Increased Levels of Plasma p3-Alcα35, a Major Fragment of Alcadeinα by γ-Secretase Cleavage, in Alzheimer's Disease

p3-Alc alpha is a metabolic fragment of Alcadein alpha (Alc alpha). Similar to the generation of the p3 fragment from amyloid-beta protein precursor (A beta PP) processing, Alc alpha is cleaved by alpha- and gamma-secretases, leading to the secretion of p3-Alc alpha peptides into cerebrospinal fluid (CSF). p3-Alc alpha is also detected in the plasma, similar to amyloid-beta (A beta), which is a metabolic fragment of A beta PP cleaved by amyloidogenic beta- and gamma-secretases. Because p3-Alc alpha is a non-aggregatable and stable peptide, unlike aggregatable A beta and metabolically labile p3 of A beta PP, the changes of p3-Alc alpha in quality and/or quantity in CSF and plasma are expected to be a marker for assessing alteration of substrate cleavage by gamma-secretase, such as A beta generation from A beta PP. The present study describes a sandwich enzyme-linked immunosorbent assay for quantifying levels of p3-Alc alpha 35, the major form of the p3-Alc alpha species, and examines levels of p3-Alc alpha 35 in the plasma of three independent Japanese cohorts. In two of the three cohorts, the p3-Alc alpha 35 levels were significantly increased with a concomitant decrease in the Mini-Mental State Examination score, or in clinically diagnosed Alzheimer's disease (AD) patients, when compared with age-matched non-demented subjects. The values were significantly lower in AD subjects who were administered donepezil, when compared to AD subjects without donepezil treatment. The increase in plasma p3-Alc alpha 35 levels may indicate an endophenotype in subjects in whom AD is due to a progressing cognitive impairment in subjects with a gamma-secretase malfunction, or a disorder of the clearance of peptides.