Advanced glycation end products and protein carbonyl levels in plasma reveal sex-specific differences in Parkinson's and Alzheimer's disease

Amit Sharma,Daniela Weber,Jana Raupbach,Tikam Chand Dakal,Klaus Fließbach,Alfredo Ramirez,Tilman Grune,Ullrich Wüllner

doi:10.1016/j.redox.2020.101546

Abstract

Neurodegenerative diseases (NDD) such as Alzheimer's (AD) and Parkinson's disease (PD) are distinct clinical entities, however, the aggregation of key neuronal proteins, presumably leading to neuronal demise appears to represent a common mechanism. It has become evident, that advanced glycation end products (AGEs) trigger the accumulation of such modified proteins, which eventually contributes to pathological aspect of NDDs. Increased levels of AGEs are found in amyloid plaques in AD brains and in both advanced and early PD (incidental Lewy body disease). The molecular mechanisms by which AGE dependent modifications may modulate the susceptibility towards NDDs, however, remain enigmatic and it is unclear, whether AGEs may serve as biomarker of NDD. In the present study, we examined AGEs (CML: Carboxymethyllysine and CEL: Carboxyethyllysine), markers of oxidative stress and micronutrients in the plasma of PD and AD patients and controls. As compared to healthy controls, AD females displayed lower levels of CEL while higher levels of CML were found in AD and PD patients. A somewhat similar pattern was observed for protein carbonyls (PC), revealing lower values exclusively in AD females, whereas AD males displayed significantly higher values compared to healthy controls and PD. Sex-specific differences were also observed for other relevant markers such as malondialdehyde, 3-nitrotyrosine, γ -tocopherols, retinol, plasma proteins and α-carotene, while α-tocopherols, β-carotene, lutein/zeaxanthin, β-cryptoxanthin and lycopene showed no relevant association. Taken together, our study suggests yet unappreciated differences of the distribution of AGEs among the sexes in NDD. We therefore suggest to make a clear distinction between sexes when analyzing oxidative (AGEs)-related stress and carbonyl-related stress and vitamins.

Highlights

More than three decades ago, oxidative stress and reactive oxygen species (ROS) have emerged as putative contributing factors in neurodegenerative diseases (NDD) [1,2,3]
Plasma levels of CML were found to be significantly higher in both Parkinson's disease (PD) and Alzheimer's disease (AD) patients compared to age matched healthy controls (HC) (Males: Cont vs PD: p < 0,0001; Cont vs AD p < 0,0001; Females: Cont vs PD: p = 0,0032; Cont vs AD p = 0,0180, Mann–Whitney test) (Fig. 1, Supplementary Table 1)
Sex specific differences for CEL have been reported previously in multiple sclerosis, where authors observed significantly lower CEL plasma levels in HC females as compared to HC males and tended to be lower in male patients compared to the females [16]

Summary

Introduction

More than three decades ago, oxidative stress and reactive oxygen species (ROS) have emerged as putative contributing factors in neurodegenerative diseases (NDD) [1,2,3]. Oxidative stress induces glycoxidation reactions, modifications of free amino groups in proteins, resulting in the generation of advanced lipoxidation and glycation end products (ALEs and AGEs). Glycation as a spontaneous age‐dependent posttranslational modification impacts the structure and function of several proteins. The presence of glycated forms of Aβ and tau in Alzheimer's disease (AD) and the immunohistochemical localization of AGEs suggests, that protein glycation acts as a common detrimental posttranslational modification of major NDD – associated proteins [7,8]. Li et al synthesized the glycated Aβ in vitro and treated the hippocampal neurons and suggested that the glycated Aβ42 could be a new therapeutic target for AD [9]

Methods

Results

Conclusion