TY - JOUR
T1 - Human cerebrospinal fluid 6E10- immunoreactive protein species contain amyloid precursor protein fragments
AU - Grant, Marianne K.O.
AU - Handoko, Maureen
AU - Rozga, Malgorzata
AU - Brinkmalm, Gunnar
AU - Portelius, Erik
AU - Blennow, Kaj
AU - Ashe, Karen H.
AU - Zahs, Kathleen R.
AU - Liu, Peng
N1 - Publisher Copyright:
© 2019 Grant et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2019/2
Y1 - 2019/2
N2 - In a previous study, we reported that levels of two types of protein species-a type of ∼55- kDa species and a type of ∼15-kDa species-are elevated in the lumbar cerebrospinal fluid (CSF) of cognitively intact elderly individuals who are at risk for Alzheimer's disease (AD). These species are immunoreactive to the monoclonal antibody 6E10, which is directed against amino acids 6-10 of amyloid-β (Aβ), and their levels correlate with levels of total tau and tau phosphorylated at Thr181. In this study, we investigated the molecular composition of these AD-related proteins using immunoprecipitation (IP)/Western blotting coupled with IP/mass spectrometry. We show that canonical Aβ 1-40/42 peptides, together with amyloid-β precursor protein (APP) fragments located N-terminally of Aβ, are present in the ∼55-kDa, 6E10-immunoreactive species. We demonstrate that APP fragments located N-terminally of Aβ, plus the N-terminal region of Aβ, are present in the ∼15-kDa, 6E10-immunoreactive species. These findings add to the catalog of AD-related Aβ/APP species found in CSF and should motivate further study to determine whether these species may serve as biomarkers of disease progression.
AB - In a previous study, we reported that levels of two types of protein species-a type of ∼55- kDa species and a type of ∼15-kDa species-are elevated in the lumbar cerebrospinal fluid (CSF) of cognitively intact elderly individuals who are at risk for Alzheimer's disease (AD). These species are immunoreactive to the monoclonal antibody 6E10, which is directed against amino acids 6-10 of amyloid-β (Aβ), and their levels correlate with levels of total tau and tau phosphorylated at Thr181. In this study, we investigated the molecular composition of these AD-related proteins using immunoprecipitation (IP)/Western blotting coupled with IP/mass spectrometry. We show that canonical Aβ 1-40/42 peptides, together with amyloid-β precursor protein (APP) fragments located N-terminally of Aβ, are present in the ∼55-kDa, 6E10-immunoreactive species. We demonstrate that APP fragments located N-terminally of Aβ, plus the N-terminal region of Aβ, are present in the ∼15-kDa, 6E10-immunoreactive species. These findings add to the catalog of AD-related Aβ/APP species found in CSF and should motivate further study to determine whether these species may serve as biomarkers of disease progression.
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U2 - 10.1371/journal.pone.0212815
DO - 10.1371/journal.pone.0212815
M3 - Article
C2 - 30817799
AN - SCOPUS:85062329123
SN - 1932-6203
VL - 14
JO - PloS one
JF - PloS one
IS - 2
M1 - e0212815
ER -