TY - JOUR
T1 - Testing the link between isoaspartate and Alzheimer's disease etiology
AU - Wang, Jijing
AU - Guo, Cong
AU - Meng, Zhaowei
AU - Zwan, Marissa D.
AU - Chen, Xin
AU - Seelow, Sven
AU - Lundström, Susanna L.
AU - Rodin, Sergey
AU - Teunissen, Charlotte E.
AU - Zubarev, Roman A.
N1 - Funding Information: This work has been supported by China Scholarship Council (KI‐CSC), Horizon 2020 project TopSpec, National Natural Science Foundation of China (Grant 11804218), Zorgonderzoek Nederland medische wetenschappen (ZonMw‐Memorabel, project no. 73305095003; a project in the context of the Dutch Deltaplan Dementie), Gieskes‐Strijbis Foundation, Alzheimer Nederland (Dutch Alzheimer's Society), Hersenstichting (Dutch Brain Foundation), and Ministry of Science and Higher Education of the Russian Federation (agreement no. 075‐15‐2020‐899). Publisher Copyright: © 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
PY - 2022
Y1 - 2022
N2 - Isoaspartate (isoAsp) is a damaging amino acid residue formed in proteins as a result of spontaneous deamidation. IsoAsp disrupts protein structures, making them prone to aggregation. Here we strengthened the link between isoAsp and Alzheimer's disease (AD) by novel approaches to isoAsp analysis in human serum albumin (HSA), the most abundant blood protein and a major carrier of amyloid beta (Aβ) and phosphorylated tau (p-tau) in blood. We discovered a reduced amount of anti-isoAsp antibodies (P < 0.0001), an elevated isoAsp level in HSA (P < 0.001), more HSA aggregates (P < 0.0001), and increased levels of free Aβ (P < 0.01) in AD blood compared to controls. We also found that deamidation significantly reduces HSA capacity to bind with Aβ and p-tau (P < 0.05). These suggest the presence in AD of a bottleneck in clearance of Aβ and p-tau, leading to their increased concentrations in the brain and facilitating their aggregations there.
AB - Isoaspartate (isoAsp) is a damaging amino acid residue formed in proteins as a result of spontaneous deamidation. IsoAsp disrupts protein structures, making them prone to aggregation. Here we strengthened the link between isoAsp and Alzheimer's disease (AD) by novel approaches to isoAsp analysis in human serum albumin (HSA), the most abundant blood protein and a major carrier of amyloid beta (Aβ) and phosphorylated tau (p-tau) in blood. We discovered a reduced amount of anti-isoAsp antibodies (P < 0.0001), an elevated isoAsp level in HSA (P < 0.001), more HSA aggregates (P < 0.0001), and increased levels of free Aβ (P < 0.01) in AD blood compared to controls. We also found that deamidation significantly reduces HSA capacity to bind with Aβ and p-tau (P < 0.05). These suggest the presence in AD of a bottleneck in clearance of Aβ and p-tau, leading to their increased concentrations in the brain and facilitating their aggregations there.
KW - Alzheimer's disease (AD)
KW - aging
KW - blood analysis
KW - deamidation
KW - enzyme-linked immunosorbent assay (ELISA)
KW - human serum albumin (HSA)
KW - in vitro diagnostics
KW - mass spectrometry
KW - protein aggregation
UR - http://www.scopus.com/inward/record.url?scp=85135529336&partnerID=8YFLogxK
U2 - https://doi.org/10.1002/alz.12735
DO - https://doi.org/10.1002/alz.12735
M3 - Article
C2 - 35924765
SN - 1552-5260
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
ER -