Increased poly(ADP-ribosyl)ation of nuclear proteins in Alzheimer's disease

Abstract

Experimental studies indicate that overactivation of the DNA repair protein poly(ADP-ribose) polymerase (PARP) in response to oxidative damage to DNA can cause cell death due to depletion of NAD+. Oxidative damage to DNA and other macromolecules has been reported to be increased in the brains of patients with Alzheimer's disease. In the present study we sought evidence of PARP activation in Alzheimer's disease by immunostaining sections of frontal and temporal lobe from autopsy material of 20 patients and 10 controls, both for PARP itself and for its end-product, poly(ADP-ribose). All of the brains had previously been subjected to detailed neuropathological examination to confirm the diagnosis of Alzheimer's disease or, in the controls, to exclude Alzheimer's disease-type pathology. Double immunolabelling for poly(ADP-ribose) and microtubule-associated protein 2 (MAP2), glial fibrillary-acidic protein (GFAP), CD68, A beta-protein or tau was used to assess the identity of the cells with poly(ADP-ribose) accumulation and their relationship to plaques and neurofibrillary tangles. Both PARP- and poly(ADP-ribose)-immunolabelled cells were detected in a much higher proportion of Alzheimer's disease (20 out of 20) brains than of control brains (5 out of 10) (P = 0.0018). Double-immunolabelling for poly(ADP-ribose) and markers of neuronal, astrocytic and microglial differentiation (MAP2, GFAP and CD68, respectively) showed many of the cells containing poly(ADP-ribose) to be neurons. Most of these were small pyramidal neurons in cortical laminae 3 and 5. A few of the cells containing poly(ADP-ribose) were astrocytes. No poly(ADP-ribose) accumulation was detected in microglia. Double-immunolabelling for poly(ADP-ribose) and tau or A beta-protein indicated that the cells with accumulation of poly(ADP-ribose) did not contain tangles and relatively few occurred within plaques. Our findings indicate that there is enhanced PARP activity in Alzheimer's disease and suggest that pharmacological interventions aimed at inhibiting PARP may have a role in slowing the progression of the disease.

Quantification of Poly(ADP-Ribose)-Modified Proteins in Cerebrospinal Fluid from Infants and Children after Traumatic Brain Injury

“…(Whalen et al, 1999) and pharmacological PARP-1 inhibitors (LaPlaca et al, 2001;Satchell et al, 2003;Clark et al, 2007). Although, to the best of our knowledge, there have been no clinical studies implicating a role for PARP activation after TBI, there is a report showing increased PAR in human brain after stroke (Love et al, 1999). Based on preclinical studies, testing the effect of PARP inhibitors in patients with severe TBI appears justified.…”

Increased expression and activation of poly(ADP-ribose) polymerase (PARP) contribute to retinal ganglion cell death following rat optic nerve transection

“…27 The common feature in the pathogen- Figure 3 Poly(ADP-ribose) polymer immunohistochemistry on retinal sections to monitor PARP activation after ON transection with or without 3-ABA treatment. Note GCL-specific, nuclear immunoreactivity 1 day (B) and, less prominent, 3 days (C) after ON axotomy without a specific therapy, indicative for RGC-specific PARP activation.…”

Variants and Polymorphisms of DNA Repair Genes and Neurodegenerative Diseases

“…PARP-1 poly-ADP-ribosylates several proteins involved in DNA repair including histones, thus inducing local relaxation of the chromatin structure and facilitating the access of repair proteins to damaged DNA. There is evidence for widespread DNA SSBs and DSBs in AD brains, as well as increased PARP-1 activity (Love et al, 1999). Two independent groups evaluated PARP-1 gene polymorphisms as putative AD risk factors.…”