Proteomic and Biological Profiling of Extracellular Vesicles from Alzheimer’s Disease Human Brain Tissues

Abstract

<jats:title>Abstract</jats:title><jats:sec><jats:title>Introduction</jats:title><jats:p>Extracellular vesicles (EVs) from human Alzheimer’s disease (AD) biospecimens contain amyloid-β peptide (Aβ) and tau. While AD EVs are known to affect brain disease pathobiology, their biochemical and molecular characterizations remain ill defined.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>EVs were isolated from the cortical grey matter of 20 AD and 18 control brains. Tau and Aβ levels were measured by immunoassay. Differentially expressed EV proteins were assessed by quantitative proteomics and machine learning.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Levels of pS396 tau and Aβ were significantly elevated in AD EVs. High levels of neuron- and glia- specific factors are detected in control and AD EVs, respectively. Machine learning identified ANXA5, VGF, GPM6A and ACTZ in AD EV compared to controls. They distinguished AD EVs from controls in the test sets with 88% accuracy.</jats:p></jats:sec><jats:sec><jats:title>Discussion</jats:title><jats:p>In addition to Aβ and tau, ANXA5, VGF, GPM6A and ACTZ are new signature proteins in AD EVs.</jats:p></jats:sec>

Proteomic analysis of extracellular vesicles in cerebrospinal fluid of patients with Alzheimer’s disease

“…Among these proteins, GPM6A, a membrane glycoprotein involved in neural differentiation 56 showed high expression in the cerebral cortex, basal ganglia and cerebellum. This molecule has been recently reported as differentially expressed in EV derived from AD brain tissues 57 . In our data, GPM6A was not included in our candidate list, but showed an increasing trend in AD P100 EVs (table S4).…”

Enrichment of neurodegenerative microglia signature in brain-derived extracellular vesicles isolated from Alzheimer’s disease mouse model

“…We compare the EV proteomics data to human AD brain-derived EV proteomics data (20), the 380 proteins were common between CAST.APP/PS1 brain-derived EVs and human AD brainderived EVs (Supplementary Figure S3). The APOE, CAMKV, ANXA5 and VGF showed a similar correlation with these EVs, suggesting that Ab deposition may be the major pathology for the upregulation of these molecules in EVs.…”

“…These EVs contain proteins, mRNA, non-coding RNAs (such as microRNA) and lipids, can transfer these molecules from cells to cells, and can be transported to biofluids, such as and cerebrospinal fluid and blood. In the central nervous system (CNS), brain-derived EVs contain Protein profiling of CAST.APP/PS1 mouse brain-derived EVs 6 multiple AD-associated proteins such as Ab, a-synuclein, APP, cyclin-dependent kinase 5, PSEN1, and tau, and play important roles in Ab deposition and tauopathy (15)(16)(17)(18)(19)(20). Moreover, it has been reported that inhibition of EV synthesis reduced Ab plaque deposition in the mouse model of AD, and stimulation of EV secretion increased intracellular transfer of prion protein in AD mouse models (16,17).…”

Exosomes as Emerging Biomarker Tools in Neurodegenerative and Neuropsychiatric Disorders—A Proteomics Perspective

“…Another comprehensive study using label free quantitative proteomics coupled with a machine learning method reported a panel of four exosome proteins that could identify AD patients with 88% accuracy [ 92 ]. These biomarkers were annexin-A5 (ANXA5), NGF-induced growth factor (VGF), neuronal membrane glycoprotein M6-a (GPM6A), and alpha-centractin (ACTZ).…”