Detection and quantification of Aβ−3–40 (APP669‐711) in cerebrospinal fluid

• Published in: Journal of neurochemistry Vol. 160; no. 5; pp. 578 - 589
• Main Authors: Klafki, Hans‐Wolfgang, Wirths, Oliver, Mollenhauer, Brit, Liepold, Thomas, Rieper, Petra, Esselmann, Hermann, Vogelgsang, Jonathan, Wiltfang, Jens, Jahn, Olaf
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.03.2022
• Subjects: Alzheimer Disease - cerebrospinal fluid; Alzheimer Disease - diagnostic imaging; Alzheimer's disease; Amyloid; Amyloid beta-Peptides - cerebrospinal fluid; Amyloid precursor protein; biomarker; Biomarkers; Biomarkers - cerebrospinal fluid; Blood plasma; Cerebrospinal fluid; Clinical trials; Humans; Immunoassay; Immunoprecipitation; Mass spectrometry; Mass spectroscopy; Neurodegenerative diseases; Peptide Fragments - cerebrospinal fluid; Peptides; Positron emission; Positron emission tomography; Statistical analysis; tau Proteins - cerebrospinal fluid; Tomography; β-Amyloid; mass spectrometry; biomarker; Alzheimer's disease; cerebrospinal fluid; immunoprecipitation; immunoassay
• ISSN: 0022-3042; 1471-4159; 1471-4159
• DOI: 10.1111/jnc.15571

Neurochemical biomarkers can support the diagnosis of Alzheimer’s disease and may facilitate clinical trials. In blood plasma, the ratio of the amyloid‐β (Aβ) peptides Aβ−3–40/Aβ1–42 can predict cerebral amyloid‐β pathology with high accuracy (Nakamura et al., 2018). Whether or not Aβ−3–40 (aka. amyloid precursor protein (APP) 669–711) is also present in cerebrospinal fluid (CSF) is not clear. Here, we investigated whether Aβ−3–40 can be detected in CSF and to what extent the CSF Aβ−3–40/Aβ42 ratio is able to differentiate between individuals with or without amyloid‐β positron emission tomography (PET) evidence of brain amyloid. The occurrence of Aβ−3–40 in human CSF was assessed by immunoprecipitation followed by mass spectrometry. For quantifying the CSF concentrations of Aβ−3–40 in 23 amyloid PET‐negative and 17 amyloid PET‐positive subjects, we applied a sandwich‐type immunoassay. Our findings provide clear evidence of the presence of Aβ−3–40 and Aβ−3–38 in human CSF. While there was no statistically significant difference in the CSF concentration of Aβ−3–40 between the two diagnostic groups, the CSF Aβ−3–40/Aβ42 ratio was increased in the amyloid PET‐positive individuals. We conclude that Aβ−3–40 appears to be a regular constituent of CSF and may potentially serve to accentuate the selective decrease in CSF Aβ42 in Alzheimer's disease. Cerebral amyloid‐β pathology can be predicted by the Aβ−3–40/Aβ1–42 peptide ratio in blood plasma (Nakamura et al., 2018, Nature 554, 249). However, it is still unclear whether Aβ−3–x peptides occur in cerebrospinal fluid (CSF). By immunoprecipitation‐mass spectrometry (IP‐MS), we show that Aβ−3–40 and Aβ−3–38 are regular constituents of CSF. The CSF Aβ−3–40/Aβ42 ratio, measured with a sandwich immunoassay, was found to be increased in individuals with positron emission tomography (PET) evidence of brain amyloid. Thus, CSF Aβ−3–40 may serve to accentuate the selective decrease in CSF Aβ42 in Alzheimer's disease.