Testing the link between isoaspartate and Alzheimer's disease etiology

Abstract

doi: bioRxiv preprint RESEARCH IN CONTEXT1. Systematic review: We reviewed the evidence that associates isoaspartate (isoAsp) residue in blood proteins with the etiology of Alzheimer's disease (AD). However, the link between isoAsp in blood and aggregation of amyloid beta (Aß) peptide and phosphorylated tau (pTau) protein in brain remained unclear. Interpretation:For the first time we demonstrate that isoAsp-containing human serum albumin (HSA) forms aggregates with reduced binding capacity toward Aß peptide and pTau protein. Using a novel ELISA, we discovered in AD blood elevated levels of isoAsp in HSA, together with reduced endogenous anti-isoAsp antibody levels, suggesting hampered Aß and pTau clearance in AD. Future directions:As degradation of the innate anti-isoAsp defenses may take years to develop, investigation of the isoAsp role in early stages of AD is warranted. And enrollment of different neurodegenerative disease cohorts will illustrate if isoAsp is AD-specific or universal to diseases related to aging.

Deamidation-related blood biomarkers show promise for early diagnostics of neurodegeneration

“…1A) and the de ciency of IgGs against deamidated HSA in AD blood compared to controls (Fig. 1B), validating the results from Amsterdam cohort [17]. The normalized signals re ecting the isoAsp level in plasma HSA were increased by 9% on average (P < 0.0001) while the average signal of anti-aHSA IgG was lower by 6% (P < 0.0001) in AD patients compared to healthy donors.…”

“…The IgG antibodies were puri ed from plasma using the Melon Gel IgG Puri cation Kit (Thermo Fisher Scienti c, San Diego, CA, USA). To determine in each sample the amount of IgG against aged HSA (aHSA, ≈ 60% isoAsp), the puri ed IgG antibodies were used as the primary antibody in the indirect ELISA [17], while the secondary antibody was Goat anti-Human IgG (H + L) Secondary Antibody conjugated with HRP (Thermo Fisher Scienti c, San Diego, CA, USA). To eliminate the effect of sample location on the plate, the data were normalized by the average reading in each row and column.…”

“…Our recent ndings have strengthened the link between isoAsp and AD pathology [17]. Using a novel enzyme-linked immunosorbent assay (ELISA) [18], we discovered that the accumulation of isoAsp in human serum albumin (HSA) leads to a diminished HSA capacity to carry Aß and pTau, and thus to clear these damaging molecules in the blood circulatory system, which has been recognized as a major contributor to their accumulation in brain [19].…”

“…Using a novel enzyme-linked immunosorbent assay (ELISA) [18], we discovered that the accumulation of isoAsp in human serum albumin (HSA) leads to a diminished HSA capacity to carry Aß and pTau, and thus to clear these damaging molecules in the blood circulatory system, which has been recognized as a major contributor to their accumulation in brain [19]. By studying an Amsterdam cohort, we have found that isoAsp levels in HSA strongly correlate with AD [17]. Furthermore, native immunoglobulins (IgGs) speci c to deamidated HSA that could protect the human organism from the damaging effect of deamidation have been found signi cantly reduced in AD [17].…”

“…By studying an Amsterdam cohort, we have found that isoAsp levels in HSA strongly correlate with AD [17]. Furthermore, native immunoglobulins (IgGs) speci c to deamidated HSA that could protect the human organism from the damaging effect of deamidation have been found signi cantly reduced in AD [17]. However, questions remained related to the performance of these biomarkers in non-Caucasian patients, speci city to AD of these biomarkers, and their ability to detect early disease stages.…”