Tandem mass spectrometry-based identification of protein profiles in the cerebrospinal fluid of Alzheimer’s dementia patients

Abstract

Background: Alzheimer’s disease (AD) is the most common form of dementia and about two thirds cases are diagnosed late due to a long asymptomatic phase. There exists the need for newer biomarkers which can add accuracy to AD diagnosis, detect AD at an early stage, as also lend new pathogenic insights into AD. Recent AD biomarker discovery has focused on proteomic approaches, especially in the cerebrospinal fluid. Methods: We used a bottom-up proteomic approach. Cerebrospinal fluid (CSF) samples from 6 patients with AD and 6 controls were digested with trypsin and analyzed by using LC-MS/MS (tandem mass spectrometry). The peptide data from CSF samples of both AD and control groups was then subjected to bioinformatics analysis with STRING version 11.0. Protein-protein interaction networks were constructed, and enrichment analysis performed.Results: Significant up-regulation of 13 proteins in the CSF was observed in AD cases in comparison to controls, while 30 proteins were down-regulated. APOE and LGALS3BP were the upregulated proteins involved in closed network and the downregulated proteins were F2, PENK, IGF2, APOH, SAA1, AHSG, SPP1 and CD44. APOE, APOH, F2 and PENK shared common involvement in multiple biological processes as evident on enrichment. Regulation of insulin like growth factor involving IGF2, F2, APOE and AHSG and glycosaminoglycan binding involving APOE, APOH, F2, SAA1, and CD44 were major pathways of interest determined on bioinformatic analysis.Conclusion: Our study identified novel tentative biomarkers of AD which included F2, PENK and SAA1, as well as reinforced earlier described biomarkers such as APOE and AHSG. These findings need to be validated in larger sample sizes to evaluate their utility as true biomarkers. Further, the pathways of interest- insulin like growth factor regulation and glycosaminoglycan binding need to be studied further in the context of AD.

Role of Apolipoproteins in Neurodegenerative Diseases

“…However, in a proteomic study using CSF samples from Alzheimer's patients and controls, it was reported that a significant decrease in the amount of apoH was detected in the CSF of Alzheimer's patients compared to controls (Misra et al, 2021).…”

“…Intestine, liver, brain, spleen, kidney, adrenals and other (Dominiczak & Caslake, 2011) Chylomicron remnants, mature VLDL, VLDL remnants, LDL and HDL (Dominiczak & Caslake, 2011) Alzheimer's disease (Farrer et al, 1997;Hong et al, 2020;Koizumi et al, 2018) Parkinson's disease (Mata et al, 2014;Real et al, 2023;Tsuang et Liver (Leduc et al, 2008) Chylomicron, VLDL (Nakaya et al, 1980) Alzheimer's disease (Misra et al, 2021;Öhrfelt et al, 2011) ApoJ (Clusterin/CLU) Testis, prostate, brain (Vitali et al, 2014) HDL (Vitali et al, 2014) Alzheimer's disease (Calero et al, 2000;Foster et al, 2019;Zlokovic et al, 1996) Parkinson's disease (Lenzi et al, 2020;Lin et al, 2021;Maarouf et al, 2012;Přikrylová Vranová et al, 2010;Zhang et al, 2012) Multiple sclerosis (van Luijn et al, 2016) the brain is absorbed by the blood-brain barrier as lipoprotein-bound cholesterol (Balazs et al, 2004;Vitali et al, 2014). Atherosclerotic changes can occur in the entire vascular system, including the blood vessels associated with the brain (Tóth et al, 2020).…”

“…Apolipoprotein H (apoH, beta-2-glycoprotein 1), which prevents the activation of blood coagulation, is a lipid-binding protein (Misra et al, 2021). In one study, it was stated that the amount of apoH was significantly increased in CSF samples of those with moderate to severe AD (Öhrfelt et al, 2011).…”