Interrelations of Alzheimer´s disease candidate biomarkers neurogranin, fatty acid‐binding protein 3 and ferritin to neurodegeneration and neuroinflammation

• Published in: Journal of neurochemistry Vol. 157; no. 6; pp. 2210 - 2224
• Main Authors: Brosseron, Frederic, Kleemann, Kilian, Kolbe, Carl‐Christian, Santarelli, Francesco, Castro‐Gomez, Sergio, Tacik, Pawel, Latz, Eicke, Jessen, Frank, Heneka, Michael T.
• Format: Journal Article
• Language: English
• Published: New York Blackwell Publishing Ltd 01.06.2021
• Subjects: Alzheimer's disease; Alzheimer´s disease; Apolipoprotein E; biomarker; Biomarkers; Cell adhesion; Cell adhesion molecules; Cerebrospinal fluid; Damage; Fatty acid-binding protein; Fatty acids; Ferritin; Growth factors; Inflammation; Inflammatory response; Isoforms; Leukocyte migration; Macrophage migration inhibitory factor; Neurodegeneration; Neurodegenerative diseases; Neurogranin; neuroinflammation; Proteins; Psychiatry; Tau protein; Vascular cell adhesion molecule 1; Vascular endothelial growth factor
• ISSN: 0022-3042; 1471-4159; 1471-4159
• DOI: 10.1111/jnc.15175

There is growing evidence that promising biomarkers of inflammation in Alzheimer´s disease (AD) and other neurodegenerative diseases correlate strongest to levels of tau or neurofilament, indicating an inflammatory response to neuronal damage or death. To test this hypothesis, we investigated three AD candidate markers (ferritin, fatty acid binding protein 3 (FABP‐3), and neurogranin) in interrelation to established AD and inflammatory protein markers. We further aimed to determine if such interrelations would be evident in pathological subjects only or also under non‐pathological circumstances. Cerebrospinal fluid levels of the three proteins were quantified in samples from the University Clinic of Bonn (UKB) Department of Neurodegenerative Diseases & Geriatric Psychiatry, Germany. Data were analyzed based on clinical or biomarker‐defined stratification of subjects with adjustment for covariates age, sex, and APOE status. Levels of ferritin, FABP‐3 and neurogranin were elevated in subjects with pathological levels of t‐tau independent of beta‐amyloid status. The three markers correlated with each other, tau isoforms, age, and those inflammatory markers previously described as related to neurodegeneration, predominantly sTREM2, macrophage migration inhibitory factor, soluble vascular endothelial growth factor receptor, soluble vascular cell adhesion molecule 1 (sVCAM‐1), and C1q. These interrelations existed in subjects with pathological and sub‐pathological tau levels, in particular for FABP‐3 and neurogranin. Relations to ferritin were independent of absolute levels of tau, too, but showed differing trajectories between pathological and non‐pathological subjects. A specific set of inflammatory markers is highly related to markers of neuronal damage such as tau, neurogranin, or FABP‐3. These proteins could be used as readouts of the inflammatory response during the neurodegeneration phase of AD. Alzheimer´s disease candidate biomarkers ferritin, fatty acid‐binding protein 3 (FABP‐3), and neurogranin (RED) were tested in cerebrospinal fluid for their relation to inflammatory markers (PURPLE), classical AD biomarkers (ORANGE) and covariates (BLUE) using samples & data from the University Clinic of Bonn (UKB) Department of Neurodegenerative Diseases & Geriatric Psychiatry, Germany. The three candidate proteins represent neurodegeneration markers independent of subject’s amyloid status and correlate strongest to those inflammation markers that are likely to represent the inflammatory response to neurodegeneration, such as sTREM2, MIF, sVEGF‐R, sVCAM‐1, and C1q.