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.
Highlights
The activation of inflammatory pathways in the brain is increasingly emphasized as a major risk factor for the development and progression of neurodegenerative disease [1,2,3]
cerebrospinal fluid (CSF) human LRG (hLRG) concentrations were negatively correlated with the MMSE score (r = -0.271, p = 0.003, n = 115) using Spearman rank correlation (Figure 1C)
We noted a significant increase in the number of Leucine-rich α2-glycoprotein (LRG)-positive cells in Parkinson’s disease with dementia (PDD) and progressive supranuclear palsy (PSP) as compared to that in normal control (NC) (p < 0.001) and idiopathic normal pressure hydrocephalus (iNPH) (p < 0.001) (Figure 2D)
Summary
The activation of inflammatory pathways in the brain is increasingly emphasized as a major risk factor for the development and progression of neurodegenerative disease [1,2,3]. Long-term use of anti-inflammatory drugs reduces the risk of Alzheimer’s disease (AD) and Parkinson’s disease (PD) [4,5,6], and animal studies have provided additional support for this hypothesis [7,8,9]. Leucine-rich α2-glycoprotein (LRG) was first identified as a trace protein in human serum in 1977 [11]. This 24-amino acid consensus sequence, termed the leucine-rich repeat (LRR), has since been identified in a large family of proteins [12]. Like C-reactive protein (CRP), LRG might serve as a diagnostic biomarker in some inflammatory conditions
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