Abstract
Pathological hallmarks of Alzheimer’s disease (AD) are deposits of amyloid beta (Aβ) and hyper-phosphorylated tau aggregates in brain plaques. Recent studies have highlighted the importance of Aβ and tau-containing extracellular vesicles (EVs) in AD. We therefore examined EVs separated from cerebrospinal fluid (CSF) of AD, mild cognitive impairment (MCI), and control (CTRL) patient samples to profile the protein composition of CSF EV. EV fractions were separated from AD (n = 13), MCI (n = 10), and CTRL (n = 10) CSF samples using MagCapture Exosome Isolation kit. The CSF-derived EV proteins were identified and quantified by label-free and tandem mass tag (TMT)-labeled mass spectrometry. Label-free proteomics analysis identified 2546 proteins that were significantly enriched for extracellular exosome ontology by Gene Ontology analysis. Canonical Pathway Analysis revealed glia-related signaling. Quantitative proteomics analysis, moreover, showed that EVs expressed 1284 unique proteins in AD, MCI and CTRL groups. Statistical analysis identified three proteins—HSPA1A, NPEPPS, and PTGFRN—involved in AD progression. In addition, the PTGFRN showed a moderate correlation with amyloid plaque (rho = 0.404, p = 0.027) and tangle scores (rho = 0.500, p = 0.005) in AD, MCI and CTRL. Based on the CSF EV proteomics, these data indicate that three proteins, HSPA1A, NPEPPS and PTGFRN, may be used to monitor the progression of MCI to AD.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most commonly described dementia, characterized by the accumulation of amyloid plaques in neurons [1].Amyloid plaques are primarily composed of insoluble amyloid beta peptide (Aβ) deposits, and they represent toxicity to surrounding brain cells
We provide a quantitative proteomic profiling of extracellular vesicles (EVs) separated from AD, mild cognitive impairment (MCI), and CTRL cerebrospinal fluid (CSF) samples by affinity capture methods and show CSF EV molecules altered during progression to AD from MCI or HC
The EVs separated from AD, MCI and CTRL CSF were analyzed by Transmission electron microscopy (TEM)
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most commonly described dementia, characterized by the accumulation of amyloid plaques in neurons [1]. There are several other emerging CSF biomarkers of neuronal/synaptic injury including visinin-like protein 1, synaptosomal-associated protein 25, neurogranin, synaptotagmin-1, presynaptic marker growth-associated protein 43, and neuroinflammation-related Chitinase-3-like protein1 These markers are increased in AD and MCI compared with controls [16,17,18,19]. It is known that brain-derived EVs contain pathogenic proteins, such as tau, Aβ, α-synuclein, and superoxide dismutase, and it was reported that EVs play a role in cell-to-cell propagation of the disease in brain [34,35,36,37,38,39] It has been, reported that the EVs contain total tau (t-tau) and phosphorylated tau (p-tau), which are transported from brain to CSF in AD patients, but there are no significant differences between AD and non-demented control (CTRL) samples [40]. We provide a quantitative proteomic profiling of EVs separated from AD, mild cognitive impairment (MCI), and CTRL cerebrospinal fluid (CSF) samples by affinity capture methods and show CSF EV molecules altered during progression to AD from MCI or HC
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