Skip to main content
. Author manuscript; available in PMC: 2015 Feb 1.
Published in final edited form as: Neurobiol Dis. 2013 Oct 2;62:10.1016/j.nbd.2013.09.018. doi: 10.1016/j.nbd.2013.09.018

Figure 3. The neuroprotective vs neurotoxic hypothesis.

Figure 3

The apparent discrepancy between the neuroprotective and neurotoxic hypothesis, with regard to the role played by the HO/BVR system in the pathogenesis of AD, could be solved by considering different phases in the progression of the pathology. Panel A, neuroprotective. By considering oxidative stress as a central event in AD pathology, it is conceivable that during an initial phase, which could be represented by an early stage even preceding MCI, the elevation of oxidative stress levels promotes the increase of HO-1 and BVR-A protein levels which could still work properly in order to counteract, the noxious effects related to augmented oxidative and nitrosative stress levels through: (i) the production of antioxidant and antinitrosative bilirubin; and (ii) the pleiotropic functions of BVR regulating cell survival. With the progression of the pathology through the progression from MCI and AD, characterized by a continuous increase of oxidative stress levels, the neuroprotective activities mediated by the HO/BVR system would not be sufficiently efficacious anymore. Panel B, neurotoxic. Taking into account the observed impairment of BVR-A in both MCI and AD (Barone et al., 2011a; Barone et al., 2011b), the presence of both oxidative post-translational modifications and Ser phosphorylation on HO-1 in AD brain makes it difficult to state which post translational modification precedes the other and at least two interpretations could be conceivable: (1) oxidative stress promotes the increase of HO-1 oxidative damage (e.g., increased PC and HNE-adducts to key amino acids within HO-1). Consequently, the cell tries to restore the functionality of the protein by increasing Ser residue phosphorylation; (2) Oxidative stress promotes the increase of Ser-residue phosphorylation in order to activate protein functions, but HO-1 quickly becomes a target for oxidative post-translational modifications, that in turn could impair its function (Barone et al., 2012a). Arrows, stimulation; dotted lines, inhibition.