Kauppinen, Tiina M. Suh, Sang Won. Higashi, Youichirou. Berman, Ari E. Escartin, Carole. Won, Seok Joon. Wang, Chao. Cho, Seo-Hyun. Gan, Li. Swanson, Raymond A.

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

Journal of Neuroinflammation. 8:152, 2011.
Abstract
BACKGROUND: Amyloid beta (Abeta) 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 Abeta, 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-kappaB. The purpose of this study was to evaluate whether PARP-1 activation is involved in Abeta-induced microglial activation, and whether PARP-1 inhibition can modify microglial responses to Abeta.

METHODS: hAPPJ20 mice, which accumulate Abeta 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. Abeta peptide was also injected into brain of wt and PARP-1-/- mice to directly determine the effects of PARP-1 on Abeta-induced microglial activation. The effect of PARP-1 on Abeta-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-kappaB activation was evaluated in microglia infected with a lentivirus reporter gene.

RESULTS: The 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, Abeta1-42 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 Abeta-induced NF-kappaB activation, morphological transformation, NO release, TNFalpha release, and neurotoxicity. Conversely, PARP-1 inhibition increased release of the neurotrophic factors TGFbeta and VEGF, and did not impair microglial phagocytosis of Abeta peptide.

CONCLUSIONS: These results identify PARP-1 as a requisite and previously unrecognized factor in Abeta-induced microglial activation, and suggest that the effects of PARP-1 are mediated, at least in part, by its interactions with NF-kappaB. The suppression of Abeta-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.