title: Poly(ADP-ribose)polymerase-1 modulates microglial responses to amyloid β.
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.
authors: Department 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
authors: Tiina M
authors: TM
authors: Kauppinen
authors: Sang Won
authors: SW
authors: Suh
authors: Youichirou
authors: Y
authors: Higashi
authors: Ari E
authors: AE
authors: Berman
authors: Carole
authors: C
authors: Escartin
authors: Seok Joon
authors: SJ
authors: Won
authors: Chao
authors: C
authors: Wang
authors: Seo-Hyun
authors: SH
authors: Cho
authors: Li
authors: L
authors: Gan
authors: Raymond A
authors: RA
authors: Swanson
mesh_terms: D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D064026:Calbindins; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D008568:Memory / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D064030:S100 Calcium Binding Protein G / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D064026:Calbindins; D016207:Cytokines; D016328:NF-kappa B; D064030:S100 Calcium Binding Protein G; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases