Human cerebrospinal fluid 6E10-immunoreactive protein species contain amyloid precursor protein fragments

In a previous study, we reported that levels of two types of protein species-a type of similar to 55kDa species and a type of similar to 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-beta (A beta), 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 A beta(1-40/42) peptides, together with amyloid-beta precursor protein (APP) fragments located N-terminally of A beta, are present in the similar to 55-kDa, 6E10-immunoreactive species. We demonstrate that APP fragments located N-terminally of A beta, plus the N-terminal region of A beta, are present in the similar to 15-kDa, 6E10-immunoreactive species. These findings add to the catalog of AD-related A beta/APP species found in CSF and should motivate further study to determine whether these species may serve as biomarkers of disease progression.