The 28-amino acid form of an APLP1-derived Aβ-like peptide is a surrogate marker for Aβ42 production in the central nervous system

Surrogate markers for the Alzheimer disease (AD)-associated 42-amino acid form of amyloid-beta (A beta 42) have been sought because they may aid in the diagnosis of AD and for clarification of disease pathogenesis. Here, we demonstrate that human cerebrospinal fluid (CSF) contains three APLP1-derived A beta-like peptides (APL1 beta) that are generated by beta- and gamma-cleavages at a concentration of similar to 4.5 nM. These novel peptides, APL1 beta 25, APL1 beta 27 and APL1 beta 28, were not deposited in AD brains. Interestingly, most g-secretase modulators (GSMs) and familial AD-associated presenilin1 mutants that up-regulate the relative production of A beta 42 cause a parallel increase in the production of APL1 beta 28 in cultured cells. Moreover, in CSF from patients with pathological mutations in presenilin1 gene, the relative APL1 beta 28 levels are higher than in non-AD controls, while the relative A beta 42 levels are unchanged or lower. Most strikingly, the relative APL1 beta 28 levels are higher in CSF from sporadic AD patients (regardless of whether they are at mild cognitive impairment or AD stage), than those of non-AD controls. Based on these results, we propose the relative level of APL1 beta 28 in the CSF as a candidate surrogate marker for the relative level of A beta 42 production in the brain.