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

Abstract

Background The strongest risk factor of neurodegenerative diseases (NDDs) is aging. Spontaneous asparaginyl deamidation leading to formation of isoaspartate (isoAsp) has been correlated with protein aggregation in NDDs. Methods Two cohorts consisting of 140 subjects were studied. Cohort 1 contained patients with AD and healthy controls, while Cohort 2 recruited subjects with mild cognitive impairment (MCI), vascular dementia (VaD), frontotemporal dementia (FTD), Parkinson’s disease (PD) and healthy controls. The levels of isoAsp in plasma human albumin (HSA), the most abundant protein in plasma, as well as the levels of immunoglobulin G (IgG) specific against deamidated HSA were measured. Apart from the memory tests, plasma biomarkers for NDDs reported in literature were also quantified, including amyloid beta (Aβ) peptides Aβ40 and Aβ42, neurofilament light protein (NfL), glial fibrillary acidic protein (GFAP) and phosphorylated tau 181 (p-tau181) protein. Results Deamidation products of blood albumin were significantly elevated in vascular dementia and frontotemporal dementia (P < 0.05), but less so in PD. Intriguingly, the deamidation levels were significantly (P < 0.01) associated with the memory test scores for all tested subjects. Deamidation biomarkers performed superiorly (accuracy up to 92%) compared with blood biomarkers Aß42/Aß40, NfL, GFAP and p-tau181 in separating mild cognitive impairment from healthy controls. Conclusion We demonstrated the diagnostic capacity of deamidation-related biomarkers in predicting NDDs at the early stage of disease, and the biomarker levels significantly correlated with cognitive decline, strongly supporting the role of deamidation in triggering neurodegeneration and early stages of disease development. Prospective longitudinal studies with a longer observation period and larger cohorts should provide a more detailed picture of the deamidation role in NDD progression.

SpotLight proteomics identifies variable sequences of blood antibodies specific against deamidated human serum albumin

“…It has been hypothesized that a bottleneck in this clearance process, resulting in accumulation of deamidated proteins in blood, can trigger neurodegeneration. This hypothesis has been strengthened in the recent studies [20,27] in which the IgG levels of antibodies against aHSA were found to be significantly reduced in patients with AD, MCI and VaD compared to healthy donors.…”

“…Previously, we have shown that Fc-glycosylation patterns of pAbs of AD patients differ from those in healthy controls with a lower abundance of complex galactosylated and sialylated forms in AD [20]. Now we investigated whether the IgG Fc-glycosylation pattern would be different between pAbs enriched against fHSA and aHSA.…”

“…Deamidation, if left unchecked, sets in motion a protein aggregation cascade that can ultimately lead to deteriorated health, ageing and neurodegeneration [15][16][17][18]. IsoAsp in blood proteins is therefore a risk factor for, e.g., AD [19] and other neurodegenerative diseases [20].…”

“…However, the level of such pAbs in AD was found to be significantly diminished [15]. To test whether this is a common phenomenon in neurodegeneration, we have in a recent study purified IgGs from plasma samples of patients with AD, mild cognitive decline (MCI), frontotemporal dementia (FTD), vascular dementia (VaD), Parkinson's disease (PD) and healthy controls (total n = 180) [20]. Using the artificially aged HSA (aHSA, isoAsp level ~ 60%) as an antigen, we have compared the levels of the IgGs against aHSA in these different disease groups with healthy donors.…”

SOBA (soluble oligomer binding assay): A breakthrough or the early diagnosis of Alzheimer's disease

“…As a result, patients with neurodegenerative diseases (NDDs), including AD, had higher levels of isoAsp in their serum albumin. 11 This provides the foundation of an additional diagnostic technique for the early detection of NDDs. Therefore, future studies should employ a multimodal strategy that combines the SOBA technique with deamidation biomarker analysis, which can significantly improve the reliability and sensitivity of this strategy for early detection in at-risk or asymptomatic individuals.…”