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N-Terminally Truncated and Pyroglutamate-Modified Aβ Forms Are Measurable in Human Cerebrospinal Fluid and Are Potential Markers of Disease Progression in Alzheimer’s Disease

Authors :
Guido Domingo
Luisa Benussi
Claudia Saraceno
Michela Bertuzzi
Roland Nicsanu
Antonio Longobardi
Sonia Bellini
Alfredo Cagnotto
Mario Salmona
Giuliano Binetti
Roberta Ghidoni
Source :
Frontiers in Neuroscience, Vol 15 (2021)
Publication Year :
2021
Publisher :
Frontiers Media S.A., 2021.

Abstract

Alzheimer’s disease (AD) is a pathology characterized by the accumulation in the brain of intracellular and extracellular amyloid-β (Aβ) aggregates, especially of Aβ1–40 and Aβ1–42 peptides. It is known that N-terminally truncated or modified Aβ forms also exist in AD brains and cerebrospinal fluid (CSF), and they play a key role in the pathogenesis of the disease. Herein, we developed an antibody-free method based on Solid-Phase Extraction and Electrospray Ionization Liquid Chromatography Mass Spectrometry for the identification and quantitation in human CSF of Aβ isoforms. In human CSF, we could detect and quantify a panel of 19 Aβ isoforms, including N-terminally truncated and pyroglutamate-modified forms, never quantified before in CSF. Among these, we identified novel N-terminally truncated Aβ species: four bound to copper and two phosphorylated forms, which were found to be the most common proteoforms in human CSF along with Aβ1–40, Aβ3–40, and AβpE11–42. We tested the newly developed and validated method in a pilot study on CSF from elderly individuals with subjective memory complaints (SMCs, n = 9), mild cognitive impairment (MCI, n = 18), and AD (n = 15); along with Aβ1–42, five N-terminally truncated forms (Aβ11–40, Aβ3–42, AβpE11–42, AβpE3–40, and Aβ4–40 Cu2+) are altered in AD/MCI. Thus, we demonstrated that N-terminally truncated and pyroglutamate-modified Aβ can be quantified in human CSF, and five of them, along with Aβ1–42, are potential markers of AD progression. The described method could represent a useful tool for patients’ stratification and monitoring. Moreover, the newly identified Aβ CSF species might represent new potential therapeutic targets.

Details

Language :
English
ISSN :
1662453X
Volume :
15
Database :
Directory of Open Access Journals
Journal :
Frontiers in Neuroscience
Publication Type :
Academic Journal
Accession number :
edsdoj.12cc86340c14def8a5fb846b2682e52
Document Type :
article
Full Text :
https://doi.org/10.3389/fnins.2021.708119