Correlations between soluble α/β forms of amyloid precursor protein and Aβ38, 40, and 42 in human cerebrospinal fluid

Cerebrospinal fluid (CSF) biomarkers are now widely used for diagnosis of Alzheimer disease (AD) in atypical clinical forms, for differential and early diagnosis, or for stratification of patients in clinical trials. Among these biomarkers, different forms of amyloid peptides (A beta) produced by the cleavage of a transmembrane precursor protein called APP (amyloid precursor protein) have a major role. A beta peptides exist in different length the most common ones having 40 (A beta 40), 42 (A beta 42), or 38 (A beta 38) amino acids in length. APP processing by gamma-secretase releases also an amino-terminal secreted fragment called sA beta PP-beta while an alternative nonamyloidogenic cleavage of APP, through an alpha-secretase, liberates another fragment called sA beta PP-alpha. To decipher the molecular and pathological mechanisms leading to the production and the detection of these entities is essential for the comprehension and the prevention of AD. In this report, we present the results of the multiplex measurement of CSF A beta 38, A beta 40, A beta 42, sA beta PP-alpha, and sA beta PP-beta in 60 patients mostly with dementia eventually segregated between neurochemical dementia diagnostic (NDD) positive and negative groups. The NDD classification was based on our routine Tau, P-tau(181), and A beta(42) cutoff values. We confirmed previous findings regarding the correlation between sA beta PP-alpha and sA beta PP-beta, as well as the potential interest of these new biomarkers. We also studied the correlation between sA beta PPs and A beta peptides, as well as between A beta peptides themselves. We observed a strong correlation between A beta 38 and sA beta PP-beta which suggested that the production of this peptide was in direct relation with beta secretase activities. We also reported a strong correlation between A beta 38 and A beta 40, while A beta 42 was correlated to these fragments only in nonpathological situations. These results enlighten the complex relationships between these molecular markers in both physiological and pathological situations. Our results are important for the further use of these analytes for AD diagnosis as well as for validating the cell biological hypotheses of APP processing and A beta fragment production. (C) 2010 Elsevier B.V. All rights reserved.