Testing the link between isoaspartate and Alzheimer's disease etiology

Abstract

Isoaspartate (isoAsp) is a damaging amino acid residue formed in proteins as a result of spontaneous deamidation. IsoAsp disrupts the secondary and higher order structures of proteins, damaging their functions and making them prone to aggregation. An association has been suggested between isoAsp and Alzheimers Disease (AD). Here we strengthened the link between isoAsp and AD by novel approaches to isoAsp analysis in blood human serum albumin (HSA), the most abundant blood protein, a major carrier of amyloid beta (A{beta}) peptide and phosphorylated tau (pTau) protein in blood and a key participant in their clearance pathway. We discovered a reduced amount of anti-isoAsp antibodies (P < .0001), an elevated isoAsp level in HSA (P < .001), more HSA aggregates (P < .0001) and increased levels of free A{beta} (P < .01) in AD blood compared to healthy controls. We also found that deamidation significantly reduces HSA capacity to bind with A{beta} and pTau (P < .05). These findings support the presence in AD of a bottleneck in clearance of A{beta} and pTau leading to their increased concentrations in brain and facilitating their aggregations there. RESEARCH IN CONTEXTO_LISystematic review: We reviewed the evidence that associates isoaspartate (isoAsp) residue in blood proteins with the etiology of Alzheimers disease (AD). However, the link between isoAsp in blood and aggregation of amyloid beta (A{beta}) peptide and phosphorylated tau (pTau) protein in brain remained unclear. C_LIO_LIInterpretation: For the first time we demonstrate that isoAsp-containing human serum albumin (HSA) forms aggregates with reduced binding capacity toward A{beta} 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 A{beta} and pTau clearance in AD. C_LIO_LIFuture 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. C_LI O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY