Dataset Information

Human brain glycoform coregulation network and glycan modification alterations in Alzheimer's disease.

ABSTRACT: Despite the importance of protein glycosylation to brain health, current knowledge of glycosylated proteoforms or glycoforms in human brain and their alterations in Alzheimer's disease (AD) is limited. Here, we report a proteome-wide glycoform profiling study of human AD and control brains using intact glycopeptide-based quantitative glycoproteomics coupled with systems biology. Our study identified more than 10,000 human brain N-glycoforms from nearly 1200 glycoproteins and uncovered disease signatures of altered glycoforms and glycan modifications, including reduced sialylation and N-glycan branching and elongation as well as elevated mannosylation and N-glycan truncation in AD. Network analyses revealed a higher-order organization of brain glycoproteome into networks of coregulated glycoforms and glycans and discovered glycoform and glycan modules associated with AD clinical phenotype, amyloid-β accumulation, and tau pathology. Our findings provide valuable insights into disease pathogenesis and a rich resource of glycoform and glycan changes in AD and pave the way forward for developing glycosylation-based therapies and biomarkers for AD.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC10997212 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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Human brain glycoform coregulation network and glycan modification alterations in Alzheimer's disease.

Zhang Qi Q Ma Cheng C Chin Lih-Shen LS Pan Sheng S Li Lian L

Science advances 20240405 14

Despite the importance of protein glycosylation to brain health, current knowledge of glycosylated proteoforms or glycoforms in human brain and their alterations in Alzheimer's disease (AD) is limited. Here, we report a proteome-wide glycoform profiling study of human AD and control brains using intact glycopeptide-based quantitative glycoproteomics coupled with systems biology. Our study identified more than 10,000 human brain N-glycoforms from nearly 1200 glycoproteins and uncovered disease si ...[more]

PMID: 38579000

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Project description:Follicle-stimulating hormone (FSH), an α/β heterodimeric glycoprotein hormone, consists of functionally significant variants resulting from the presence or absence of either one of two FSHβ subunit N-glycans. The two most abundant variants are fully-glycosylated FSH24 (based on 24 kDa FSHβ band in Western blots) and hypo-glycosylated FSH21 (21 kDa band, lacks βAsn24 glycans). Due to its ability to bind more rapidly to the FSH receptor and occupy more FSH binding sites than FSH24, hypo-glycosylated FSH21 exhibits greater biological activity. Endoglycosidase F1-deglycosylated FSH bound to the complete extracellular domain of the FSH receptor crystallized as a trimeric complex. It was noted that a single biantennary glycan attached to FSHα Asn52 might preemptively fill the central pocket in this complex and prevent the other two FSH ligands from binding the remaining ligand-binding sites. As the most active FSH21 preparations possessed more rapidly migrating α-subunit bands in Western blots, we hypothesized that Asn52 glycans in these preparations were small enough to enable greater FSH21 receptor occupancy in the putative FSHR trimer model. Highly purified hFSH oligosaccharides derived from each FSH subunit, were characterized by electrospray ionization-ion mobility-collision-induced dissociation (ESI-IM-CID) mass spectrometry. FSHβ glycans typically possessed core-linked fucose and were roughly one third bi-antennary, one third tri-antennary and one third tetra-antennary. FSHα oligosaccharides largely lacked core fucose and were bi- or tri-antennary. Those αAsn52 glycans exhibiting tetra-antennary glycan m/z values were found to be tri-antennary, with lactosamine repeats accounting for the additional mass. Selective αAsn52 deglycosylation of representative pituitary hFSH glycoform Superdex 75 gel filtration fractions followed by ESI-IM-CID mass spectrometry revealed tri-antennary glycans predominated even in the lowest molecular weight FSH glycoforms. Accordingly, the differences in binding capacity of the same receptor preparation to different FSH glycoforms are likely the organization of the FSH receptor in cell membranes, rather than the αAsn52 oligosaccharide.

Project description:BackgroundThe complicated cellular and biochemical changes that occur in brain during Alzheimer's disease are poorly understood. In a previous study we used an unbiased label-free quantitative mass spectrometry-based proteomic approach to analyze these changes at a systems level in post-mortem cortical tissue from patients with Alzheimer's disease (AD), asymptomatic Alzheimer's disease (AsymAD), and controls. We found modules of co-expressed proteins that correlated with AD phenotypes, some of which were enriched in proteins identified as risk factors for AD by genetic studies.MethodsThe amount of information that can be obtained from such systems-level proteomic analyses is critically dependent upon the number of proteins that can be quantified across a cohort. We report here a new proteomic systems-level analysis of AD brain based on 6,533 proteins measured across AD, AsymAD, and controls using an analysis pipeline consisting of isobaric tandem mass tag (TMT) mass spectrometry and offline prefractionation.ResultsOur new TMT pipeline allowed us to more than double the depth of brain proteome coverage. This increased depth of coverage greatly expanded the brain protein network to reveal new protein modules that correlated with disease and were unrelated to those identified in our previous network. Differential protein abundance analysis identified 350 proteins that had altered levels between AsymAD and AD not caused by changes in specific cell type abundance, potentially reflecting biochemical changes that are associated with cognitive decline in AD. RNA binding proteins emerged as a class of proteins altered between AsymAD and AD, and were enriched in network modules that correlated with AD pathology. We developed a proteogenomic approach to investigate RNA splicing events that may be altered by RNA binding protein changes in AD. The increased proteome depth afforded by our TMT pipeline allowed us to identify and quantify a large number of alternatively spliced protein isoforms in brain, including AD risk factors such as BIN1, PICALM, PTK2B, and FERMT2. Many of the new AD protein network modules were enriched in alternatively spliced proteins and correlated with molecular markers of AD pathology and cognition.ConclusionsFurther analysis of the AD brain proteome will continue to yield new insights into the biological basis of AD.

Project description:Alzheimer's disease (AD) is one of the most common forms of dementia that has slowly negative impacts on memory and cognition. With the assistance of multimodal brain networks and graph-based analysis approaches, AD-related network disruptions support the hypothesis that AD can be identified as a dysconnectivity syndrome. However, as the recent emerging of individual-based morphological network research of AD, the utilization of multiple morphometric features may provide a broader horizon for locating the lesions. Therefore, the present study applied the newly proposed individual morphological brain network with five commonly used morphometric features (cortical thickness, regional volume, surface area, mean curvature, and fold index) to explore the topological aberrations and their relationship with cognitive functioning alterations in the early stage of AD. A total of 40 right-handed participants were selected from Open Access Series of Imaging Studies Database with 20 AD patients (age ranged from 70 to 79, CDR = 0.5) and 20 age/gender-matched healthy controls. The significantly affected connections (p < 0.05 with FDR correction) were observed across multiple regions, both enhanced and attenuated correlations, primarily related to the left entorhinal cortex (ENT). In addition, profoundly changed Mini Mental State Examination (MMSE) score and global efficiency (p < 0.05) were noted in the AD patients, as well as the pronounced inter-group distinctions of betweenness centrality, global and local efficiency (p < 0.05) in the higher MMSE score zone (28-30), which indicating the potential role of graphic properties in determination of early-stage AD patients. Moreover, the reservations (regions in the occipital and frontal lobes) and alterations (regions in the right temporal lobe and cingulate cortex) of hubs were also detected in the AD patients. Overall, the findings further confirm the selective AD-related disruptions in morphological brain networks and also suggest the feasibility of applying the morphological graphic properties in the discrimination of early-stage AD patients.

Dataset Information

Human brain glycoform coregulation network and glycan modification alterations in Alzheimer's disease.

Publications

Human brain glycoform coregulation network and glycan modification alterations in Alzheimer's disease.

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