ABI3 deletion in TgCRND8 mice is associated with reduced amyloid plaque pathology and altered glial response
Open accessAbstract
Recent genome-wide association studies (GWAS) have identified several rare coding variants in a cluster of immune-related genes that are significantly associated with Alzheimer’s disease. This includes the risk variant (S209F) in ABI3 , a gene encoding the Abl Interactor family member 3 protein that is highly expressed in microglia, but little is known about its function in these cells and its association with AD. We have investigated the effects of ABI3 deletion on AD pathological features in the transgenic (Tg) CRND8 APP mouse model by immunofluorescence (IF) staining and confocal microscopy. We have observed that ABI3 expression is localized to microglia in the mouse brain and that the ABI3 immunoreactivity levels are increased in the TgCRND8 mice. The loss of ABI3 leads to a significant reduction of amyloid plaque numbers and size in the 9-month-old TgCRND8 mice. This is also accompanied by a reduced number of microglia clustering around the plaques. On the basis of these observations, we hypothesize that the loss of ABI3 may lead to changes in microglial behavior which directly or indirectly leads to reduced AD pathology in mice.
AI snapshot
Written from the paper’s full text.
TL;DR
In 9-month-old TgCRND8 APP mice, deletion of ABI3-GNGT2 was associated with reduced amyloid plaque number, size, density, and Aβ42-positive area, plus fewer plaque-associated microglia. ABI3 immunoreactivity localized to microglia, was increased in TgCRND8 mice, and correlated with microglial proximity to plaques.
Key findings
- ABI3 immunoreactivity was mainly localized to Iba-1-positive microglia/macrophages in the dentate gyrus and CA1 of 9-month-old C57/Bl6 non-transgenic mouse brain; no ABI3 immunoreactivity was observed in Iba-1-positive microglia in age-matched ABI3-GNGT2−/− negative controls (N=10 mice, two sections each).
- ABI3 immunoreactivity per cell in microglia was significantly increased in 9-month-old TgCRND8 mice versus age-matched non-transgenic C57 controls (P value ~0.0004; N=10 C57, n=8 TgCRND8). ABI3 integrated density showed a moderate/weak negative correlation with Iba-1-positive microglia distance from plaque center (Pearson ~0.3229; N=8 TgCRND8, 100 measurements from 16 sections).
- In 9-month-old TgCRND8 ABI3-GNGT2−/− (Tg KO) versus Tg WT mice, mean plaque number was lower in cortex (P value ~0.0011) and hippocampus (P value <0.0001); mean plaque area was smaller (P value <0.0001); plaque density and Aβ42-positive brain area were also lower (P value <0.0001). N=3 Tg WT, n=2 Tg KO.
- Mean microglia per plaque within a 20 μm radius from the plaque edge was significantly lower in Tg KO versus Tg WT (P value ~0.0021), while microglia numbers were significantly higher within that radius in both Tg WT (P value <0.0001) and Tg KO (P value ~0.0001) brains.
Methods
- Abi3-deficient mice (Abi3tm1.1(KOMP)Vlcg; 9515 bp deletion eliminating exons 1–8; C57/Bl6 background) were cross-bred with TgCRND8 APP transgenic mice (C57:C3H background) to generate APP+/− ABI3−/− animals; brain tissue was collected at 9 months of age.
- Immunofluorescence staining and confocal microscopy were used with antibodies against ABI3, Iba1, β-Amyloid 1-16, and GAPDH; images were quantified with ImageJ (Fiji) and analyzed in Prism, with significance at p<0.05.
- Statistical tests included Welch’s t-test, unpaired t-test with Welch’s correction, Kruskal-Wallis ANOVA, and ANOVA with Tukey post-test as specified in figure legends; two sections per brain were imaged and quantified.
Limitations
- Stated: the ABI3 knockout line also ablates the neighboring gene GNGT2, so some effects may be due to GNGT2 loss; the authors could not detect GNGT2 protein in microglia. Studies were only at 9 months, and time-course studies from 3 months are needed. The data cannot distinguish altered plaque formation from improved microglial clearance.
- Stated: opposing observations have been reported in 5xFAD ABI3-GNGT2−/− mice on an SJL genetic background, where amyloid-beta pathology was significantly increased; genetic background effects may influence ABI3 signaling.
- Evident from the text: plaque and microglia quantification used very small groups (N=3 Tg WT, n=2 Tg KO), and the study relies on a double ABI3-GNGT2 deletion, limiting specificity for ABI3; no in vivo time-course imaging was performed.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
7 of 8 cited sources checked · 2 supported · 0 flagged · accuracy not yet measured
- Premisecitation
In the B6N(Cg)-Abi3tm1.1(KOMP)Vlcg/J mouse line, loss of ABI3 is accompanied by ablation of the neighboring gene GNGT2.
“It's important to note that as reported by other groups, in the B6N(Cg)-Abi3tm1.1(KOMP)Vlcg/Jmouse line the loss of ABI3 is accompanied by the ablation of the neighboring gene, GNGT2, therefore we will be referring to these mice as ABI3-GNGT2 -/-7 .”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [7] source
- Findingown data
The mean number of amyloid beta plaques in both the cortex and hippocampus is significantly lower in 9-month-old TgCRND8 ABI3-GNGT2 -/- (Tg KO) mice compared to age-matched Tg WT mice.
“The mean number of plaques in both the cortex (P value ~ 0.0011) and hippocampus (P value <0.0001) of the Tg KO mouse brain was significantly lower compared to Tg WT.”
- Also stated in: § Image acquisition, analysis and statistics · plain
“The mean number of amyloid beta plaques measured was significantly lower in both the cortex (P value ~ 0.0011) and the hippocampus (P value <0.0001) of Tg KO mouse brains compared to age-matched Tg WT mouse brains (Figure4.A].”
Quote in the paperSubstantial claim - Also stated in: § Image acquisition, analysis and statistics · plain
- Findingown data
The mean number of microglia per plaque is significantly higher within the 20μm radius from the plaque edge in both 9-month-old Tg WT and Tg KO mouse brains.
“The mean number of microglia per plaque was significantly higher in the 20μm radius from the plaque edge in both Tg WT (P value <0.0001) and Tg KO mouse brains (P value ~0.0001).”
Quote in the paperNot a substantial claim - Findingown data
ABI3 immunoreactivity per cell in microglia is significantly increased in 9-month-old TgCRND8 mice relative to age-matched non-transgenic C57 control mice.
“ABI3 immunoreactivity levels are increased in the TgCRND8 mice.”
- Also stated in: § Abstract · plain
“ABI3 immunoreactivity per cell in microglia is significantly increased in TgCRND8 mice relative to non-transgenic age-matched mice [Figure 2].”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
In 9-month-old TgCRND8 mice, increased ABI3 immunoreactivity is especially prominent in microglia surrounding amyloid plaques in the cortex and hippocampus.
“The increased ABI3 staining (red) was especially prominent in the microglia (green) surrounding the amyloid plaques (magenta) in the cortex and hippocampus of the mouse brain tissues studied.”
Quote in the paperSubstantial claim
- Findingown data
ABI3 immunoreactivity is mainly localized to Iba-1 positive microglia/macrophages in the hippocampus (dentate gyrus and CA1) of 9-month-old non-transgenic C57/BI6 mouse brain.
“ABI3 expression is localized to microglia in the mouse brain”
- Also stated in: § Abstract · plain
“here we show that ABI3 immunoreactivity (red) is mainly localized to Iba-1 positive microglia/macrophages (green) in two hippocampal regions (Dentate Gyrus [Figure 1.A] and CA1 [Figure 1.B]) of 9-month-old C57/BI6 non-transgenic (NonTg) mouse brain, using IF.”
Quote in the paperSubstantial claim - Also stated in: § Abstract · plain
- Findingown data
The mean number of microglia in the proximity of plaques (20μm radius from the plaque edge) is significantly lower in 9-month-old TgCRND8 ABI3-GNGT2 -/- (Tg KO) mice compared to age-matched Tg WT mice.
“The mean number of microglia in the proximity of plaques (20μm radius from the plaque edge) was significantly lower in Tg KO mouse brains compared to Tg WT mice (P value~0.0021)[Figure 5].”
Quote in the paperSubstantial claim - Findingown data
The mean amyloid plaque area (size) is significantly smaller in 9-month-old TgCRND8 ABI3-GNGT2 -/- (Tg KO) mice compared to age-matched Tg WT mice.
“The mean plaque area measured in Tg KO mouse brains was significantly lower compared to Tg WT (P value <0.0001).”
- Also stated in: § Image acquisition, analysis and statistics · plain
“The amyloid plaque size, measured in μm 2 , was also significantly smaller in Tg KO mouse brains compared to age-matched Tg WT brains (P value <0.0001) (Figure 4.B].”
Quote in the paperSubstantial claim - Also stated in: § Image acquisition, analysis and statistics · plain
- Findingown data
The mean Aβ42 positive brain area is significantly lower in 9-month-old TgCRND8 ABI3-GNGT2 -/- (Tg KO) mice compared to age-matched Tg WT mice.
“The mean Aβ42 positive brain area (measured in μm2) was significantly lower in Tg KO mouse brains compared to Tg WT.”
- Also stated in: § Image acquisition, analysis and statistics · plain
“Both the plaque density (%) and the Aβ42 positive brain area (in μm2) were significantly lower in Tg KO mouse brains compared to Tg WT mouse brains (P value <0.0001) [Figure 4.C, D].”
Quote in the paperSubstantial claim - Also stated in: § Image acquisition, analysis and statistics · plain
- Findingown data
ABI3 integrated density in Iba-1 positive microglia is moderately negatively correlated with the distance of the cell from the center of amyloid plaques in 9-month-old TgCRND8 mouse brain.
“We observed a moderate negative correlation between ABI3 integrated density levels and the distance of Iba-1 positive microglia from the plaque center, suggesting that ABI3 might be performing specific functions in the microglia populations that cluster around amyloid plaques [Figure 3].”
Quote in the paperSubstantial claim - Findingown data
Amyloid beta plaque density is significantly lower in 9-month-old TgCRND8 ABI3-GNGT2 -/- (Tg KO) mice compared to age-matched Tg WT mice.
“The plaque density was significantly lower in Tg KO mouse brains compared to Tg WT (P value <0.0001)”
- Also stated in: § Image acquisition, analysis and statistics · plain
“Both the plaque density (%) and the Aβ42 positive brain area (in μm2) were significantly lower in Tg KO mouse brains compared to Tg WT mouse brains (P value <0.0001) [Figure 4.C, D].”
Quote in the paperSubstantial claim - Also stated in: § Image acquisition, analysis and statistics · plain
- Interpretationreasoning
Given ABI3's involvement in actin cytoskeleton reorganization and cell movement in microglia, the possibility that lower plaque numbers resulted from improved microglial clearance of plaques seems more plausible than altered disease pathogenesis/plaque formation.
“Given the involvement of ABI3 in actin cytoskeleton reorganization and cell movement in microglia, the latter possibility seems more plausible.”
Quote in the paperSubstantial claim - Study design and conductown data
Loss of ABI3 expression in the ABI3 knockout (-/-) mouse line (B6N(Cg)-Abi3tm1.1(KOMP)Vlcg/J) was confirmed by western blotting and immunofluorescence.
“the loss of ABI3 expression in the ABI3 knockout ( -/-) mouse line (B6N(Cg)-Abi3tm1.1(KOMP)Vlcg/J)by western blotting and IF.”
Quote in the paperSubstantial claim - Interpretationown data
ABI3 may modulate the risk of Alzheimer's disease through regulating microglial response to amyloid pathology.
“suggesting that ABI3 could modulate the risk of AD through regulating microglial response to amyloid pathology.”
Quote in the paperSubstantial claim- Rests on an assumption: Findings from the TgCRND8 mouse model of amyloid pathology are relevant to human Alzheimer's disease risk.
- Study design and conductown data
The commercially acquired ABI3 antibody (rabbit anti-ABI3, abcam ab81152) was validated for sensitivity in selectively detecting ABI3 protein using ABI3 -/- derived microglia lysates and brain tissue sections.
“We tested the commercially acquired ABI3 antibody (rabbit anti-ABI3, abcam ab81152) for its sensitivity in selectively detecting ABI3 protein by western blotting and immunostaining in ABI3 -/-derived microglia lysates and brain tissue sections respectively.”
Quote in the paperSubstantial claim
- Classified as probably not a substantial claim. 10
- May combine two claims. 7
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe S209F variant of ABI3 (rs616338:p.Ser209Phe) is associated with increased risk of Alzheimer's disease (OR = 1.43, p = 4.5 × 10-10, MAF = 0.008).
“The S209F variant of ABI3 (rs616338:p.Ser209Phe) is associated with increased risk of AD (OR = 1.43, p = 4.5 × 10-10, MAF = 0.008) 3 .”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [3] source
Classified as probably not a substantial claim.
PremisecitationInnate immune system activation, in particular microglia, is considered a contributing factor to Alzheimer's disease pathogenesis rather than a consequence of pathology.
“Currently, the innate immune system activation, in particular microglia, is considered a contributing factor to AD pathogenesis rather than a consequence of pathology 2 .”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [2] source
The Microglia section says prolonged microglial activation exacerbates AD pathology, supporting its role as a contributor. But the Inflammation in AD section says neuroinflammation is typically thought to result from other AD pathologies or risk factors, rather than being causal on its own. The source therefore does not support the claim’s ‘rather than a consequence’ distinction. Page numbers are unavailable in our copy. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationPrior research has shown increased ABI3 gene expression in human primary monocytes following long-term (24 hours) immune stimulation by IFN-γ.
“Prior research has also shown increased ABI3 gene expression in human primary monocytes following long-term (24 hours) immune stimulation by IFN-γ 9 .”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [9] source
The Results (Innate Immune Stimuli–Induced Transcriptomes) and Materials and Methods (Stimulation Assays) describe measuring gene expression in primary human monocytes after 24 hours of IFN-γ stimulation. Neither passage reports that ABI3 expression increased, and a search for ABI3 in our copy found no such result. Page numbers were not provided. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationABI3 is believed to be involved in actin cytoskeleton regulation by participating in the WAVE regulatory complexes, but its exact function in the cell remains unknown.
“Similar to other ABI proteins, ABI3 is also believed to be involved in the actin cytoskeleton regulation by participating in the WASP family Verprolin homolog protein (WAVE) regulatory complexes (WRC), but its exact function in the cell remains unknown 5 .”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [5] source
The Introduction identifies ABI3 as a WAVE regulatory complex component, and the Results report its interaction with WAVE2 and CYFIP1, supporting the proposed link to actin-cytoskeleton regulation. The Introduction says the precise mechanism of ABI3’s cytoskeleton-remodeling effect in thyroid cells is unknown; it does not establish that ABI3’s exact function is unknown in cells generally. (LLM, conf=0.83)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn the brain, the ABI3 transcript is present in microglia and at lower levels in non-myeloid cells including neurons.
“In the brain, the ABI3 transcript is present in microglia and at lower levels in non-myeloid cells including neurons 6 .”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [6] source
The ‘RNA-Seq analysis identifies novel cell type-enriched genes’ section compares expression across brain cell types, but does not identify ABI3. Searches for ABI3, Abi3, and its full gene name found no passage in our copy establishing its presence in microglia or lower expression in neurons and other non-myeloid cells. (LLM, conf=0.74)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationPrevious reports have shown ABI3 expression in microglia and increased expression levels in Alzheimer's disease brains, especially in microglia surrounding amyloid plaques.
“Previous reports have shown ABI3 expression in microglia and increased expression levels in AD brains, especially in the microglia surrounding the amyloid plaques 8 .”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [8] source
The Results report ABI3 expression in microglia and clusters of ABI3-positive microglia associated with amyloid plaques in AD brains. But the quantitative analysis reports no significant difference in ABI3-immunolabeled area between AD, control, and NHD brains, so the claimed overall increase in AD brains is not supported. (LLM, conf=0.88)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataGNGT2 protein is not detectable in microglia, suggesting its expression level is likely below the detection limits of the assays used.
“However, we have been unable to detect GNGT2 protein in microglia suggesting that the expression level is likely below the detection limits of assays used.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenAll animal studies were approved by the Animal Care Committees of the University of Toronto and the University Health Network and were performed in accordance with the guidelines of the Canadian Council on Animal Care.
“All animal studies were approved by the Animal Care Committees of the University of Toronto and the University Health Network and were performed in accordance with the guidelines of the Canadian Council on Animal Care.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
Study design and conductown dataThe presence of the APP transgene (TgCRND8 strain) was confirmed by genomic DNA dot blot.
“The presence of the APP (TgCRND8 strain; PMID: 11279122) was confirmed by genomic DNA dot blot.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationreasoningThe effects of ABI3-GNGT2 -/- in TgCRND8 mice could be due to loss of function of GNGT2; this possibility cannot be rejected.
“Since GNGT2 transcript is also present in microglia, we cannot reject the possibility that some of the effects of ABI3-GNGT2 -/-could be due to loss of function of GNGT2.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataKnockout of ABI3-GNGT2 in TgCRND8 APP mice reduces amyloid beta pathology and the number of plaque-associated microglia.
“Notably, the knockout of ABI3-GNGT2 led to a reduction of amyloid beta pathology and the number of plaque-associated microglia in the TgCRND8 APP mouse model, suggesting that ABI3 could modulate the risk of AD through regulating microglial response to amyloid pathology.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationPrevious studies have reported higher microglia numbers within the radius of 20-30μm from the plaque edge and significant synapse loss within the distance of 20μm from the plaque edge.
“Previous studies have reported higher microglia numbers within the radius of 20-30μm from the plaque edge and significant synapse loss within the distance of 20μm from the plaque edge 10 .”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] source
The paper relies on this without support.
Findings from the TgCRND8 mouse model of amyloid pathology are relevant to human Alzheimer's disease risk.
“We have investigated the effects of ABI3 deletion on AD pathological features in the transgenic (Tg) CRND8 APP mouse model by immunofluorescence (IF) staining and confocal microscopy.”
“suggesting that ABI3 could modulate the risk of AD through regulating microglial response to amyloid pathology.”
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Innate Immune Activity Conditions the Effect of Regulatory Variants upon Monocyte Gene Expression
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mosGraphFlow: a novel integrative graph AI model mining disease targets from multi-omic dataPreprint
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Abi3 S212F Alzheimer's disease variant alters plaque structure and disrupts microglia
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Therapeutic Strategies Targeting Amyloid-β in Alzheimer’s Disease
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- Authors
- Ghaffari, D., Griffin, J., & St George-Hyslop, P.
- Affiliations
- University of Toronto (CA)
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2023-10-07
- OpenAlex
- W4387460339
- Cited by
- 3
- References
- 12
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Funders
- Consortium canadien en neurodégénérescence associée au vieillissement
- Alzheimer Society (ZEN-18-529769)
- Canadian Institutes of Health Research (406915)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- ABI3, Alzheimer's disease, amyloid plaques, microglia, TgCRND8 mice, APP transgenic mice, glial response, immune-related genes, gene deletion
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