title: Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer's disease.
abstract: Insulin resistance causes diminished glucose uptake in similar regions of the brain in Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2). Brain tissue studies suggested that insulin resistance is caused by low insulin receptor signaling attributable to its abnormal association with more phospho (P)-serine-type 1 insulin receptor substrate (IRS-1) and less P-tyrosine-IRS-1. Plasma exosomes enriched for neural sources by immunoabsorption were obtained once from 26 patients with AD, 20 patients with DM2, 16 patients with frontotemporal dementia (FTD), and matched case control subjects. At 2 time points, they were obtained from 22 others when cognitively normal and 1 to 10 yr later when diagnosed with AD. Mean exosomal levels of extracted P-serine 312-IRS-1 and P-pan-tyrosine-IRS-1 by ELISA and the ratio of P-serine 312-IRS-1 to P-pan-tyrosine-IRS-1 (insulin resistance factor, R) for AD and DM2 and P-serine 312-IRS-1 and R for FTD were significantly different from those for case control subjects. The levels of R for AD were significantly higher than those for DM2 or FTD. Stepwise discriminant modeling showed correct classification of 100% of patients with AD, 97.5% of patients with DM2, and 84% of patients with FTD. In longitudinal studies of 22 patients with AD, exosomal levels of P-serine 312-IRS-1, P-pan-tyrosine-IRS-1, and R were significantly different 1 to 10 yr before and at the time of diagnosis compared with control subjects. Insulin resistance reflected in R values from this blood test is higher for patients with AD, DM2, and FTD than case control subjects; higher for patients with AD than patients with DM2 or FTD; and accurately predicts development of AD up to 10 yr prior to clinical onset.
authors.affiliation: Intramural Research Program, National Institute on Aging, Baltimore, Maryland, USA;
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Kapogiannis
authors.affiliation: Memory and Aging Center, Department of Neurology, and.
authors.forename: Adam
authors.initials: A
authors.lastname: Boxer
authors.affiliation: Jewish Home of San Francisco, San Francisco, California, USA; Department of Medicine, University of California-San Francisco Medical Center, San Francisco, California, USA;
authors.forename: Janice B
authors.initials: JB
authors.lastname: Schwartz
authors.affiliation: Sanders-Brown Center on Aging, University of Kentucky, Lexington, Kentucky, USA; and.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Abner
authors.affiliation: Intramural Research Program, National Institute on Aging, Baltimore, Maryland, USA;
authors.forename: Arya
authors.initials: A
authors.lastname: Biragyn
authors.affiliation: Jewish Home of San Francisco, San Francisco, California, USA;
authors.forename: Umesh
authors.initials: U
authors.lastname: Masharani
authors.affiliation: Jewish Home of San Francisco, San Francisco, California, USA;
authors.forename: Lynda
authors.initials: L
authors.lastname: Frassetto
authors.affiliation: Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.affiliation: Memory and Aging Center, Department of Neurology, and.
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Miller
authors.affiliation: Intramural Research Program, National Institute on Aging, Baltimore, Maryland, USA; Jewish Home of San Francisco, San Francisco, California, USA; Department of Medicine, University of California-San Francisco Medical Center, San Francisco, California, USA; edward.goetzl@ucsf.edu.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Goetzl
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000378:metabolism*; D016022:Case-Control Studies; D003072:Cognition Disorders / Q000097:blood; D003430:Cross-Sectional Studies; D004797:Enzyme-Linked Immunosorbent Assay; D055354:Exosomes / Q000378:metabolism*; D005260:Female; D057180:Frontotemporal Dementia / Q000097:blood; D005786:Gene Expression Regulation; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins
keywords: dementia; insulin resistance; senescence