Increased Expression of Immature Mannose-Containing Glycoproteins and Sialic Acid in Aged Mouse Brains

Abstract

Aging represents the accumulation of changes in an individual over time, encompassing physical, psychological, and social changes. Posttranslational modifications of proteins such as glycosylation, including sialylation or glycation, are proposed to be involved in this process, since they modulate a variety of molecular and cellular functions. In this study, we analyzed selected posttranslational modifications and the respective proteins on which they occur in young and old mouse brains. The expression of neural cell adhesion molecule (NCAM), receptor for advanced glycation endproducts (RAGE), as well as the carbohydrate-epitopes paucimannose and high-mannose, polysialic acid, and O-GlcNAc were examined. We demonstrated that mannose-containing glycans increased on glycoproteins in aged mouse brains and identified synapsin-1 as one major carrier of paucimannose in aged brains. In addition, we found an accumulation of so-called advanced glycation endproducts, which are generated by non-enzymatic reactions and interfere with protein function. Furthermore, we analyzed the expression of sialic acid and found also an increase during aging.

Mammalian brain glycoproteins exhibit diminished glycan complexity compared to other tissues

“…Here we emphasized the most abundant N- and O-glycans in the brain and their potential physiological roles, but this makes no assumption of the function or importance of structures that exist at very low abundance. Subtle changes in glycosylation can lead to major consequences at the protein, cell, and circuit level, so it is essential to understand how such variation is regulated at the genetic 20 , epigenetic 120 , transcriptional 121 , developmental 41 , 50 , regional 40 , 52 , 122 , and organismal levels 67 , 68 , 123 . The contribution of glycosylation to health and disease has been appreciated in many contexts, especially the nervous system 124 .…”

“…Systematic approaches to capture the diversity of all protein glycans in the brain have been attempted using glycomic analysis 37 , 39 – 44 , glycoproteomics 45 – 48 , microarrays 49 , western blotting 50 , and MALDI-Imaging techniques 51 , 52 . While the majority of these have produced complementary results, they tend to be individually limited by sample size, regional specificity, a single sex, or the technical constraints of a single method.…”

Mass spectrometry methods for analysis of extracellular matrix components in neurological diseases

“…Sialic acids have been implicated in neuronal plasticity, myelin stability, and remodeling of neuronal connections, and sialyltransferase‐deficient mice have displayed neurological symptoms such as impaired coordination and cognitive deficits (Rawal & Zhao, 2021; Yoo et al, 2015). Both sialylation and the presence of immature high mannose‐containing glycans have been linked to aging, with possible implications for decreased brain function (Simon et al, 2019).…”

Minimal epitope for Mannitou IgM on paucimannose-carrying glycoproteins

“…It was subsequently characterized as being able to specifically recognize paucimannose-carrying glycoproteins (PMPs) (Bajt et al 1990;Zipser et al 2012). Other PMPs with important neurobiological functions have been detected using Mannitou, among others human neutrophil elastase (Loke et al 2017), synapsin-1 (Simon et al 2019) and AHNAK (Becker et al 2019). Intriguing discoveries point to paucimannose N-glycans (PMGs) as facilitators of an effective immune response during physiological and pathophysiological conditions (Loke et al 2016).…”

“…A recent wide cancer glycomics analysis from human cancer cell lines and tissue samples illustrated that different cancer types and the disease progression stage can be stratified based on the distribution and ratios of paucimannosidic N-glycans (Chatterjee et al 2019). Both the rare incidence of paucimannose N-glycosylation in the extracellular environment and its upregulation to give potent signals and communicate with the immune system have made Mannitou a useful tool for the detection of paucimannose epitopes (Zipser et al 2012;Dahmen et al 2015;Thaysen-Andersen et al 2015;Loke et al 2017;Becker et al 2019;Chatterjee et al 2019;Simon et al 2019). Paucimannose-carrying proteins are exposed on the plasma membrane of transforming cells as opposed to high-mannosecarrying proteins predominantly hidden in the cytoplasm of normal cells (Loke et al 2016), enabling their targeting by monoclonal antibodies such as Mannitou IgM.…”