Abstract
BackgroundBrain degenerative protein modifications (DPMs) are associated with the apparition and progression of dementia, and at the same time, Alzheimer’s disease with cerebrovascular disease (AD + CVD) is the most prevalent form of dementia in the elder population. Thus, understanding the role(s) of brain DPMs in this dementia subtype may provide novel insight on the disease pathogenesis and may aid on the development of novel diagnostic and therapeutic tools. Two essential DPMs known to promote inflammation in several human diseases are the ureido DPMs (uDPMs) arginine citrullination and lysine carbamylation, although they have distinct enzymatic and non-enzymatic origins, respectively. Nevertheless, the implication of uDPMs in the neuropathology of dementia remains poorly understood.MethodsIn this study, we use the state-of-the-art, ultracentrifugation-electrostatic repulsion hydrophilic interaction chromatography (UC-ERLIC)-coupled mass spectrometry technology to undertake a comparative characterization of uDPMs in the soluble and particulate postmortem brain fractions of subjects diagnosed with AD + CVD and age-matched controls.ResultsAn increase in the formation of uDPMs was observed in all the profiled AD + CVD brains. Citrulline-containing proteins were found more abundant in the soluble fraction of AD + CVD whereas homocitrulline-containing proteins were preferentially abundant in the particulate fraction of AD + CVD brains. Several dementia-specific citrulline residues were also identified in soluble proteins previously categorized as pro-immunogenic, which include the receptor P2X7, alpha-internexin, GFAP, CNP, MBP, and histones. Similarly, diverse dementia-specific homocitrulline residues were also observed in the particulate fractions of AD + CVD in proteins that have been vastly implicated in neuropathology. Intriguingly, we also found that the amino acids immediately flanking arginine residues may specifically influence the increase in protein citrullination.ConclusionsTaken together, these results indicate that uDPMs widely contribute to the pathophysiology of AD + CVD by promoting neuroinflammation and proteinopathy. Furthermore, the obtained results could help to identify disease-associated proteins that can act as potential targets for therapeutic intervention or as novel biomarkers of specific neuropathology.
Highlights
Brain degenerative protein modifications (DPMs) are associated with the apparition and progression of dementia, and at the same time, Alzheimer’s disease with cerebrovascular disease (AD + Cerebrovascular disease (CVD)) is the most prevalent form of dementia in the elder population
To characterize the molecular composition of brain amyloids, we proposed the use of sodium deoxycholate (SDC), a detergent that allowed in-solution digestion and multidimensional chromatography, to improve the identification of posttranslationally modified peptides [37]
Citrullination and carbamylation are involved in the neuropathology of AD + CVD through different means
Summary
Brain degenerative protein modifications (DPMs) are associated with the apparition and progression of dementia, and at the same time, Alzheimer’s disease with cerebrovascular disease (AD + CVD) is the most prevalent form of dementia in the elder population. Understanding the role(s) of DPMs is expected to provide novel insight on the pathogenesis of these aging-associated diseases, and it may aid on the development of new diagnostic and therapeutic tools Two of these crucial DPMs that are thought to contribute to the neuropathology of dementia are citrullination and carbamylation [8,9,10]. Cit and HCit, favor protein denaturation and proteolysis and can be recognized by the immune system as non-naturally coded amino acids [6, 7, 11, 18] This former fact leads to the apparition of autoimmunity and inflammation, which are at the very basis of several chronic human diseases [19,20,21]
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