1. Department of Pharmacology and Therapeutics, University of Manitoba, Winnipeg, MB, Canada; 2. Department of Neurology, University of California San Francisco, San Francisco, CA, USA
Nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) has a key role in regulation of inflammatory responses due its ability to co-activate transcription factor NF-κB. In brain the microglia are the driving inflammatory cells and they functions contribute in neurodegenerative process, but also promote recovery and neuronal survival. The effects of PARP-1 ablation in microglial functions, both beneficial and detrimental were evaluated to establish whether PARP-1 ablation can be utilized as a modulator of microglial functions; reducing neurotoxic actions, while promoting responses that support neuronal viability.
PARP-1 inhibition/depletion in in vitro reduces neurotoxic aspects of microglial activation (release of NO, pro-inflammatory cytokines), but preserves their ability to release trophic factors and anti-inflammatory cytokines, and provide controlled phagocytosis. Accordingly, in in vivo model of Alzheimer’s disease (hAPPJ20) PARP-1 depletion reduces glial activation and inflammatory responses, while promoting neuronal survival. In combine these studies highlight PARP-1 intervention as a potential way to modulate microglial responses towards neuroprotective phenotype.
The systemic PARP-1 inhibition might not be desired approach in clinical settings, since immerging evidence suggest importance of neuronal PARP-1activation in long term memory formation. My future studies innovate in this area utilizing microglia-targeting lentiviral vectors to regulate exclusively microglial PARP-1 expression, without interfering neuronal or astrocytic PARP-1. The disease interests will remain in AD, but also extend to post-traumatic dementia and ischemic stroke.