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Pharmacological ablation of astrocytes reduces Aβ degradation and synaptic connectivity in an ex vivo model of Alzheimer’s disease
Open accessPublished version of a preprint
Abstract
Background: Astrocytes provide a vital support to neurons in normal and pathological conditions. In Alzheimer’s disease (AD) brains, reactive astrocytes have been found surrounding amyloid plaques, forming an astrocytic scar. However, their role and potential mechanisms whereby they affect neuroinflammation, amyloid pathology, and synaptic density in AD remain unclear. Methods: To explore the role of astrocytes on Aβ pathology and neuroinflammatory markers, we pharmacologically ablated them in organotypic brain culture slices (OBCSs) from 5XFAD mouse model of AD and wild-type (WT) littermates with the selective astrocytic toxin L-alpha-aminoadipate (L-AAA). To examine the effects on synaptic circuitry, we measured dendritic spine number and size in OBCSs from Thy-1-GFP transgenic mice incubated with synthetic Aβ42 or double transgenics Thy-1-GFP/5XFAD mice treated with LAAA or vehicle for 24 h. Results: Treatment of OBCSs with L-AAA resulted in an increased expression of pro-inflammatory cytokine IL-6 in conditioned media of WTs and 5XFAD slices, associated with changes in microglia morphology but not in density. The profile of inflammatory markers following astrocytic loss was different in WT and transgenic cultures, showing reductions in inflammatory mediators produced in astrocytes only in WT sections. In addition, pharmacological ablation of astrocytes led to an increase in Aβ levels in homogenates of OBCS from 5XFAD mice compared with vehicle controls, with reduced enzymatic degradation of Aβ due to lower neprilysin and insulin-degrading enzyme (IDE) expression. Furthermore, OBSCs from wild-type mice treated with L-AAA and synthetic amyloid presented 56% higher levels of Aβ in culture media compared to sections treated with Aβ alone, concomitant with reduced expression of IDE in culture medium, suggesting that astrocytes contribute to Aβ clearance and degradation. Quantification of hippocampal dendritic spines revealed a reduction in their density following L-AAA treatment in all groups analyzed. In addition, pharmacological ablation of astrocytes resulted in a decrease in spine size in 5XFAD OBCSs but not in OBCSs from WT treated with synthetic Aβ compared to vehicle control. Conclusions: Astrocytes play a protective role in AD by aiding Aβ clearance and supporting synaptic plasticity.
Overview
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Written from the paper’s full text.
TL;DR
Pharmacological ablation of astrocytes in organotypic brain cultures from 5XFAD and wild-type mice increased Aβ levels and inflammatory signaling while reducing Aβ-degrading enzymes and dendritic spine density/size. The authors conclude astrocytes are protective in Alzheimer’s disease by supporting Aβ clearance and synaptic connectivity.
Key findings
- Treatment with 1 mM L-AAA for 24 h selectively reduced GFAP/Aldh1a1 astrocyte staining without affecting neuronal viability or tissue integrity; 48 h disrupted tissue organization.
- L-AAA increased IL-6 in conditioned media from both WT and 5XFAD slices and changed microglia morphology without changing microglia density; astrocyte-produced mediators TGF-β1, MCP1, and MIP-1α were reduced only in WT sections.
- In 5XFAD organotypic cultures, L-AAA led to a 65% increase in Aβ1-42 levels, with only a slight increase in Aβ1-40, and reduced neprilysin and IDE expression; APP, CTFs, and BACE1 were unchanged.
- In WT cultures treated with synthetic Aβ42, L-AAA increased Aβ in culture media by >56% and reduced secreted IDE; dendritic spine density fell by 33% in CA1 across groups, and spine size showed a further 47% decrease only in 5XFAD slices.
Methods
- Organotypic brain culture slices (OBCSs) were prepared from postnatal day 7 WT, 5XFAD, Thy-1-GFP, and Thy-1-GFP/5XFAD mice, sectioned at 300 μm, cultured for 2 weeks, and treated for 24 h with vehicle or 1 mM L-AAA; some WT slices received 0.6 μM synthetic Aβ42.
- Outcomes were measured by ELISA for Aβ40/Aβ42 and cytokines/chemokines, Western blot, qPCR, immunofluorescence, propidium iodide staining, and MATLAB/ImageJ-based quantification of dendritic spines and microglia morphology.
- Statistical analysis used unpaired Student’s t tests, repeated-measures 1- or 2-way ANOVA with Tukey post hoc, Kolmogorov-Smirnov normality testing, and significance at P < 0.05.
Limitations
- The paper states that organotypic cultures and chemical L-AAA ablation have limitations, and that future work should test adult brain slices with mature morphology, metabolism, and tau/Aβ deposition surrounded by activated glia.
- The text makes evident that L-AAA ablates all astrocytes rather than only reactive/GFAP-positive astrocytes, and that effects on neprilysin and IDE may be indirect through other cell types.
- The text also notes that synthetic Aβ effects can depend on concentration, incubation time, and fibrillar versus oligomeric form, and that cultures at this age do not show Aβ plaque deposition.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
13 of 25 cited sources checked · 9 supported · 2 flagged · accuracy not yet measured
- Interpretationown data
Expression of neprilysin was decreased following astrocytic loss.
“We have demonstrated, using two different approaches, that the expression of neprilysin was decreased following astrocytic loss ([17] and present study).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [17] Katsouri L, Birch AM, Renziehausen AWJ, Zach C, Aman Y, Steeds H, Bonsu A, Palmer EOC, Mirzaei N, Ries M, Sastre M. Ablation of reactive astrocytes exacerbates disease pathology in a model of Alzheimer’s disease. Glia. 2020;68(5):1017–30. source
- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
- Interpretationcitation
These results reinforce the function of astrocytes regulating synapsis in AD.
“These results reinforce the function of astrocytes regulating synapsis in AD, shown by us and others [17, 43].”
Quote in the paperSubstantial claim1 of 2 sources checked- cites [17] Katsouri L, Birch AM, Renziehausen AWJ, Zach C, Aman Y, Steeds H, Bonsu A, Palmer EOC, Mirzaei N, Ries M, Sastre M. Ablation of reactive astrocytes exacerbates disease pathology in a model of Alzheimer’s disease. Glia. 2020;68(5):1017–30. source
- cites [43] Willem K, Lieneke K, Marie O, Oscar S, Milos P. M. HE. GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer’s disease. Glia. 2015;63(6):1036–56. source
- Findingown data
Following astrocytic loss, the profile of inflammatory markers differed between WT and transgenic cultures.
“The profile of inflammatory markers following astrocytic loss was different in WT and transgenic cultures”
Quote in the paperNot a substantial claim - Findingown data
At 48 h, L-AAA treatment largely disrupted tissue organization in OBCSs.
“However, at 48 h, tissue organization was largely disrupted (Fig. S1G).”
Quote in the paperSubstantial claim - Findingown data
L-AAA treatment led to only a slight increase in Aβ1-40 levels compared with vehicle controls.
“the expression of Aβ1-40 was only slightly increased compared with vehicle controls (Fig. 4a)”
Quote in the paperNot a substantial claim
- Findingown data
L-AAA reduced enzymatic degradation of Aβ due to lower neprilysin and IDE expression.
“with reduced enzymatic degradation of Aβ due to lower neprilysin and insulin-degrading enzyme (IDE) expression”
Quote in the paperSubstantial claim - Findingown data
L-AAA treatment changed microglia morphology to a more amoeboid-like and less ramified state in transgenic OBCSs and in all sections.
“high magnification images showed a change in the morphology of microglia, being more amoeboid-like and less ramified in transgenic OBCSs and in all sections following treatment with L-AAA”
Quote in the paperNot a substantial claim - Findingown data
L-AAA increased Aβ levels in homogenates of OBCS from 5XFAD mice compared with vehicle controls.
“pharmacological ablation of astrocytes led to an increase in Aβ levels in homogenates of OBCS from 5XFAD mice compared with vehicle controls”
Quote in the paperSubstantial claim - Findingown data
L-AAA treatment for 24 h did not affect tissue integrity in OBCSs.
“demonstrating that the incubation with L-AAA for 24 h did not affect tissue integrity (Fig. S1H-K)”
Quote in the paperSubstantial claim - Findingown data
Reductions in inflammatory mediators produced in astrocytes occurred only in WT sections.
“showing reductions in inflammatory mediators produced in astrocytes only in WT sections”
Quote in the paperNot a substantial claim - Findingown data
WT OBCSs treated with L-AAA and synthetic amyloid had 56% higher Aβ levels in culture media compared to sections treated with Aβ alone.
“OBSCs from wild-type mice treated with L-AAA and synthetic amyloid presented 56% higher levels of Aβ in culture media compared to sections treated with Aβ alone”
Quote in the paperSubstantial claim - Findingown data
L-AAA treatment did not change microglia density in 5XFAD OBCSs compared with vehicle controls.
“it did not reveal changes in the density of microglia in sections of 5XFAD mice treated with 1 mM L-AAA compared with vehicle treated controls (Fig. 2a–d)”
Quote in the paperNot a substantial claim - Findingown data
L-AAA decreased spine size in 5XFAD OBCSs but not in WT OBCSs treated with synthetic Aβ compared to vehicle control.
“pharmacological ablation of astrocytes resulted in a decrease in spine size in 5XFAD OBCSs but not in OBCSs from WT treated with synthetic Aβ compared to vehicle control.”
Quote in the paperSubstantial claim - Findingown data
Microglia density was increased in sections from 5XFAD mice compared with WT, significant in the hippocampus.
“showed an increase in the density of microglia in sections from 5XFAD mice compared with WTs, which was significant in the hippocampus (Fig. 2d)”
Quote in the paperNot a substantial claim - Findingown data
WT OBCSs treated with L-AAA and synthetic amyloid had reduced IDE expression in culture medium.
“concomitant with reduced expression of IDE in culture medium”
Quote in the paperSubstantial claim - Findingown data
L-AAA treatment increased microglia soma size, particularly in the transgenic hippocampus.
“while the soma size was increased, particularly in microglia of the transgenic hippocampus, typical of a reactive state (Fig. 2f)”
Quote in the paperNot a substantial claim - Findingown data
L-AAA treatment reduced hippocampal dendritic spine density in all groups analyzed.
“Quantification of hippocampal dendritic spines revealed a reduction in their density following L-AAA treatment in all groups analyzed.”
Quote in the paperSubstantial claim - Findingown data
L-AAA treatment did not change IL-1β, IL-10, and IL-4 levels in all groups analyzed.
“IL-1β, IL-10, and IL-4 levels were unchanged by L-AAA treatment in all groups analyzed (Fig. 3c–e).”
Quote in the paperNot a substantial claim - Findingown data
At this age, cultures do not show Aβ deposition in plaques.
“At this age, cultures do not show Aβ deposition in plaques (Fig. S1M).”
Quote in the paperNot a substantial claim - Findingown data
L-AAA treatment for 24 h reduced GFAP and Aldh1a1 staining in OBCSs.
“Our results show a remarkable reduction on GFAP and Aldh1a1 staining after 24 h treatment (Fig. 1a–d, Fig. S1A-F)”
Quote in the paperSubstantial claim - Findingown data
L-AAA treatment increased IL-6 expression in both WT and transgenic sections.
“the expression of pro-inflammatory cytokine IL-6 was increased in both WT and transgenic sections treated with L-AAA (Fig. 3b)”
Quote in the paperSubstantial claim - Findingown data
L-AAA treatment increased IL-6 expression in conditioned media of WT and 5XFAD OBCSs.
“Treatment of OBCSs with L-AAA resulted in an increased expression of pro-inflammatory cytokine IL-6 in conditioned media of WTs and 5XFAD slices”
- Also stated in: § Pharmacological ablation of astrocytes leads to an increase in the expression of pro-inflammatory markers · plain
“the expression of pro-inflammatory cytokine IL-6 was increased in both WT and transgenic sections treated with L-AAA (Fig. 3b)”
Quote in the paperNot a substantial claim - Also stated in: § Pharmacological ablation of astrocytes leads to an increase in the expression of pro-inflammatory markers · plain
- Findingown data
Pharmacological ablation of astrocytes leads to higher Aβ levels.
“showing that pharmacological ablation of astrocytes leads to higher Aβ levels.”
Quote in the paperSubstantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
- Findingown data
Treatment with synthetic Aβ42 in WT slices had no effect on spine density.
“Treatment with synthetic Aβ42 in WT slices had no effect in spine density.”
Quote in the paperNot a substantial claim - Findingown data
Pro-inflammatory cytokine IL-6 produced by microglia and astrocytes was increased in both WT and transgenic slices following L-AAA.
“pro-inflammatory cytokine IL-6 produced by microglia and astrocytes was increased in both WT and transgenic slices”
Quote in the paperNot a substantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
- Findingown data
Aβ levels in culture media were higher (>56%) in L-AAA treated WT sections compared with vehicle-treated control.
“Analysis of Aβ in culture media by Western blot revealed higher levels of Aβ in L-AAA treated sections (>56%) compared with vehicle-treated control (Fig. 4h, i).”
Quote in the paperSubstantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
- Findingown data
L-AAA induced a significant reduction of insulin-degrading enzyme (Ide) gene expression in OBCSs.
“and insulin-degrading enzyme (Ide) gene expression (Fig. 4c, e).”
Quote in the paperSubstantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
- Findingown data
L-AAA treatment led to a reactive phenotype in microglia.
“but led to a reactive phenotype”
Quote in the paperNot a substantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
- Findingown data
BACE1 expression did not change in any of the groups analysed.
“the expression of the β-secretase (BACE1) did not change either in any of the groups analysed (Fig. 4b).”
Quote in the paperSubstantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
- Findingown data
Microglia from transgenic cultures had higher Il-1β levels compared to WT sections.
“We observed that microglia from transgenic cultures seemed to have a different phenotype, compared to WT sections, showing more amoeboid-like morphology and higher Il-1β levels and a reduction in TGF-β and MCP1, representative of a pro-inflammatory profile.”
Quote in the paperNot a substantial claim - Findingown data
L-AAA induced a reduction in cytokines and chemokines produced in astrocytes (TGF-β, MIP-1α, MCP1, ApoE) in organotypic cultures of wild-type mice.
“L-AAA induced a reduction in cytokines and chemokines produced in astrocytes (such as TGF-β, MIP-1α, and MCP1 as well as ApoE) in organotypic cultures of wild-type mice”
Quote in the paperNot a substantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
- Findingown data
IDE expression levels were significantly reduced in the media of cultures treated with L-AAA.
“the expression levels of IDE were significantly reduced in the media of cultures treated with L-AAA (Fig. 4h, i).”
Quote in the paperSubstantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
- Findingown data
TNFα expression was reduced in media from 5XFAD sections compared with WT OBCSs.
“TNFα expression was reduced in media from 5XFAD sections compared with WT OBCSs”
Quote in the paperNot a substantial claim - Findingown data
Microglia from transgenic cultures had more amoeboid-like morphology compared to WT sections.
“We observed that microglia from transgenic cultures seemed to have a different phenotype, compared to WT sections, showing more amoeboid-like morphology and higher Il-1β levels and a reduction in TGF-β and MCP1, representative of a pro-inflammatory profile.”
Quote in the paperNot a substantial claim - Findingown data
L-AAA induced a significant reduction of the protein and mRNA levels of neprilysin in OBCSs.
“we found that L-AAA induced a significant reduction of the protein and mRNA levels of neprilysin (Fig. 4c, d)”
Quote in the paperSubstantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
- Findingown data
L-AAA induced no changes in those cytokines and chemokines in transgenic slides.
“with no changes in transgenic slides.”
Quote in the paperNot a substantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
- Findingown data
L-AAA treatment caused a 33% reduction in dendritic spine density in the CA1 area of the hippocampus in all groups.
“Quantification of dendritic spines revealed a 33% reduction in their density in the CA1 area of the hippocampus in all groups following L-AAA treatment (Fig. 5a, b).”
Quote in the paperSubstantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
- Findingown data
Microglia from transgenic cultures had a reduction in TGF-β and MCP1 compared to WT sections.
“We observed that microglia from transgenic cultures seemed to have a different phenotype, compared to WT sections, showing more amoeboid-like morphology and higher Il-1β levels and a reduction in TGF-β and MCP1, representative of a pro-inflammatory profile.”
Quote in the paperNot a substantial claim - Findingown data
ApoE protein levels were only reduced in WT sections after L-AAA treatment.
“ApoE protein levels were only reduced in WT sections (Fig. 4f, g).”
Quote in the paperNot a substantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
- Findingown data
L-AAA treatment did not influence the density of microglia.
“L-AAA treatment did not influence the density of microglia”
Quote in the paperNot a substantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
- Findingown data
Full-length APP and CTFs expression were unaltered after L-AAA treatment in OBCS homogenates.
“The expression of full-length APP and the CTFs were found unaltered after L-AAA treatment (Fig. 4b)”
Quote in the paperSubstantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
- Findingown data
Spine size was reduced in 5XFAD mice and in wild-type sections treated with Aβ1-42 compared with wild-type controls.
“spine size was reduced in 5XFAD mice and in wild-type sections treated with Aβ1-42 compared with wild-type controls.”
Quote in the paperNot a substantial claim - Premisecitation
Reactive astrocytes are involved in the degradation and clearance of Aβ.
“we and others have reported that reactive astrocytes are involved in the degradation and clearance of Aβ [13, 14].”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation
L-AAA causes selective astrocytic toxicity and death.
“which causes selective astrocytic toxicity and death [18]”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18] Nishimura RN, Santos D, Fu ST, Dwyer BE. Induction of cell death by L-alphaaminoadipic acid exposure in cultured rat astrocytes: relationship to protein synthesis. Neurotoxicology. 2000;21(3):313–20.
- Rests on an assumption: L-AAA binds to the cysteine glutamate antiporter, which is expressed in astrocytes but not in microglia or neurons, allowing selective targeting of astrocytes.
- Interpretationown data
Astrocytes contribute to Aβ clearance and degradation.
“suggesting that astrocytes contribute to Aβ clearance and degradation”
Quote in the paperSubstantial claim - Interpretationown data
L-AAA treatment results in astrocytic death in OBCSs.
“L-AAA treatment results in astrocytic death in organotypic brain cultures”
Quote in the paperSubstantial claim- Rests on an assumption: L-AAA binds to the cysteine glutamate antiporter, which is expressed in astrocytes but not in microglia or neurons, allowing selective targeting of astrocytes.
- Interpretationown data
Depletion of astrocytes results in an increase of the pro-inflammatory profile in organotypic brain cultures.
“These results suggest that depletion of astrocytes results in an increase of the pro-inflammatory profile in organotypic brain cultures.”
Quote in the paperSubstantial claim - Interpretationown data
The effects of L-AAA on dendritic spine density and size suggest a neuroprotective role of astroglia on memory processes.
“the effects of L-AAA on dendritic spine density and size suggest a neuroprotective role of astroglia on memory processes.”
Quote in the paperSubstantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
- Interpretationown data
The effect of L-AAA on cytokine and chemokine expression is different in WT and transgenic sections.
“Our data indicate that the effect of L-AAA on cytokine and chemokine expression is different in WT and transgenic sections”
Quote in the paperNot a substantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
- Interpretationown data
Astrocytes are involved in mechanisms of amyloid degradation and clearance, rather than affecting amyloid generation.
“the results from our studies suggest that astrocytes are involved in mechanisms of amyloid degradation and clearance, rather than affecting amyloid generation.”
Quote in the paperSubstantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
- Rests on an assumption: Reduced neprilysin/IDE expression corresponds to reduced enzymatic degradation of Aβ.
- Interpretationown data
The stability of synthetic Aβ1-42 peptide in the medium was increased by incubation with L-AAA, due to reduced Aβ degradation.
“These data indicate that the stability of synthetic Aβ1-42 peptide in the medium was increased by incubation with L-AAA, due to reduced Aβ degradation.”
Quote in the paperSubstantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
- Rests on an assumption: Reduced neprilysin/IDE expression corresponds to reduced enzymatic degradation of Aβ.
- Rests on an assumption: Synthetic Aβ1-42 stability in culture media reflects Aβ degradation mechanisms in brain.
- Interpretationown data
The elevation of inflammatory cytokines following incubation with L-AAA may not be exclusively secondary to an increase in Aβ.
“indicating the elevation on inflammatory cytokines following incubation with L-AAA may not be exclusively secondary to an increase in Aβ.”
Quote in the paperNot a substantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
- Interpretationown data
Cleavage of APP was not affected by the loss of astrocytes.
“suggesting that the cleavage of APP was not affected by the loss of astrocytes.”
Quote in the paperSubstantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
- Interpretationown data
L-AAA treatment contributed to a pro-inflammatory environment.
“contributing to a pro-inflammatory environment.”
Quote in the paperNot a substantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
- Interpretationown data
The phenotype/profile of astrocytes in WT animals is different from that in transgenic mice.
“suggesting that the phenotype of the astrocytes could be different in transgenic animals.”
- Also stated in: § Conclusions · hedged
“we show that the profile of astrocytes in WT animals seems to be different to that in transgenic mice.”
Quote in the paperSubstantial claim - Also stated in: § Conclusions · hedged
- It may state two separate claims as one. 20
- Probably not a substantial claim. 9
- The quote only partly states this claim. 1
It may state two separate claims as one.
PremisecitationThe consensus is that reduction in astrocyte density leads to higher amyloid levels, without changes in its aggregation or deposition.
“Therefore, it seems that the consensus is that the reduction in astrocyte density leads to higher amyloid levels, without changes in its aggregation or deposition.”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [29] Kraft AW, Hu X, Yoon H, Yan P, Xiao Q, Wang Y, et al. Attenuating astrocyte activation accelerates plaque pathogenesis in APP/PS1 mice. FASEB J. 2013;27(1):187–98. source
The Results (Fig. 6E) found no significant difference in astrocyte density between genotypes; the deletions altered astrocyte activation and morphology instead. The Discussion reports increased plaque burden in the mice with attenuated astrocyte activation and concludes that reactive gliosis restricts plaque appearance and growth. Both points run contrary to the claimed reduction in density without a change in deposition. (LLM, conf=0.90)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured - cites [30] Kamphuis W, Kooijman L, Orre M, Stassen O, Pekny M, Hol EM. GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer’s disease. Glia. 2015;63:1036–56. source
- cites [31] Furman JL, Sama DM, Gant JC, Beckett TL, Murphy MP, Bachstetter AD, Van Eldik LJ, Norris CM. Targeting astrocytes ameliorates neurologic changes in a mouse model of Alzheimer’s disease. J Neurosci. 2012;32:16129–40. source
The Results section on glial activation reports that Gfa2-VIVIT reduced astrocyte size but did not reduce the number of GFAP-labeled cells. The Results section on amyloid pathology reports lower Aβ levels alongside fewer and smaller amyloid deposits—not higher levels without a change in deposition. It also describes the role of neuroglia in amyloid pathology as controversial, rather than a consensus. (LLM, conf=0.91)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
Probably not a substantial claim.
PremisecitationOrganotypic culture allows the study of the brain in its original structure.
“This technique allows the study of the brain in its original structure [19, 20].”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [19] Hurtado de Mendoza T, Balana B, Slesinger PA, Verma IM. Organotypic cerebellar cultures: apoptotic challenges and detection. J Vis Exp. 2011;(51):2564. source
- cites [20] Humpel C. Organotypic brain slice cultures: A review. Neuroscience. 2015;305:86–98. source
- Rests on an assumption: L-AAA does not cross the blood-brain barrier.
It may state two separate claims as one.
PremisecitationLoss of proliferating astrocytes leads to increased amyloid levels and exacerbated memory loss in the APP23 model of AD.
“We have recently shown that the loss of proliferating astrocytes leads to increased amyloid levels and exacerbated memory loss in the APP23 model of AD [17].”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [17] Katsouri L, Birch AM, Renziehausen AWJ, Zach C, Aman Y, Steeds H, Bonsu A, Palmer EOC, Mirzaei N, Ries M, Sastre M. Ablation of reactive astrocytes exacerbates disease pathology in a model of Alzheimer’s disease. Glia. 2020;68(5):1017–30. source
It may state two separate claims as one.
PremisecitationAstrocytes can produce Aβ peptidases such as neprilysin and IDE, as well as ApoE.
“Astrocytes can produce Aβ peptidases, such as neprilysin and IDE as well as the Apolipoprotein E (ApoE) [15]”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [15] Ries M, Sastre M. Mechanisms of Aβ clearance and degradation by glial cells. Front Aging Neurosci. 2016;8:160. source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationNeprilysin is mainly expressed in neurons but can also be found in activated astrocytes and microglia.
“Neprilysin is mainly expressed in neurons [32] but can also be found in activated astrocytes and microglia [15]”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [32] Fukami S, Watanabe K, Iwata N, Haraoka JLB, Gerard, et al. Ab-degrading endopeptidase, neprilysin, in mouse brain: synaptic and axonal localization inversely correlating with Ab pathology. Neurosci Res. 2002;43:39–56. source
- cites [15] Ries M, Sastre M. Mechanisms of Aβ clearance and degradation by glial cells. Front Aging Neurosci. 2016;8:160. source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationThe effect of synthetic Aβ might depend on the concentration of amyloid, the incubation time, and the presence of fibrillar or oligomeric amyloid.
“the effect of synthetic Aβ might depend on the concentration of amyloid, the incubation time, and the presence of fibrillar or oligomeric amyloid [41].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [41] Lorenzo A, Yankner BA. Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. PNAS. 1994;91:12243–7. source
The Abstract reports that fibrillar Aβ was neurotoxic in primary rat hippocampal cultures, whereas amorphous Aβ was not, supporting a dependence on physical form. Our copy does not establish that the effect depends on amyloid concentration or incubation time, and it does not compare fibrils with oligomers. (LLM, conf=0.87)
Experimental — accuracy not yet measured
It may state two separate claims as one.
PremisecitationAstrocytes are involved in the clearance of Aβ through the BBB via the AQP4 channels expressed in their end feet and are also able to phagocytose amyloid.
“astrocytes are involved in the clearance of Aβ through the BBB via the AQP4 channels expressed in their end feet and are also able to phagocytose amyloid [6, 34, 35].”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [6] Wyss-Coray T, Loike JD, Brionne TC, Lu E, Anankov R, Yan F, et al. Adult mouse astrocytes degrade amyloid-β in vitro and in situ. Nat Med. 2003;9(4):453–7. source
- cites [34] Nagele RG, D'Andrea MR, Lee H, Venkataraman V, Wang HY. Astrocytes accumulate Ab42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res. 2003;971(2):197–209. source
- cites [35] Igarashi H, Suzuki Y, Kwee IL, Nakada T. Water influx into cerebrospinal fluid is significantly reduced in senile plaque bearing transgenic mice, supporting beta-amyloid clearance hypothesis of Alzheimer’s disease. Neurol Res. 2014;36:1094–8. source
The Introduction identifies AQP-4 on astrocyte end feet and links AQP-4-regulated CSF flow to beta-amyloid clearance. The Discussion describes drainage toward the CSF through perivascular spaces, not Aβ clearance through the BBB. Neither section says astrocytes phagocytose amyloid. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationPrevious reports have detected a reduction in synaptic spines after injections of fibrillar Aβ42 in rat brain.
“Previous reports have looked at the effect of injections of fibrillar Aβ42 in rat brain and detected a reduction in synaptic spines [40]”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [40] Borbély E, Horváth J, Furdan S, Bozsó Z, Penke B, Fülöp L. Simultaneous changes of spatial memory and spine density after intrahippocampal administration of fibrillar aβ1-42 to the rat brain. Biomed Res Int. 2014;2014:345305. source
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationApoE is mainly produced in astrocytes but can be synthesized by microglia.
“ApoE is mainly produced in astrocytes but can be synthesized by microglia [15].”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [15] Ries M, Sastre M. Mechanisms of Aβ clearance and degradation by glial cells. Front Aging Neurosci. 2016;8:160. source
It may state two separate claims as one.
Findingown dataL-AAA treatment for 24 h did not affect the viability and number of neurons in OBCSs.
“without affecting the viability and number of neurones (Fig. 1e–h and j)”
Quote in the paperSubstantial claimIt may state two separate claims as one.
Findingown dataL-AAA treatment reduced the number of processes, process area, and process perimeter of microglia in OBCSs.
“demonstrated a reduction in the number of processes, in the process area and the process perimeter of slices treated with L-AAA (Fig. 2e, Fig. 2f)”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataMedia from transgenic 5XFAD slices showed higher IL-1β levels and reduced TNFα, TGFβ, and MCP1 expression compared with WT sections.
“media from transgenic 5XFAD slices showed different cytokine profile, with higher Il-1β levels and reduced TNFα, TGFβ, and MCP1 expression, compared with WT sections”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataL-AAA treatment reduced TGF-β1, MCP1(CCL2), and MIP-1α (CCL3) only in wild-type sections.
“other cytokines and chemokines mostly produced by astrocytes, such as TGF-β1, MCP1(CCL2), and MIP-1α (CCL3) [28], were reduced by incubation with L-AAA only in wild-type sections (Fig. 3f–h)”
Quote in the paperNot a substantial claimThe quote only partly states this claim.
Findingown dataL-AAA treatment led to a 65% increase in the levels of Aβ1-42 in homogenates of OBCS from 5XFAD mice compared with vehicle controls.
“L-AAA treatment led to a 65% increase in the levels of Aβ1-42”
- Also stated in: § Results · plain
“pharmacological ablation of astrocytes led to an increase in Aβ levels in homogenates of OBCS from 5XFAD mice compared with vehicle controls”
Quote in the paperSubstantial claim- Also stated in: § Results · plain
It may state two separate claims as one.
Findingown dataL-AAA treatment was associated with changes in microglia morphology but not density.
“associated with changes in microglia morphology but not in density”
Quote in the paperNot a substantial claimIt may state two separate claims as one.
Findingown dataPharmacological ablation of astrocytes resulted in a further 47% decrease in spine size only in slices from 5XFAD mice and not in wild-type slices incubated with synthetic Aβ.
“Pharmacological ablation of astrocytes resulted in a further 47% decrease in the spine size only in slices from 5XFAD mice and not in wild-type slices incubated with synthetic Aβ (Fig. 5).”
Quote in the paperSubstantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
It may state two separate claims as one.
Findingnone givenIn wild-type tissue, L-AAA treatment also seems to affect the number of dendritic spines in sections treated with synthetic Aβ, but not their size.
“In wild-type tissue, L-AAA treatment also seems to affect the number of dendritic spines in sections treated with synthetic Aβ, but not their size.”
Quote in the paperNot a substantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
It may state two separate claims as one.
Interpretationown dataAstrocytes play a protective role in AD by aiding Aβ clearance and supporting synaptic plasticity.
“Astrocytes play a protective role in AD by aiding Aβ clearance and supporting synaptic plasticity.”
Quote in the paperSubstantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
Study design and conductcitationThe number of animals and group sizes were calculated using InVivoStat.
“We calculated the number of animals and group sizes to be used via InVivoStat, an R-based statistical package [26].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26] Clark RA, Shoaib M, Hewitt KN, Stanford SC, Bate ST. A comparison of InVivoStat with other statistical software packages for analysis of data generated from animal experiments. J Psychopharmacology. 2012;26:1136–42. source
It may state two separate claims as one.
InterpretationreasoningAstrocytes may contribute to the activation of other glial cells, affecting their morphology and inflammatory profile.
“our results indicate that astrocytes are different in WT and transgenic mice and may contribute to the activation of other glial cells, affecting their morphology and inflammatory profile.”
Quote in the paperNot a substantial claimProbably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationIDE is produced and secreted by neurons, oligodendrocytes, and microglia in the brain.
“IDE is produced and secreted by neurons, oligodendrocytes, and microglia in the brain [33]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [33] Bernstein H, Lendeckel U, Bukowska A, Ansorge S, Ernst T, Stauch R, Bogers B. Regional and cellular distribution patterns of insulin-degrading enzyme in the adult human brain and pituitary. J Chem Neuroanat. 2008;35:216–24. source
It may state two separate claims as one.
Interpretationown dataPharmacological ablation of astrocytes affects synaptic density, which contributes to the exacerbation of spine density and size in transgenic 5XFAD sections.
“we demonstrate the effect of pharmacological ablation of astrocytes on synaptic density, which contributes to the exacerbation of the spine density and size in transgenic 5XFAD sections.”
Quote in the paperSubstantial claim- Rests on an assumption: L-AAA selectively ablates astrocytes without affecting other cell types.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
PremisecitationL-AAA affected the cellular and synaptic properties in the lamprey spinal cord, suggesting a role of astrocytes in network locomotor activity.
“In previous studies, it was shown that L-AAA affected the cellular and synaptic properties in the lamprey spinal cord, suggesting a role of astrocytes in network locomotor activity [42].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42] Baudoux S, Parker D. Glial-toxin-mediated disruption of spinal cord locomotor network function and its modulation by 5-HT. Neuroscience. 2008;153(4):1332–43. source
Probably not a substantial claim. The paper’s conclusions may not depend on it.
PremisecitationAstrocytes can trigger microglia activation and regulate their cellular functions through the release of cytokines, chemokines, and growth factors.
“astrocytes can trigger microglia activation and regulate their cellular functions through the release of cytokines, chemokines, and growth factors [39].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Jha MK, Jo M, Kim J-H, Suk K. Microglia-astrocyte crosstalk: an intimate molecular conversation. Neuroscientist. 2019;25(3):227–40. source
It may state two separate claims as one.
Interpretationown dataOur results support the role of astrocytes on the removal of Aβ and the regulation of neuroinflammation in AD.
“Our results support the role of astrocytes on the removal of Aβ and the regulation of neuroinflammation in AD.”
Quote in the paperSubstantial claimIt may state two separate claims as one.
InterpretationreasoningAll of these observations point to a protective role of astrocytes in AD, particularly mediating amyloid degradation and clearance, which can be compromised in AD brain at later stages.
“Therefore, all of these observations point out to a protective role of astrocytes in AD, particularly mediating amyloid degradation and clearance, which can be compromised in AD brain at later stages.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The role and potential mechanisms whereby astrocytes affect neuroinflammation, amyloid pathology, and synaptic density in AD remain unclear.
“However, their role and potential mechanisms whereby they affect neuroinflammation, amyloid pathology, and synaptic density in AD remain unclear.”
The paper relies on this without support.
L-AAA does not cross the blood-brain barrier.
“Because this drug does not cross the BBB, we sought to investigate the effect of pharmacological ablation of astrocytes in organotypic cultures.”
The paper relies on this without support.
L-AAA binds to the cysteine glutamate antiporter, which is expressed in astrocytes but not in microglia or neurons, allowing selective targeting of astrocytes.
“This drug binds to the cysteine glutamate antiporter, which is expressed in astrocytes, but not in microglia or neurons, allowing it to selectively target astrocytes.”
The paper relies on this without support.
5XFAD mice have a more aggressive phenotype than other transgenic models of amyloidosis and allow detection of pathological changes in brain slices after only 2 weeks in culture.
“5XFAD mice were used because their phenotype is more aggressive than other transgenic models of amyloidosis and allow the detection of pathological changes in brain slices after only 2 weeks in culture.”
The paper relies on this without support.
L-AAA selectively ablates astrocytes without affecting other cell types.
“Although the use of organotypic cultures of brain sections and of a chemical (L-AAA) to remove astrocytes has its limitations”
The paper relies on this without support.
Organotypic brain slice cultures recapitulate key aspects of Alzheimer's disease relevant to astrocyte function.
“an ex vivo model of AD”
The paper relies on this without support.
Reduced neprilysin/IDE expression corresponds to reduced enzymatic degradation of Aβ.
“due to reduced Aβ degradation”
The paper relies on this without support.
Synthetic Aβ1-42 stability in culture media reflects Aβ degradation mechanisms in brain.
“the stability of synthetic Aβ1-42 peptide in the medium was increased by incubation with L-AAA”
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?
Pharmacological inhibition of astrocytes in organotypic brain culture slices results in an increase in Aβ.
“Another study demonstrated that pharmacological inhibition of astrocytes in organotypic brain culture slices resulted in an increase in A β (Davis et al., 2021)”
From Inhibition of the mitochondrial pyruvate carrier in astrocytes reduces amyloid and tau accumulation in the 3xTgAD mouse model of Alzheimer's disease (2024) · cites this paper as Davis et al., 2021
Apoe-deficient astrocytes upregulate genes associated with inhibition of Aβ fibrillization (Ptgds and Cst3) and regulation of protein degradation (Ubb, Ubc and Ctsl).
“Interestingly, Apoe-deficient astrocytes upregulate genes associated with inhibition of Aβ fibrillization (Ptgds and Cst3) and regulation of protein degradation (Ubb, Ubc and Ctsl) (Apelt et al, 2003; Davis et al, 2021; Liu et al, 2017a; Wegiel et al, 2000).”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Davis et al, 2021
The Background and Discussion describe astrocytes’ role in Aβ clearance and changes in ApoE, neprilysin, and IDE after astrocyte loss. Searches for Apoe-deficient astrocytes and the named genes found no passage reporting upregulation of Ptgds, Cst3, Ubb, Ubc, or Ctsl. (LLM, conf=0.76)
Experimental — accuracy not yet measured
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Metadata
- Authors
- Davis, N., Mota, B. C., Stead, L., Palmer, E. O. C., Lombardero, L., Rodríguez-Puertas, R., de Paola, V., Barnes, S. J., & Sastre, M.
- Affiliations
- Hammersmith Hospital (GB)
- University of the Basque Country (ES)
- Corresponding author
- Sastre, Magdalena
- Venue
- Journal of Neuroinflammation
- Published
- 2021-03-17
- Volume
- 18
- Issue
- 1
- Pages
- 73-73
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC7972219
- OpenAlex
- W3113481963
- Semantic Scholar
- 39b4e540ed1a8de01230e2922d44aa892d7ff07e
- Cited by
- 65
- References
- 42
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 16 · 2023: 9 · 2022: 11 · 2021: 6
- FWCI
- 5.46
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- Communities in ADDI (University of the Basque Country) (submittedVersion, other-oa)
- Communities in ADDI (Universidad del Pais Vasco) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Hispana (submittedVersion, cc-by)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Funders
- Imperial College London
- Medical Research Council (MR/P006434/1)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- astrocytes, Alzheimer's disease, amyloid-beta clearance, amyloid beta degradation, 5xFAD mice, neuroinflammation, interleukin-6, microglia, neprilysin, insulin-degrading enzyme, dendritic spines, synaptic connectivity
- MeSH terms
- Alzheimer Disease, Animals, Astrocytes, Encephalitis, Humans, Mice, Transgenic, Neural Pathways, Peptide Fragments, Synapses, 2-Aminoadipic Acid, Interleukin-6, Amyloid beta-Peptides, Cell Size, Dendritic Spines, Mice
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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.
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