AUTHOR=Domingo Guido , Benussi Luisa , Saraceno Claudia , Bertuzzi Michela , Nicsanu Roland , Longobardi Antonio , Bellini Sonia , Cagnotto Alfredo , Salmona Mario , Binetti Giuliano , Ghidoni Roberta 

TITLE=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

JOURNAL=Frontiers in Neuroscience

VOLUME=Volume 15 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2021.708119

DOI=10.3389/fnins.2021.708119

ISSN=1662-453X

ABSTRACT=Alzheimer’s disease (AD) is a pathology characterized by the accumulation in brain of intra- 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 brain 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: 4 bound to copper and 2 phosphorylated forms, which resulted 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 complains (SMCs, n=9), Mild Cognitive Impairment (MCI, n=18) and AD patients (n=15); along with Aβ1-42, 5 N-truncated forms (Aβ11-40, Aβ3-42, AβpE11-42, AβpE3-40, Aβ4-40 Cu2+) are altered in AD/MCI. Thus, we demonstrated that N-truncated and pyroglutamate-modified Aβ can be quantified in human CSF and 5 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.