.

β-amyloid pathology accelerates the accumulation of tau pathology or enhances its spreading in humans and mice.

“Evidence in humans and mice supports the mechanistic model that β-amyloid pathology accelerates the accumulation of tau pathology or enhances its spreading (Pooler et al., 2015; He et al., 2018; Jack et al., 2018; Jacobs et al., 2018)”

• cites Pooler et al., 2015Not checked yet

  Not checked in the free run.

• cites He et al., 2018Not checked yet

  Not checked in the free run.

• cites Jack et al., 2018Not checked yet

  Not checked in the free run.

May combine two claims.

The reduction of plaque accumulation activity in PS2APP;Trem2ko brains may underlie the elevated levels of fibrillar oligomeric Aβ detected in the soluble fraction, which may in turn be a source of increased neuronal injury in these animals.

“The reduction of this plaque accumulation activity in PS2APP;Trem2ko brains may underlie the elevated levels of fibrillar oligomeric Aβ we detected in the soluble fraction, which may in turn be a source of increased neuronal injury in these animals.”