ABSTRACT
Title
Heme oxygenase/Biliverdin Reductase-A Protein Levels and Activity in the Brains of Subjects with Alzheimer Disease and Mild Cognitive Impairment.
Authors
C. Mancuso and P. Preziosi.
Institute of Pharmacology, Catholic University School of Medicine, Largo F. Vito, 1 – 00168 Rome, Italy.
Institute of Pharmacology, Catholic University School of Medicine, Largo F. Vito, 1 – 00168 Rome, Italy.
Abstract
The heme oxygenase/biliverdin reductase-A (HO/BVR-A) axis is the main metabolic pathway by which heme is degraded. The combined action of these enzymes converts heme into ferrous iron (FeII), carbon monoxide (CO), and biliverdin-IX-alpha (BV), which is the precursor of bilirubin-IX-alpha (bilirubin). This latter is a powerful endogenous cytoprotective molecule, due to the ability to scavenge free radicals. Heme oxygenase exists in two main isoforms named HO-1 and HO-2, the former inducible and the latter constitutive, respectively. Similarly, two isoforms of BVR were described and named BVR-A and BVR-B, but only BVR-A reduces BV into bilirubin. Several studies put forth the idea that the up-regulation of the HO/BVR-A system has to be considered as an early but long-lasting mechanism through which cells counteract oxidative and nitrosative damage. In addition, BVR-A was shown to regulate cell functions, in particular glucose metabolism and cell growth, secondary to its serine/threonine/tyrosine kinase activity.The activation of the HO/BVR-A system was demonstrated in both plasma and lymphocytes of Alzheimer disease (AD) patients. In addition, AD subjects exhibited an increased concentration of bilirubin in the cerebrospinal fluid with respect to control. Although these lines of evidence demonstrate the up-regulation of the HO/BVR-A axis in AD, its pathophysiological and clinical significance is still under debate. In fact, although the by-products of the HO/BVR system are well recognized for cytoprotective activity, they may become toxic for neurons if produced in excess as during condition of prolonged neuroinflammation.
Over the last years, our laboratory contributed to clarify the role of the HO-1/BVR system in neurodegenerative disorders by studying post-mortem brain samples of subjects affected by AD or mild cognitive impairment (MCI), the latter being the transitional phase between normal aging and early AD. An increase in HO-1 and BVR-A protein levels was found in the hippocampus of AD and MCI subjects, whereas HO-2 was decreased in this brain area. No significant changes were found in HO-1, HO-2 and BVR-A protein levels in AD and MCI cerebella. However, both HO-1 and BVR-A underwent post-translational modifications in AD and MCI hippocampi. In particular, HO-1 was phosphorylated on serine residues and this finding is consistent with previous data showing that this modification improves the interaction between HO-1 and BVR-A. Conversely, a significant reduction in the phosphorylation of BVR-A on serine and threonine/tyrosine residues was detected. With regard to oxidative- and nitrosative- related post-translational modifications, HO-1 was significantly oxidized and nitrated whereas BVR-A underwent nitration in AD and MCI hippocampi. Once again, oxidative and nitrosative modificants did not affect the HO/BVR-A system in the cerebellum. Since post-translational modifications could impair protein function, the activity of the HO/BVR-A system was assayed by measuring the production of bilirubin. Interestingly, the HO/BVR-A activity was significantly reduced in the hippocampus of AD and MCI individuals whereas no change was found in cerebella.
In conclusion, post-translational modifications affect the protein levels and activity of the HO-1/BVR-A system in the brain of subjects with AD or MCI. Consequently, not just the increased levels of HO-1/BVR-A, but also the changes activity and phosphorylation state, should be taken into account when considering potential biomarkers for AD and MCI.
Over the last years, our laboratory contributed to clarify the role of the HO-1/BVR system in neurodegenerative disorders by studying post-mortem brain samples of subjects affected by AD or mild cognitive impairment (MCI), the latter being the transitional phase between normal aging and early AD. An increase in HO-1 and BVR-A protein levels was found in the hippocampus of AD and MCI subjects, whereas HO-2 was decreased in this brain area. No significant changes were found in HO-1, HO-2 and BVR-A protein levels in AD and MCI cerebella. However, both HO-1 and BVR-A underwent post-translational modifications in AD and MCI hippocampi. In particular, HO-1 was phosphorylated on serine residues and this finding is consistent with previous data showing that this modification improves the interaction between HO-1 and BVR-A. Conversely, a significant reduction in the phosphorylation of BVR-A on serine and threonine/tyrosine residues was detected. With regard to oxidative- and nitrosative- related post-translational modifications, HO-1 was significantly oxidized and nitrated whereas BVR-A underwent nitration in AD and MCI hippocampi. Once again, oxidative and nitrosative modificants did not affect the HO/BVR-A system in the cerebellum. Since post-translational modifications could impair protein function, the activity of the HO/BVR-A system was assayed by measuring the production of bilirubin. Interestingly, the HO/BVR-A activity was significantly reduced in the hippocampus of AD and MCI individuals whereas no change was found in cerebella.
In conclusion, post-translational modifications affect the protein levels and activity of the HO-1/BVR-A system in the brain of subjects with AD or MCI. Consequently, not just the increased levels of HO-1/BVR-A, but also the changes activity and phosphorylation state, should be taken into account when considering potential biomarkers for AD and MCI.