Aβ1-15/16 as a Potential Diagnostic Marker in Neurodegenerative Diseases

Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) reflect brain biochemistry. Using combined immunoprecipitation and mass spectrometry, we have shown that amyloid beta 1-15 (A beta 1-15) is produced by concerted beta- and alpha-secretase cleavage of amyloid precursor protein (APP) and that the relative levels of A beta 1-16 in AD compared to controls are increased. Furthermore, drug-induced gamma-secretase inhibition enhances the relative levels of A beta 1-15 and A beta 1-16. Here, we investigate a novel immunoassay for A beta 1-15/16 in a broad range of neurodegenerative conditions. The CSF level of A beta 1-15/16 was measured by the bead-based amplified luminescent proximity homogeneous assay (Alpha technology). Concentrations of A beta 1-15/16 were analyzed in subjects with Parkinson disease (PD; n = 90), PD with dementia (PDD) (n = 32), dementia with Lewy bodies (DLB) (n = 68), AD (n = 48), progressive supranuclear palsy (PSP) (n = 45), multiple system atrophy (MSA) (n = 46), and corticobasal degeneration (CBD) (n = 12). The detecting antibody is specific to the C-terminal epitope of A beta 15. We found that a carboxypeptidase (CPB) present in fetal bovine serum (FBS), a component of the buffers used, degrades A beta 1-16 to A beta 1-15, which is then detected by the A beta 1-15/16 assay. Significantly, lower levels of A beta 1-15/16 were detected in PD, PDD, PSP, and MSA compared to other neurodegenerative diseases and controls. Using the specific A beta 1-15/16 assay, a reliable quantification of A beta 1-15 or A beta 1-15/16 in CSF samples is obtained. We found reduced levels of A beta 1-15 in parkinsonian disease groups. The molecular mechanism behind this reduction is at present unknown.