Leucine-rich α2-glycoprotein is a novel biomarker of neurodegenerative disease in human cerebrospinal fluid and causes neurodegeneration in mouse cerebral cortex

PLoS One. 2013 Sep 18;8(9):e74453. doi: 10.1371/journal.pone.0074453. eCollection 2013.

Abstract

Leucine-rich α2-glycoprotein (LRG) is a protein induced by inflammation. It contains a leucine-rich repeat (LRR) structure and easily binds with other molecules. However, the function of LRG in the brain during aging and neurodegenerative diseases has not been investigated. Here, we measured human LRG (hLRG) concentration in the cerebrospinal fluid (CSF) and observed hLRG expression in post-mortem human cerebral cortex. We then generated transgenic (Tg) mice that over-expressed mouse LRG (mLRG) in the brain to examine the effects of mLRG accumulation. Finally, we examined protein-protein interactions using a protein microarray method to screen proteins with a high affinity for hLRG. The CSF concentration of hLRG increases with age and is significantly higher in patients with Parkinson's disease with dementia (PDD) and progressive supranuclear palsy (PSP) than in healthy elderly people, idiopathic normal pressure hydrocephalus (iNPH) patients, and individuals with Alzheimer's disease (AD). Tg mice exhibited neuronal degeneration and neuronal decline. Accumulation of LRG in the brains of PDD and PSP patients is not a primary etiological factor, but it is thought to be one of the causes of neurodegeneration. It is anticipated that hLRG CSF levels will be a useful biomarker for the early diagnosis of PDD and PSP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aging / cerebrospinal fluid
  • Aging / pathology
  • Animals
  • Area Under Curve
  • Autopsy
  • Biomarkers / cerebrospinal fluid
  • Brain / pathology
  • Cell Line
  • Cerebral Cortex / metabolism*
  • Cerebral Cortex / pathology*
  • Demography
  • Female
  • Glycoproteins / cerebrospinal fluid*
  • Glycoproteins / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Nerve Degeneration / cerebrospinal fluid*
  • Nerve Degeneration / diagnosis
  • Neurodegenerative Diseases / cerebrospinal fluid*
  • Neurodegenerative Diseases / diagnosis
  • Protein Binding

Substances

  • Biomarkers
  • Glycoproteins
  • LRG1 protein, human
  • LRG1 protein, mouse

Grants and funding

This work was partly supported by Grants-in-Aid for Scientific Research (KAKENHI 23592106, 23592142). MN is funded by a Grant-in-Aid for Scientific Research (KAKENHI 23592106). M. Miyajima is funded by a Grant-in-Aid for Scientific Research (KAKENHI 23592142). HA is funded by a Research Grant from the Ministry of Health, Labour, and Welfare of Japan (2012-Nanchi). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.