title: Exosomal biomarkers of brain insulin resistance associated with regional atrophy in Alzheimer's disease.
abstract: Brain insulin resistance (IR), which depends on insulin-receptor-substrate-1 (IRS-1) phosphorylation, is characteristic of Alzheimer's disease (AD). Previously, we demonstrated higher pSer312-IRS-1 (ineffective insulin signaling) and lower p-panTyr-IRS-1 (effective insulin signaling) in neural origin-enriched plasma exosomes of AD patients vs.
  
  
  
  Here, we hypothesized that these exosomal biomarkers associate with brain atrophy in AD. We studied 24 subjects with biomarker-supported probable AD (low CSF Aβ42). Exosomes were isolated from plasma, enriched for neural origin using immunoprecipitation for L1CAM, and measured for pSer312- and p-panTyr-IRS-1 phosphotypes. MPRAGE images were segmented by brain tissue type and voxel-based morphometry (VBM) analysis for gray matter against pSer312- and p-panTyr-IRS-1 was conducted. Given the regionally variable brain expression of IRS-1, we used the Allen Brain Atlas to make spatial comparisons between VBM results and IRS-1 expression. Brain volume was positively associated with P-panTyr-IRS-1 and negatively associated with pSer312-IRS-1 in a strikingly similar regional pattern (bilateral parietal-occipital junction, R middle temporal gyrus). This volumetric association pattern was spatially correlated with Allen Human Brain atlas normal brain IRS-1 expression. Exosomal biomarkers of brain IR are thus associated with atrophy in AD as could be expected by their pathophysiological roles and do so in a pattern that reflects regional IRS-1 expression. Furthermore, neural-origin plasma exosomes may recover molecular signals from specific brain regions. Hum Brain Mapp 38:1933-1940, 2017. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging/National Institutes of Health (NIA/NIH).
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Mullins
authors.affiliation: Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging/National Institutes of Health (NIA/NIH).
authors.forename: Maja
authors.initials: M
authors.lastname: Mustapic
authors.affiliation: Department of Medicine, University of California, San Francisco.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Goetzl
authors.affiliation: Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging/National Institutes of Health (NIA/NIH).
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Kapogiannis
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000150:complications / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D001284:Atrophy / Q000000981:diagnostic imaging / Q000209:etiology; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D055354:Exosomes / Q000378:metabolism; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D047468:Immunoprecipitation; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008279:Magnetic Resonance Imaging; D008297:Male; D039842:Neural Cell Adhesion Molecule L1 / Q000378:metabolism*; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D010766:Phosphorylation; D012694:Serine / Q000378:metabolism; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D039842:Neural Cell Adhesion Molecule L1; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D012694:Serine
keywords: Alzheimer's disease; IRS-1; biomarker; exosomes; insulin resistance; magnetic resonance imaging