High membrane protein oxidation in the human cerebral cortex

Abstract

Oxidative stress is thought to be one of the main mediators of neuronal damage in human neurodegenerative disease. Still, the dissection of causal relationships has turned out to be remarkably difficult. Here, we have analyzed global protein oxidation in terms of carbonylation of membrane proteins and cytoplasmic proteins in three different mammalian species: aged human cortex and cerebellum from patients with or without Alzheimer's disease, mouse cortex and cerebellum from young and old animals, and adult rat hippocampus and cortex subjected or not subjected to cerebral ischemia. Most tissues showed relatively similar levels of protein oxidation. However, human cortex was affected by severe membrane protein oxidation, while exhibiting lower than average cytoplasmic protein oxidation. In contrast, ex vivo autooxidation of murine cortical tissue primarily induced aqueous protein oxidation, while in vivo biological aging or cerebral ischemia had no major effect on brain protein oxidation. The unusually high levels of membrane protein oxidation in the human cortex were also not predicted by lipid peroxidation, as the levels of isoprostane immunoreactivity in human samples were considerably lower than in rodent tissues. Our results indicate that the aged human cortex is under steady pressure from specific and potentially detrimental membrane protein oxidation. The pronounced difference between humans, mice and rats regarding the primary site of cortical oxidation might have contributed to the unresolved difficulties in translating into therapies the wealth of data describing successful antioxidant neuroprotection in rodents.

Appraising the Role of Iron in Brain Aging and Cognition: Promises and Limitations of MRI Methods

“…Low-level oxidative stress is a by-product of normal metabolic activity (Sohal and Orr, 2011), which, in a healthy cell, is minimized through rate-limited metabolism and further curtailed by endogenous anti-oxidants (Halliwell, 1992; Mills et al, 2010). Accumulation of unbound non-heme iron upsets that equilibrium and accelerates the rate of oxidative stress that enhances degradation of macromolecular cell components, perforates cell and mitochondrial membranes, impedes mitochondrial activity, promotes DNA mutations, and accelerates the rate of apoptosis (Halliwell, 1992; Mills et al, 2010; Hare et al, 2013; Ward et al, 2014; Granold et al, 2015). Through a separate but related mechanism, iron-catalyzed oxidative stress also increases pro-inflammatory cytokines, initiating the propagating cycle of neuroinflammation (Williams et al, 2012) that has been implicated in neurodegeneration (Xu et al, 2012; see Ward et al, 2014 for a review).…”

“…Further, brain regions with normally large amounts of iron do not consistently show differences in response to dietary intervention (e.g., Erikson et al, 1997). The failure to translate many of these therapies into human treatment may be in part due to discrepancies in relevant oxidative mechanisms and action sites between animal models and the human cerebrum, which was only recently demonstrated (Granold et al, 2015). Together, this underscores the importance of continuing improvement in the in vivo methods of iron estimation and attention to individual differences in regional brain iron deposition.…”

The roles of lipid and glucose metabolism in modulation of β-amyloid, tau, and neurodegeneration in the pathogenesis of Alzheimer disease

“…Glial lipid droplets induced by mitochondrial defects also promote neurodegeneration (Liu et al, 2015 ) suggesting a role for lipid metabolism in glial cells in neurodegeneration. Moreover, the human cortex demonstrates membrane protein oxidation (Granold et al, 2015 ) and altered phospholipid components during aging (Norris et al, 2015 ). Other than AD, impaired lipid metabolism has been reported in several neurodegenerative diseases.…”

The Effect of Polyphenols on Protein Degradation Pathways: Implications for Neuroprotection

“…Neurons are post-mitotic, bipolar cells, and, thus, thought to be particularly vulnerable to toxic protein aggregates. Indeed, neuronal accumulation of heavily oxidized, aggregation-prone proteins plays a causal role in the pathogenesis of age-associated neurodegenerative diseases, such as Alzheimer’s disease [ 5 , 6 ] and Parkinson’s disease [ 7 ]. In fact, they are generically considered as proteinopathies or protein conformational diseases [ 8 ].…”