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

Abstract

BackgroundAmyloid 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.MethodshAPPJ20 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.ResultsThe hAPPJ20 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 hAPPJ20/PARP-1-/- mice. Similarly, Aβ1-42 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.ConclusionsThese 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.

Sirtuins and their interactions with transcription factors and poly(ADP-ribose) polymerases

“…The co-operation between PARP-1 and numerous TFs also includes NF-κB and is important for neurodegeneration in Alzheimer's disease [95], for brain ischaemia [80], etc. Despite the pro-survival physiological significance of PARP-1, its excessive activation by DNA damage induced by ROS/RNS (reactive nitrogen species) [187], Aβ, or mutagens [189] has long been associated with cell death.…”

The new insight on the regulatory role of the vitamin D3 in metabolic pathways characteristic for cancerogenesis and neurodegenerative diseases

“…The PARP-1 activity in the astrocytes was increased, suggesting that PARP-1-immunoreactive astrocytes may play an important role in the pathogenesis and progression of ALS (Kim et al, 2003;Kim et al, 2004). The microglial response in mice lacking PARP-1 expression or activity was blocked after Aβ 42 injection, compared to robust microglial activation in wild-type mice, thus confirming the protective role of PARP-1 genetic or pharmacological inhibition (Kauppinen et al, 2011). The age-related increase in cleavage of PARP-1 was all attenuated in hippocampal tissue prepared from Wistar rats that received dexamethasone and vitamin D 3 (Moore et al, 2007).…”

Oxidative Stress Events and Neuronal Dysfunction in Alzheimer’s Disease: Focus on APE1/Ref-1-Mediated Survival Strategies

“…Enhancement of PARP-1 activity and accumulation of PAR is observed in the brains of AD patients [ 135 ]. A recent study has established the role of PARP-1 in microglial activation by its interaction with NF-kB [ 136 ]. Recently, the mitochondrial localisation of PARP-1 and its interaction with mitochondrial protein, mitofi lin, has been established [ 137 ].…”