Leucine-Rich α2-Glycoprotein Is a Novel Biomarker of Neurodegenerative Disease in Human Cerebrospinal Fluid and Causes Neurodegeneration in Mouse Cerebral Cortex

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.

LRG1 suppresses the migration and invasion of hepatocellular carcinoma cells

“…Levels of LRG1 expression were negatively correlated with FIGO (International Federation of Gynecology and Obstetrics) stage and lymphatic metastasis [19]. Besides, LRG1 expressions were different in certain kinds of tumors and many benign diseases from healthy subjects [12][13][14][15][16][17][18]. In this study, we first uncovered that the levels of LRG1 mRNA and protein were significantly downregulated in HCC tissues compared with their corresponding peritumoral tissues (Fig.…”

“…Serum LRG1 was upregulated in various kinds of benign diseases, such as suspected acute appendicitis of children [12], and activated ulcerative colitis [13]. It could be served as a diagnostic or prognostic biomarker for certain inflammatory conditions in hepatocytes like CRP [14] and neurodegeneration in mouse cerebral cortex [15]. Recently, accumulating evidences showed that LRG1 was closely correlated with various kinds of tumors such as ovarian cancer [16], gastric cancer [17], and non-small cell lung cancer [18].…”

Cerebrospinal fluid biomarkers for prognosis of long-term cognitive treatment outcomes in patients with idiopathic normal pressure hydrocephalus

“…We obtained lumbar CSF before and after LPS. All CSF samples were centrifuged to remove cells and debris, aliquoted, and stored in polypropylene tubes at − 80°C until biochemical analysis [18].…”

Alterations in glucose concentrations affect DNA methylation at Lrg1 in an ex vivo rat cortical slice model of preterm brain injury

“…We chose to focus on Lrg1, which encodes a protein involved in neovascularisation and angiogenesis and is distributed throughout the brain, particularly in the deep cerebral cortex, in astrocytes and their processes associated with blood vessels (Nakajima et al ., ; Miyajima et al ., ). Recent studies have demonstrated a potential role for Lrg1 in neuronal diseases; Lrg1 expression increases with age in both humans and mice (Miyajima et al ., ) and is increased further in cerebrospinal fluid and brain tissue of patients with Alzheimer's or Parkinson's disease with dementia (Miyajima et al ., ). Indeed, in humans, cognitive function declines with greater cerebrospinal fluid LRG1 concentrations (Miyajima et al ., ).…”

“…Recent studies have demonstrated a potential role for Lrg1 in neuronal diseases; Lrg1 expression increases with age in both humans and mice (Miyajima et al ., ) and is increased further in cerebrospinal fluid and brain tissue of patients with Alzheimer's or Parkinson's disease with dementia (Miyajima et al ., ). Indeed, in humans, cognitive function declines with greater cerebrospinal fluid LRG1 concentrations (Miyajima et al ., ). In mice, Lrg1 overexpression in glia and neurons results in early neuronal decline and neurodegeneration, supporting a role for Lrg1 in neuronal loss (Miyajima et al ., ).…”