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

Abstract

The p3-Alcα is a metabolic fragment of Alcadeinα (Alcα). Like Alzheimer's amyloid β-protein precursor (AβPP) to generate p3 fragment, Alcα is cleaved by α-and γ-secretases to secrete p3-Alcα peptides in the cerebrospinal fluid (CSF). The p3-Alcα are also detected in the plasma as is amyloid-β (Aβ) which is a metabolic fragment of AβPP cleaved by an amyloidogenic β-and γ-secretases. Because p3-Alcα is a non-aggregatable and stable peptide, unlike aggregatable Aβ and metabolically labile p3 of AβPP, the changes of p3-Alcα in quality and/or quantity in CSF and plasma are expected as a marker for assessing alteration of substrate cleavage by γ-secretase such as Aβ generation from AβPP. The present study describes a sandwich enzyme-linked immunosorbent assay (sELISA) for quantifying levels of p3-Alcα35, the major form of the p3-Alcα species, and examines levels of p3-Alcα35 in the plasma of three independent Japanese cohorts. In two of the three cohorts, the p3-Alcα35 levels were significantly increased with a concomitant decrease in the mini mental state examination (MMSE) score, or in clinically diagnosed 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-Alcα35 levels may indicate an endophenotype in subjects in whom AD is due to a progressing cognitive impairment in subjects with a γ-secretase malfunction, or a disorder of the clearance of peptides.

Decrease in p3‐Alcβ37 and p3‐Alcβ40, products of Alcadein β generated by γ‐secretase cleavages, in aged monkeys and patients with Alzheimer's disease

“…This antibody reacts to all p3‐Alcβ species, but not p3‐Alcα and p3‐Alcγ peptides. In sELISA, Fab' fragments of affinity‐purified IgG of #826 were conjugated with horseradish peroxidase and used to detect the captured p3‐Alcβ with tetramethylbenzidine colorimetrically at OD 450 [27].…”

“…These lines of evidence suggest that the function and metabolism of Alcs are also closely involved in AD pathobiology. In this study, we validated new specific sandwich enzyme‐linked immunosorbent assay (sELISA) systems to specifically quantify p3‐Alcβ37 and p3‐Alcβ40 and quantified these peptides in human and monkey CSF, as investigated for p3‐Alcα in blood and CSF of patients with AD [26–28]. The results may provide important insight into the alteration of p3‐Alcβ levels in AD pathogenesis.…”

Decreased N-Acetyl Aspartate/Myo-Inositol Ratio in the Posterior Cingulate Cortex Shown by Magnetic Resonance Spectroscopy May Be One of the Risk Markers of Preclinical Alzheimer’s Disease: A 7-Year Follow-Up Study

“…Ideal screening methods for capturing subjects at risk of early MCI/AD or preclinical AD must be accessible, easy to perform, non-invasive and low-cost. Novel blood-based biomarkers for AD/MCI have been proposed as an alternative method; however, there are currently no verified blood-based biomarkers that are specific to AD/MCI [ 16–19 ].…”

Specific Triazine Herbicides Induce Amyloid-β42 Production

“…Triazines shift the cleavage pattern of alcadeinsα, another γ-secretase substrate [24][25][26][27][28], in a way similar to the AβPP cleavage shift, suggesting a direct effect on γ-secretase rather than on its substrates. Altogether these data support our hypothesis that the HCE contains products able to modulate γ-secretase activity towards the production of high MW, aggregation-prone, AD-associated amyloids.…”