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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Poly(ADP-ribose)polymerase-1 modulates microglial responses to amyloid β
Tiina M Kauppinen1, Sang Won Suh, Youichirou Higashi
1Department of Neurology, University of California, San Francisco, and Veterans Affairs Medical Center, 4150 Clement Street (127), San Francisco, CA 94121, USA. Tiina.Kauppinen@ucsf.edu
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.
Insights
Poly(ADP-ribose) polymerase-1 (PARP-1) drives amyloid-beta-induced microglial activation and neurotoxicity in Alzheimer's disease (AD). Inhibiting PARP-1 reduces these harmful effects, offering a potential therapeutic strategy for AD.
Area of Science:
- Neuroscience
- Neuroinflammation
- Alzheimer's Disease Research
Background:
- Amyloid beta (Aβ) accumulation and microglial activation are hallmarks of Alzheimer's disease (AD), contributing to neuroinflammation and disease progression.
- The nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) is known to regulate microglial activation via interactions with the transcription factor NF-κB.
- The precise role of PARP-1 in Aβ-induced microglial activation remains to be fully elucidated.
Purpose of the Study:
- To investigate the involvement of PARP-1 in Aβ-induced microglial activation.
- To determine if PARP-1 inhibition can modulate microglial responses to Aβ in the context of AD.
Main Methods:
- Crossed hAPP(J20) mice (Aβ accumulating) with PARP-1(-/-) mice to assess PARP-1 depletion effects on microglial activation, synaptic integrity, and cognition.
- Administered Aβ peptide directly into the brains of wild-type and PARP-1(-/-) mice to study direct effects.
- Utilized primary microglia and microglia-neuron co-cultures with PARP-1(-/-) cells and a PARP-1 inhibitor to evaluate cytokine production and neurotoxicity, assessing NF-κB activation.
Main Results:
- hAPP(J20) mice exhibited microglial activation, reduced hippocampal CA1 calbindin, and cognitive deficits, which were attenuated in hAPP(J20)/PARP-1(-/-) mice.
- Direct Aβ(1-42) injection induced microglial responses in wild-type mice, but this response was blocked in PARP-1 deficient mice.
- PARP-1 activity was essential for Aβ-induced NF-κB activation, microglial transformation, NO/TNFα release, and neurotoxicity; PARP-1 inhibition enhanced neurotrophic factor release (TGFβ, VEGF) without impairing phagocytosis.
Conclusions:
- PARP-1 is identified as a critical mediator of Aβ-induced microglial activation, partly through its interaction with NF-κB.
- PARP-1 inhibition effectively suppressed Aβ-induced microglial activation and neurotoxicity.
- Targeting PARP-1 presents a promising therapeutic avenue for Alzheimer's disease and other conditions involving microglial neurotoxicity.
