CoChat
Sign Up
Cited by 113Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

The DOI matches its Crossref record; 69 of the 70 references it cites were found in a registry or an index.

Poly(ADP-ribose)polymerase-1 modulates microglial responses to amyloid β

Open access
Kauppinen, Tiina M, Suh, Sang, Higashi, Youichirou, Berman, Ari E, Escartin, Carole, Won, Seok, Wang, Chao, Cho, Seo-Hyun, Gan, Li, Swanson, Raymond A·2011·Journal of Neuroinflammation
DOI 10.1186/1742-2094-8-152PMC PMC3247192
Open this paper in CoChat — free accountOpen PDF

Abstract

BACKGROUND: Amyloid β (Aβ) accumulates in Alzheimer's disease (AD) brain. Microglial activation also occurs in AD, and this inflammatory response may contribute to disease progression. Microglial activation can be induced by Aβ, but the mechanisms by which this occurs have not been defined. The nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) regulates microglial activation in response to several stimuli through its interactions with the transcription factor, NF-κB. The purpose of this study was to evaluate whether PARP-1 activation is involved in Aβ-induced microglial activation, and whether PARP-1 inhibition can modify microglial responses to Aβ. METHODS: hAPP(J20) mice, which accumulate Aβ with ageing, were crossed with PARP-1(-/-) mice to assess the effects of PARP-1 depletion on microglial activation, hippocampal synaptic integrity, and cognitive function. Aβ peptide was also injected into brain of wt and PARP-1(-/-) mice to directly determine the effects of PARP-1 on Aβ-induced microglial activation. The effect of PARP-1 on Aβ-induced microglial cytokine production and neurotoxicity was evaluated in primary microglia cultures and in microglia-neuron co-cultures, utilizing PARP-1(-/-) cells and a PARP-1 inhibitor. NF-κB activation was evaluated in microglia infected with a lentivirus reporter gene. RESULTS: The hAPP(J20) mice developed microglial activation, reduced hippocampal CA1 calbindin expression, and impaired novel object recognition by age 6 months. All of these features were attenuated in hAPP(J20)/PARP-1(-/-) mice. Similarly, Aβ(1-42) injected into mouse brain produced a robust microglial response in wild-type mice, and this was blocked in mice lacking PARP-1 expression or activity. Studies using microglial cultures showed that PARP-1 activity was required for Aβ-induced NF-κB activation, morphological transformation, NO release, TNFα release, and neurotoxicity. Conversely, PARP-1 inhibition increased release of the neurotrophic factors TGFβ and VEGF, and did not impair microglial phagocytosis of Aβ peptide. CONCLUSIONS: These results identify PARP-1 as a requisite and previously unrecognized factor in Aβ-induced microglial activation, and suggest that the effects of PARP-1 are mediated, at least in part, by its interactions with NF-κB. The suppression of Aβ-induced microglial activation and neurotoxicity by PARP-1 inhibition suggests this approach could be useful in AD and other disorders in which microglial neurotoxicity may contribute.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/1742-2094-8-152

Cites

69 of 69 references verified0 citation errors · 0 not checkable

Statistics

Figures

Figure 1 PARP-1 deficiency preserves calbindin expression in hAPPJ20 mice. A, Photomicrographs from hippocampus of 6 month-old mice shows calbindin staining in the molecular layer of DG and pyramidal cell layer of CA1. Quantified data (mean density) are shown in panel (B). * p < 0.05; # p < 0.05, versus wt. n = 9-11.
Figure 1 PARP-1 deficiency preserves calbindin expression in hAPPJ20 mice. A, Photomicrographs from hippocampus of 6 month-old mice shows calbindin staining in the molecular layer of DG and pyramidal cell layer of CA1. Quantified data (mean density) are shown in panel (B). * p < 0.05; # p < 0.05, versus wt. n = 9-11.CC BY · PubMed Central
Figure 2 Effect of PARP-1 gene deficiency on cognitive performance in hAPPJ20 mice. A, Object recognition memory, as measured by the percentage of visits to a familiar versus a novel object. Both the left and right objects are novel during the training session. n = 8-12; * p < 0.05 vs. familiar object, #p <.05 between the indicated groups. B, Spatial learning and memory as assessed by the Morris water maze test on sequential testing days. * p < 0.05 vs. wt; n = 8-12.
Figure 2 Effect of PARP-1 gene deficiency on cognitive performance in hAPPJ20 mice. A, Object recognition memory, as measured by the percentage of visits to a familiar versus a novel object. Both the left and right objects are novel during the training session. n = 8-12; * p < 0.05 vs. familiar object, #p <.05 between the indicated groups. B, Spatial learning and memory as assessed by the Morris water maze test on sequential testing days. * p < 0.05 vs. wt; n = 8-12.CC BY · PubMed Central
Figure 3 PARP-1 deficiency reduces microglial activation but not Aβ accumulation in hAPPJ20 mice. Microglia in cortex of 6-month old hAPPJ20 and hAPPJ20 /PARP-1-/- mouse are immunostained with Iba-1 (green). The microglia had less activated morphology in the hAPP J20 /PARP-1-/- brains, in both non-plaque areas (A) and in microglia contacting Aβ plaques (3D staining, red) (C). Dotted line shows the margins of plaque area. Arrows show microglia with differing morphologies; amoeboid, lacking visible processes in hAPPJ20 brain, and non-amoeboid with visible processes in the hAPPJ20/PARP-1-/- brain. B, Quantification of microglia activation without plaque contact is presented in stacked columns presenting the scores for both microglial number and morphology. D, Morphological quantification of microglia contacting plaques. * p < 0.05; # p < 0.05, versus wt. n = 9-11. E, ELISA measurements of Aβ1-42 and Aβ1- X. n = 8-12.
Figure 3 PARP-1 deficiency reduces microglial activation but not Aβ accumulation in hAPPJ20 mice. Microglia in cortex of 6-month old hAPPJ20 and hAPPJ20 /PARP-1-/- mouse are immunostained with Iba-1 (green). The microglia had less activated morphology in the hAPP J20 /PARP-1-/- brains, in both non-plaque areas (A) and in microglia contacting Aβ plaques (3D staining, red) (C). Dotted line shows the margins of plaque area. Arrows show microglia with differing morphologies; amoeboid, lacking visible processes in hAPPJ20 brain, and non-amoeboid with visible processes in the hAPPJ20/PARP-1-/- brain. B, Quantification of microglia activation without plaque contact is presented in stacked columns presenting the scores for both microglial number and morphology. D, Morphological quantification of microglia contacting plaques. * p < 0.05; # p < 0.05, versus wt. n = 9-11. E, ELISA measurements of Aβ1-42 and Aβ1- X. n = 8-12.CC BY · PubMed Central
Figure 4 PARP-1 regulates Aβ-induced microglial activation. A, Photomicrographs show microglial morphology and Iba-1expression (red) in mouse hippocampus 6 h after stereotaxic injection of FAM-Aβ (green) or saline vehicle. The needle track is visible (and the edge is drawn) at the left-hand edge of each composite image. Microglial activation induced by Aβ injection was blocked by the PARP-1 inhibitor PJ34 (PJ) and in PARP1-/- microglia. Injection of saline or reverse sequence Aβ (rAβ, not shown) produced microglial activation only at the needle track. B, High magnification views show ramified microglia with numerous long, thin, branched processes (arrows), and activated microglia with shorter, thickened processes (arrowheads). C, Quantification of microglia activation is presented in stacked columns presenting the scores for both microglial number and morphology. * p < 0.05; # p < 0.05 vs. saline; n = 4.
Figure 4 PARP-1 regulates Aβ-induced microglial activation. A, Photomicrographs show microglial morphology and Iba-1expression (red) in mouse hippocampus 6 h after stereotaxic injection of FAM-Aβ (green) or saline vehicle. The needle track is visible (and the edge is drawn) at the left-hand edge of each composite image. Microglial activation induced by Aβ injection was blocked by the PARP-1 inhibitor PJ34 (PJ) and in PARP1-/- microglia. Injection of saline or reverse sequence Aβ (rAβ, not shown) produced microglial activation only at the needle track. B, High magnification views show ramified microglia with numerous long, thin, branched processes (arrows), and activated microglia with shorter, thickened processes (arrowheads). C, Quantification of microglia activation is presented in stacked columns presenting the scores for both microglial number and morphology. * p < 0.05; # p < 0.05 vs. saline; n = 4.CC BY · PubMed Central
Figure 5 Microglial activation by Aβ requires microglial PARP-1 activity. A. Phase contrast images of cultured microglia. 24 hour incubation with 5 μM Aβ induces morphological transformation to the activated, amoeboid morphology in wild-type (wt) microglia. Microglial activation induced by Aβ was blocked by the PARP-1 inhibitor PJ34 (PJ, 400 nM) and in PARP-1-/- microglia. Cells treated with the reverse sequence Aβ peptide (rAβ, 5 μM) remained in resting, ramified morphology. B, Immunostaining for poly(ADP-ribose), the enzymatic product of PARP-1, showed poly(ADP-ribose) production within 60 minutes of Aβ addition, blocked by PJ34. There was no poly(ADP-ribose) signal in PARP-1-/- cells (not shown). C. Quantification of microglial activation. D, Quantification of poly(ADP-ribose) immunoreactive cells. * p < 0.05, # p < 0.05 vs. control. n = 3.
Figure 5 Microglial activation by Aβ requires microglial PARP-1 activity. A. Phase contrast images of cultured microglia. 24 hour incubation with 5 μM Aβ induces morphological transformation to the activated, amoeboid morphology in wild-type (wt) microglia. Microglial activation induced by Aβ was blocked by the PARP-1 inhibitor PJ34 (PJ, 400 nM) and in PARP-1-/- microglia. Cells treated with the reverse sequence Aβ peptide (rAβ, 5 μM) remained in resting, ramified morphology. B, Immunostaining for poly(ADP-ribose), the enzymatic product of PARP-1, showed poly(ADP-ribose) production within 60 minutes of Aβ addition, blocked by PJ34. There was no poly(ADP-ribose) signal in PARP-1-/- cells (not shown). C. Quantification of microglial activation. D, Quantification of poly(ADP-ribose) immunoreactive cells. * p < 0.05, # p < 0.05 vs. control. n = 3.CC BY · PubMed Central
Figure 6 PARP-1 regulates microglia-mediated amyloid β neurotoxicity. A, Representative microphotographs from wt neurons cultured alone, with wt microglia, or with PARP-1-/- microglia exposed to 5 μM of Aβ for 36 h. Aβ caused death of neurons cultured with wt microglia, but not in neurons cultured alone or with PARP-1-/- microglia. rAβ produced no neuronal death (not shown). Aβ-induced death of neurons in co-culture with wt microglia was blocked by the PARP-1 inhibitor PJ34 (PJ, 400 nM). B, Quantitative assessment of neuron survival, expressed relative to neurons cultured without Aβ or microglia (control). *p < 0.005; # p < 0.05 vs. control. n = 3.
Figure 6 PARP-1 regulates microglia-mediated amyloid β neurotoxicity. A, Representative microphotographs from wt neurons cultured alone, with wt microglia, or with PARP-1-/- microglia exposed to 5 μM of Aβ for 36 h. Aβ caused death of neurons cultured with wt microglia, but not in neurons cultured alone or with PARP-1-/- microglia. rAβ produced no neuronal death (not shown). Aβ-induced death of neurons in co-culture with wt microglia was blocked by the PARP-1 inhibitor PJ34 (PJ, 400 nM). B, Quantitative assessment of neuron survival, expressed relative to neurons cultured without Aβ or microglia (control). *p < 0.005; # p < 0.05 vs. control. n = 3.CC BY · PubMed Central
Figure 7 PARP-1 regulates NF-κB - mediated gene transcription in Aβ-treated microglia. A, Microglia were transfected with a reporter gene in which dEGFP expression is driven by the NF-κB p65 subunit. NF-κB transcriptional activity was evaluated after 90 min or 24 h of Aβ exposure. dEGFP expression induced by 5 μM Aβ was blocked by inhibitors of NF-κB activation (BAY 11-7082, 5 μM) or PARP-1 activation (PJ34, 400 nM). Quantified data are shown in panel (B). * p < 0.05 compared to Aβ, # p < 0.05 compared to control; n = 3. C-D, BAY and PJ34 also had parallel effects on microglial release of NO and TNFα, as assessed over 24 hours exposure to Aβ. Data are presented as a fold increase or decrease from control levels. Release from wt and PARP-1-/- microglia was not significantly different under control conditions. * p < 0.005 vs. Aβ, # p < 0.05 vs. control. n = 3-4.
Figure 7 PARP-1 regulates NF-κB - mediated gene transcription in Aβ-treated microglia. A, Microglia were transfected with a reporter gene in which dEGFP expression is driven by the NF-κB p65 subunit. NF-κB transcriptional activity was evaluated after 90 min or 24 h of Aβ exposure. dEGFP expression induced by 5 μM Aβ was blocked by inhibitors of NF-κB activation (BAY 11-7082, 5 μM) or PARP-1 activation (PJ34, 400 nM). Quantified data are shown in panel (B). * p < 0.05 compared to Aβ, # p < 0.05 compared to control; n = 3. C-D, BAY and PJ34 also had parallel effects on microglial release of NO and TNFα, as assessed over 24 hours exposure to Aβ. Data are presented as a fold increase or decrease from control levels. Release from wt and PARP-1-/- microglia was not significantly different under control conditions. * p < 0.005 vs. Aβ, # p < 0.05 vs. control. n = 3-4.CC BY · PubMed Central
Figure 8 PARP-1 modulates trophic factor release in Aβ-treated microglia. Microglial release of VEGF and TGFβ were reduced during 24 hours of Aβ exposure. This reduction was attenuated in PARP-1-/- microglia and in wt microglia treated with by inhibitors of PARP-1 (PJ34, 400 nM) or NF-κB (BAY 11-7082, 5 μM). Data are presented as a fold increase or decrease from control levels. Release from wt and PARP-1-/- microglia was not significantly different under control conditions. * p < 0.005 vs. Aβ, # p < 0.05 vs. control. n = 3-4.
Figure 8 PARP-1 modulates trophic factor release in Aβ-treated microglia. Microglial release of VEGF and TGFβ were reduced during 24 hours of Aβ exposure. This reduction was attenuated in PARP-1-/- microglia and in wt microglia treated with by inhibitors of PARP-1 (PJ34, 400 nM) or NF-κB (BAY 11-7082, 5 μM). Data are presented as a fold increase or decrease from control levels. Release from wt and PARP-1-/- microglia was not significantly different under control conditions. * p < 0.005 vs. Aβ, # p < 0.05 vs. control. n = 3-4.CC BY · PubMed Central
Figure 9 PARP-1 abrogation does not impair microglial phagocytosis of Aβ. A, Phase contrast and fluorescence images show the same field of microglia cultures. FAM-labeled Aβ (5 μM, green) is internalized by both wt and PARP-1-/- microglia, with or without a PARP-1 inhibitor (PJ34, 400 nM). B, Quantification of microglial FAM-Aβ phagocytosis activity, assessed after a 24 h exposure (n = 3). C, Orthogonal confocal views of microglia (stained with Iba-1, red) and FAM-Aβ (green) after 24 h incubation. The PARP-1-/- microglia do not assume a reactive morphology, but nevertheless engulfed the FAM-Aβ (yellow merge).
Figure 9 PARP-1 abrogation does not impair microglial phagocytosis of Aβ. A, Phase contrast and fluorescence images show the same field of microglia cultures. FAM-labeled Aβ (5 μM, green) is internalized by both wt and PARP-1-/- microglia, with or without a PARP-1 inhibitor (PJ34, 400 nM). B, Quantification of microglial FAM-Aβ phagocytosis activity, assessed after a 24 h exposure (n = 3). C, Orthogonal confocal views of microglia (stained with Iba-1, red) and FAM-Aβ (green) after 24 h incubation. The PARP-1-/- microglia do not assume a reactive morphology, but nevertheless engulfed the FAM-Aβ (yellow merge).CC BY · PubMed Central

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

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?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 70 references

Cited by

Sorted by citations

See all 113

Related

Metadata

Authors
Kauppinen, T. M., Suh, S., Higashi, Y., Berman, A. E., Escartin, C., Won, S., Wang, C., Cho, S.-H., Gan, L., & Swanson, R. A.
Affiliations
  • San Francisco VA Medical Center (US)
  • University of California, San Francisco (US)
Corresponding author
Kauppinen, Tiina M
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2011
Volume
8
Issue
1
Pages
152
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/1742-2094-8-152
PMC
PMC3247192
OpenAlex
W2147930131
Cited by
112
References
70
Citations by year
2026: 7 · 2025: 6 · 2024: 10 · 2023: 11 · 2022: 9 · 2021: 13 · 2020: 8 · 2019: 3 · 2018: 9 · 2017: 8 · 2016: 5 · 2015: 6 · 2014: 6 · 2013: 6 · 2012: 4
FWCI
3.01
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • U.S. Department of Veterans Affairs
  • American Heart Association (SDG 0835222N)
  • National Institutes of Health
  • University of California, San Francisco
  • National Institute on Aging (R01AG030207, AG030207-A2, R21AG029483, AG029483)
  • National Institute of Neurological Disorders and Stroke (NS 041421, R01NS041421)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
PARP1, amyloid-beta, microglial activation, Alzheimer's disease, NF-κB, PARP1 inhibition, neuroinflammation, neurotoxicity, cognitive impairment, TNF-α, nitric oxide, TGF-beta, vascular endothelial growth factor, microglia-neuron co-culture
MeSH terms
Poly (ADP-Ribose) Polymerase-1, Animals, Behavior, Animal, Cells, Cultured, Hippocampus, Memory, Mice, Inbred C57BL, Neurons, Phagocytosis, Poly(ADP-ribose) Polymerases, Cytokines, Amyloid beta-Peptides, NF-kappa B, Microglia, Mice, Knockout, Coculture Techniques, Mice, Calbindins, S100 Calcium Binding Protein G

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review