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Integrated Structural and Glycoproteomic Profiling Reveals Protein Conformational Remodeling and Biomarkers Across Alzheimer’s Disease Progression

ABSTRACT: Alzheimer’s disease (AD) is characterized by progressive neurodegeneration and protein misfolding, yet the structural dynamics of proteins and their post-translational modifications during disease progression remain poorly understood. Here, we present an integrated structural and glycoproteomic analysis of paired serum and cerebrospinal fluid (CSF) samples from individuals across three clinical stages: normal cognition, mild cognitive impairment, and AD. Using limited proteolysis mass spectrometry (LiP-MS) combined with high-field asymmetric waveform ion mobility spectrometry and data-independent acquisition, we identified 54 proteins exhibiting structural alterations, two of which (clusterin and ceruloplasmin) showed structural changes in both serum and CSF. Furthermore, our findings reveal potential crosstalk between protein structural changes and N-glycosylation, supported by correlations between LiP-derived structural features and glycosylation patterns in key proteins, such as haptoglobin and kininogen-1. This study demonstrates that integrating structural proteomics with glycoproteomics in matched serum and CSF samples enhances biomarker discovery and provides novel insights into the molecular mechanisms of AD. Our approach offers a powerful platform for identifying robust, minimally invasive biomarkers and for understanding post-translational modification–induced protein remodeling in neurodegenerative diseases.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Alzheimer's Disease

SUBMITTER: Haiyan Lu

LAB HEAD: Lingjun Li

PROVIDER: PXD059280 | Pride | 2026-01-02

REPOSITORIES: Pride

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Project description:s synapse degeneration is an early event in Alzheimer’s disease (AD) pathophysiology, a biofluid marker of synapse loss in living patients could be a surrogate marker of disease prognosis and therefore would be an excellent addition to the AD biomarker arsenal. With direct access to the brain interstitial fluid, the cerebrospinal fluid (CSF) is a potential source of synapse-derived proteins that could be potential biomarkers of underlying synapse degeneration. The aim of this study was to identify, verify and evaluate a set of synaptic proteins as surrogate CSF markers of underlying synapse loss in AD patients. In the Discovery Stage, we combined high-throughput shotgun proteomics of the CSF with an exhaustive search of the literature and public databases for proteomic studies of the CSF and synapse. A thorough characterization of the synaptic component of the CSF identified 210 synaptic proteins that are detectable in human CSF. We selected an initial panel of 22 candidate biomarkers for evaluation. In the Verification Stage, 12 proteins were discarded due to poor detection by targeted mass spectrometry (Selected Reaction Monitoring, SRM). We confirmed the expression of the remaining 10 proteins either directly at (Calsynytenin-1, GluR2, GluR4, Neurexins 2A and 3A, Neuroligin-2, Syntaxin-1B, Thy-1 and Vamp-2), or surrounding (Tenascin-R), the human synapse using Array Tomography microscopy and biochemical fractionation methods. We quantified the synaptic panel by SRM in CSF samples from 2 independent clinical cohorts of cognitively normal controls and all clinical stages of AD (n=140). A set of the panel proteins demonstrated a non-linear profile distinct to that of existing biomarkers whereby the CSF levels were decreased at the earliest preclinical stage of AD, reflecting reduced synaptic density in these asymptomatic individuals and elevated at later symptomatic stages when neurodegeneration is widespread. In conclusion, we have identified a set of novel synapse-specific proteins that could have clinical value for assessing disease progression in individuals at-risk for AD and potentially in other neurological disorders characterized by early synapse loss.

			Action	DRS
	2023-12-11-decoys-reviewed-contam-UP000005640.fas	Other
	A1_CSF_01FA.raw	Raw
	A1_CSF_60ACN.raw	Raw
	A1_CSF_70ACN.raw	Raw
	A1__CSF_50ACN.raw	Raw

Dataset Information

Integrated Structural and Glycoproteomic Profiling Reveals Protein Conformational Remodeling and Biomarkers Across Alzheimer’s Disease Progression

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