ABSTRACT
BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disorder. Depositions of amyloid ß peptide (Aß) and tau protein are among the major pathological hallmarks of AD. Aß and tau burden follows predictable spatial patterns during the progression of AD. Nevertheless, it remains obscure why certain brain regions are more vulnerable than others; to investigate this and dysregulated pathways during AD progression, a mass spectrometry-based proteomics study was performed. METHODS: In total 103 tissue samples from regions early (entorhinal and parahippocampal cortices - medial temporal lobe (MTL)) and late affected (temporal and frontal cortices - neocortex) by tau pathology were subjected to label-free quantitative proteomics analysis. RESULTS: Considering dysregulated proteins during AD progression, the majority (625 out of 737 proteins) was region specific, while some proteins were shared between regions (101 proteins altered in two areas and 11 proteins altered in three areas). Analogously, many dysregulated pathways during disease progression were exclusive to certain regions, but a few pathways altered in two or more areas. Changes in protein expression indicate that synapse loss occurred in all analyzed regions, while translation dysregulation was preponderant in entorhinal, parahippocampal and frontal cortices. Oxidative phosphorylation impairment was prominent in MTL. Differential proteomic analysis of brain areas in health state (controls) showed higher metabolism and increased expression of AD-related proteins in the MTL compared to the neocortex. In addition, several proteins that differentiate brain regions in control tissue were dysregulated in AD. CONCLUSIONS: This work provides the comparison of proteomic changes in brain regions affected by tau pathology at different stages of AD. Although we identified commonly regulated proteins and pathways during disease advancement, we found that the dysregulated processes are predominantly region specific. In addition, a distinct proteomic signature was found between MTL and neocortex in healthy subjects that might be related to AD vulnerability. These findings highlight the need for investigating AD's cascade of events throughout the whole brain and studies spanning more brain areas are required to better understand AD etiology and region vulnerability to disease.
Subject(s)
Alzheimer Disease/metabolism , Brain/metabolism , Proteome , tau Proteins/metabolism , Aged , Aged, 80 and over , Alzheimer Disease/pathology , Brain/pathology , Disease Progression , Female , Humans , Male , Middle Aged , Phosphorylation , ProteomicsABSTRACT
Exertional rhabdomyolysis (ERM), a condition often associated with strenuous exercise, a common practice in the military activities, can be defined as the process of injury and rupture of muscle cell membranes, with leakage of its components into the bloodstream. Creatine kinase (CK) has been used for ERM diagnosis, albeit several studies reported the discrepancy between CK levels and clinical signs or symptoms. In this study, we analyzed the biochemical profile of the blood, and the urinary proteome of ten marine soldiers in a special training course. The samples were collected in two periods, M1 and M2, which correspond to the lowest and highest CK levels during training, respectively. Quantitative urinary proteome profile of M1 and M2 showed changes in proteins involved in immune system and cell adhesion-related pathways after strenuous physical exercise. Changes in the abundance of several proteins was observed in individuals carrying genetic polymorphisms related to greater risk for muscle damage. A panel of proteins (CTSH, PIK3IP1, DEFB1, ITGB1, BCAN, and TNFRSF10C) presented high correlation with classical blood biochemical markers of ERM and AGT MET235Thr and ACE I/D polymorphisms. These proteins represent potential urine markers of muscle damage due to intense physical conditions such as military training activities. SIGNIFICANCE: This study analyzed the blood and urine of a cohort of marine soldiers enrolled in a special training program including missions with low and high exposure to strenuous exercise. The biochemical blood profile, polymorphisms mapping and mass spectrometry-based analyses of the urinary proteome was evaluated in such a controlled samples. A total of 226 urinary proteins associated to immune system, cell adhesion and redox homeostasis were significantly changes during ERM shedding lights on the disease pathogenesis. In particular, a panel of six proteins were associated to classical ERM markers and could be used as early non invasive biomarkers.