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

Science Advances, Journal Year: 2024, Volume and Issue: 10(14)

Published: April 5, 2024

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

Language: Английский

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Alzheimer's Disease Biomarker Analysis Using Targeted Mass Spectrometry

Molecular & Cellular Proteomics, Journal Year: 2024, Volume and Issue: 23(2), P. 100721 - 100721

Published: Jan. 20, 2024

Alzheimer's disease (AD) is characterised by several neuropathological changes, mainly extracellular amyloid aggregates (plaques), intraneuronal inclusions of phosphorylated tau (tangles), as well neuronal and synaptic degeneration, accompanied tissue reactions to these processes (astrocytosis microglial activation) that precede network disturbances in the symptomatic phase disease. A number biomarkers for brain changes have been developed, using immunoassays. In this review, we discuss how targeted mass spectrometry (TMS) can be used validate further characterize classes reflecting different AD pathologies, such tau- amyloid-beta dysfunction, lysosomal dysregulation, axonal damage, prospect TMS measure proteins clinical research diagnosis. advantages disadvantages relation immunoassays are discussed, complementary aspects technologies discussed.

Language: Английский

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Dual Inhibitors of Brain Carbonic Anhydrases and Monoamine Oxidase-B Efficiently Protect against Amyloid-β-Induced Neuronal Toxicity, Oxidative Stress, and Mitochondrial Dysfunction

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(5), P. 4170 - 4193

Published: March 4, 2024

We report here the first dual inhibitors of brain carbonic anhydrases (CAs) and monoamine oxidase-B (MAO-B) for management Alzheimer's disease. Classical CA (CAIs) such as methazolamide prevent amyloid-β-peptide (Aβ)-induced overproduction reactive oxygen species (ROS) mitochondrial dysfunction. MAO-B is also implicated in ROS production, cholinergic system disruption, amyloid plaque formation. In this work, we combined a reversible inhibitor coumarin chromone type with benzenesulfonamide fragments highly effective CAIs. A hit-to-lead optimization led to significant set derivatives showing potent low nanomolar inhibition target CAs (KIs range 0.1–90.0 nM) (IC50 6.7–32.6 nM). Computational studies were conducted elucidate structure–activity relationship predict ADMET properties. The most multitarget compounds totally prevented Aβ-related toxicity, reverted formation, restored functionality an SH-SY5Y cell model surpassing efficacy single-target drugs.

Language: Английский

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CSF proteomics identifies early changes in autosomal dominant Alzheimer’s disease

Cell, Journal Year: 2024, Volume and Issue: 187(22), P. 6309 - 6326.e15

Published: Sept. 26, 2024

In this high-throughput proteomic study of autosomal dominant Alzheimer's disease (ADAD), we sought to identify early biomarkers in cerebrospinal fluid (CSF) for monitoring and treatment strategies. We examined CSF proteins 286 mutation carriers (MCs) 177 non-carriers (NCs). The developed multi-layer regression model distinguished with different pseudo-trajectories between these groups. validated our findings independent ADAD as well sporadic AD datasets employed machine learning develop validate predictive models. Our identified 137 distinct trajectories MCs NCs, including eight that changed before traditional biomarkers. These are grouped into three stages: stage (stress response, glutamate metabolism, neuron mitochondrial damage), middle (neuronal death, apoptosis), late presymptomatic (microglial changes, cell communication). revealed a six-protein subset more effectively differentiated from compared conventional

Language: Английский

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The Case for Abandoning Therapeutic Chelation of Copper Ions in Alzheimer's Disease

Frontiers in Neuroscience, Journal Year: 2017, Volume and Issue: 11

Published: June 2, 2017

The "therapeutic chelation" approach to treating Alzheimer's disease (AD) evolved from the metals hypothesis, with premise that small molecules can be designed prevent transition metal-induced amyloid deposition and oxidative stress within AD brain. Over more than 20 years, countless

Language: Английский

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