Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer's disease

Dimitrios Kapogiannis, Adam Boxer, Janice B. Schwartz, Erin L. Abner, Arya Biragyn, Umesh Masharani, Lynda Frassetto, Ronald Carl Petersen, Bruce L. Miller, Edward J. Goetzl

Research output: Contribution to journalArticle

124 Citations (Scopus)

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-pantyrosine-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.

Original languageEnglish (US)
Pages (from-to)589-596
Number of pages8
JournalFASEB Journal
Volume29
Issue number2
DOIs
StatePublished - Feb 1 2015

Fingerprint

Exosomes
Insulin Receptor Substrate Proteins
Alzheimer Disease
Blood
Frontotemporal Dementia
Serine
Insulin Resistance
Insulin
Tyrosine
Brain
R Factors
Insulin Receptor
Hematologic Tests
Medical problems
Type 2 Diabetes Mellitus
Longitudinal Studies
Enzyme-Linked Immunosorbent Assay
Tissue

Keywords

  • Dementia
  • Insulin resistance
  • Senescence

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Kapogiannis, D., Boxer, A., Schwartz, J. B., Abner, E. L., Biragyn, A., Masharani, U., ... Goetzl, E. J. (2015). Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer's disease. FASEB Journal, 29(2), 589-596. https://doi.org/10.1096/fj.14-262048

Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer's disease. / Kapogiannis, Dimitrios; Boxer, Adam; Schwartz, Janice B.; Abner, Erin L.; Biragyn, Arya; Masharani, Umesh; Frassetto, Lynda; Petersen, Ronald Carl; Miller, Bruce L.; Goetzl, Edward J.

In: FASEB Journal, Vol. 29, No. 2, 01.02.2015, p. 589-596.

Research output: Contribution to journalArticle

Kapogiannis, D, Boxer, A, Schwartz, JB, Abner, EL, Biragyn, A, Masharani, U, Frassetto, L, Petersen, RC, Miller, BL & Goetzl, EJ 2015, 'Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer's disease', FASEB Journal, vol. 29, no. 2, pp. 589-596. https://doi.org/10.1096/fj.14-262048
Kapogiannis, Dimitrios ; Boxer, Adam ; Schwartz, Janice B. ; Abner, Erin L. ; Biragyn, Arya ; Masharani, Umesh ; Frassetto, Lynda ; Petersen, Ronald Carl ; Miller, Bruce L. ; Goetzl, Edward J. / Dysfunctionally phosphorylated type 1 insulin receptor substrate in neural-derived blood exosomes of preclinical Alzheimer's disease. In: FASEB Journal. 2015 ; Vol. 29, No. 2. pp. 589-596.
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