Background: Aggregatable amyloid beta-peptide (A beta) and non-aggregatable p3-Alc alpha are metabolic products of the gamma-secretase cleavage of amyloid beta-protein precursor (APP) and Alcadein alpha (Alc alpha), respectively. Familial AD (FAD)-linked mutations in the presenilin 1 or 2 (PS1 or PS2) component of gamma-secretase can cause alternative intramembranous processing of APP and Alc alpha, leading to a coordinated generation of variants of both A beta and p3-Alc alpha. Variant Alc alpha peptides have been observed in the cerebrospinal fluid (CSF) of patients with mild cognitive impairment and sporadic Alzheimer's disease (AD). Since, like APP, Alc alpha is largely expressed in brain, one might predict that alternative processing of Alca would be reflected in body fluids of some AD patients. These patients with misprocessing of multiple gamma-secretase substrates might define an endophenotype of p3-Alc alpha, in whom AD is due either to dysfunction of gamma-secretase or to a disorder of the clearance of hydrophobic peptides such as those derived from transmembrane domains.
Results: We developed a simple procedure for extraction of p3-Alc alpha from plasma and for analyzing this extract in a sensitive, p3-Alc alpha-specific sandwich enzyme-linked immunosorbent assay (ELISA) system. Plasma p3-Alca levels and A beta 40 levels were examined in sporadic AD subjects from two independent Japanese cohorts. In some of these patients, levels of plasma p3-Alc alpha were significantly higher, and were accompanied by parallel changes in A beta 40 levels. This AD-related difference was more marked in female subjects, but this phenomenon was not observed in subjects with frontotemporal lobar degeneration (FTLD).
Conclusion: Reagents and procedures have been established that enable extraction of p3-Alc alpha from plasma and for quantification of plasma p3-Alc alpha levels by ELISA. Some populations of AD subjects apparently show increased levels of both p3-Alc alpha and A beta 40. Quantification of p3-Alc alpha level may be useful as a readily accessible biomarker for a population of sporadic AD patients in which disease pathogenesis is associated with either dysfunction of gamma-secretase or with a disorder of the clearance of transmembrane domain-derived peptides.