Abstract
Compelling evidence supports the role of oxidative stress in Alzheimer’s disease (AD) pathophysiology. Interestingly, Herpes simplex virus-1 (HSV-1), a neurotropic virus that establishes a lifelong latent infection in the trigeminal ganglion followed by periodic reactivations, has been reportedly linked both to AD and to oxidative stress conditions. Herein, we analyzed, through biochemical and redox proteomic approaches, the mouse model of recurrent HSV-1 infection we previously set up, to investigate whether multiple virus reactivations induced oxidative stress in the mouse brain and affected protein function and related intracellular pathways. Following multiple HSV-1 reactivations, we found in mouse brains increased levels of oxidative stress hallmarks, including 4-hydroxynonenal (HNE), and 13 HNE-modified proteins whose levels were found significantly altered in the cortex of HSV-1-infected mice compared to controls. We focused on two proteins previously linked to AD pathogenesis, i.e., glucose-regulated protein 78 (GRP78) and collapsin response-mediated protein 2 (CRMP2), which are involved in the unfolded protein response (UPR) and in microtubule stabilization, respectively. We found that recurrent HSV-1 infection disables GRP78 function and activates the UPR, whereas it prevents CRMP2 function in mouse brains. Overall, these data suggest that repeated HSV-1 reactivation into the brain may contribute to neurodegeneration also through oxidative damage.
Highlights
Alzheimer’s disease (AD), the most common form of dementia in the elderly [1] is a multifactorial disorder, likely resulting from the combination of different risk factors, including genetic, environmental, and, likely, infectious ones [2,3]
We previously demonstrated that multiple Herpes simplex virus-1 (HSV-1) reactivations reaching the brain induced hallmarks of neurodegeneration as well as cognitive deficits in mice [25], resembling the occurrence of an AD-like phenotype
We investigated whether recurrent HSV-1 infections in mouse brain may induce a progressive increment of oxidative stress conditions, as evidenced during the development of AD [33]
Summary
Alzheimer’s disease (AD), the most common form of dementia in the elderly [1] is a multifactorial disorder, likely resulting from the combination of different risk factors, including genetic, environmental, and, likely, infectious ones [2,3]. In addition to the pathological hallmarks of the disease, such as the accumulation of misfolded protein deposits in the brain as extracellular plaques containing amyloid β-peptides (Aβs) and intraneuronal neurofibrillary tangles formed by hyperphosphorylated tau proteins, AD brains exhibit evidence of reactive oxygen species (ROS)-mediated injury [4] This includes modifications of the major components of cells, such as DNA, RNA, lipids, and proteins, occurring within oxidative stress conditions, i.e., when ROS production overcomes the antioxidant capability of the cells. Lipid peroxidation is a specific product as well as a source of oxidative stress in the brain, since this tissue is characterized by the presence of high levels of polyunsaturated fatty acids (PUFA), the substrate for lipid peroxidation, a high rate of oxygen utilization, and low level of antioxidants [6] This complex process implicates the reaction between oxygen-derived free radicals and PUFA, producing highly reactive electrophilic aldehydes that are capable of forming adducts with cysteine (Cys), lysine (Lys), or histidine (His) residues of proteins. Feot ral. (20f1u9r)th[2e5r]d. etails about the mouse model, see De Chiara et al (2019) [25]
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