TY - JOUR
T1 - Serum levels of 4-hydroxynonenal adducts and responding autoantibodies correlate with the pathogenesis from hyperglycemia to Alzheimer's disease
AU - Renuka Sanotra, Monika
AU - Huang, Wen Chung
AU - Silver, Simon
AU - Lin, Ching Yu
AU - Chang, Tsuei Chuan
AU - Nguyen, Doan Phuong Quy
AU - Lee, Ching Kuo
AU - Kao, Shu Huei
AU - Chang-Cheng Shieh, Jonathan
AU - Lin, Yung Feng
N1 - Funding Information:
This work was supported by the Ministry of Science and Technology, Taiwan R.O.C. (MOST108-2622-B-038-001-CC2). LTQ-Orbitrap Velos™ data were acquired at the Academia Sinica Common Mass Spectrometry Facilities for Proteomics and Protein Modification Analysis located at the Institute of Biological Chemistry, Academia Sinica, supported by Academia Sinica Core Facility and Innovative Instrument Project (AS-CFII-108-107). The authors thank Mr. Ronald Ling in Academia Sinica for the training of in-solution digestion and desalting techniques. We are also grateful to Ms. Rachel Sook-Yee Kam for helping on ELISA, and Mr. I-Jung Tsai for Peak7 software training.
Publisher Copyright:
© 2021 The Canadian Society of Clinical Chemists
PY - 2022/3
Y1 - 2022/3
N2 - Objective: Hyperglycemia leads to lipid peroxidation, producing 4-hydroxynonenal (HNE) adducts which correlate with the production of amyloid-beta (Aβ), one of the hallmarks of Alzheimer's disease (AD). This study is to investigate the interactions of Aβ, HNE adducts and responding autoantibodies during the pathogenesis from hyperglycemia to AD. Methods: A total of 239 Taiwanese serum samples from a healthy control group and patients with hyperglycemia, and AD with and without hyperglycemia were analyzed. Aβ was immunoprecipitated from randomly pooled serum in each group and immunoblotted. Synthetic Aβ1-16 and Aβ17-28 peptides were modified with HNE in vitro and verified with LC-MS/MS. The levels of Aβ, HNE adducts, and autoantibody isotypes IgG and IgM against either native or HNE-modified Aβ were determined with ELISA. The diagnostic power of potential biomarkers was evaluated. Results: Increased fasting glucose and decreased high-density-lipoprotein cholesterol in AD groups indicated abnormal metabolism in the pathogenesis progression from hyperglycemia to AD. Indeed, serum Aβ, HNE adducts and most of the autoantibodies recognizing either native or HNE-modified Aβ were increased in the diseased groups. However, HNE adducts had better diagnostic performances than Aβ for both hyperglycemia and AD. Additionally, HNE-Aβ peptide levels were increased, and the responding autoantibodies (most notably IgM) were decreased in hyperglycemic AD group compared to the hyperglycemia only group, suggesting an immunity disturbance in the pathogenesis progression from hyperglycemia to AD. Conclusion: Hyperglycemia increases the level of HNE adducts which may be neutralized by responding autoantibodies. Depletion of these autoantibodies promotes AD-like pathogenesis. Thus, levels of a patient's HNE adducts and associated responding autoantibodies are potential biomarkers for AD with diabetes.
AB - Objective: Hyperglycemia leads to lipid peroxidation, producing 4-hydroxynonenal (HNE) adducts which correlate with the production of amyloid-beta (Aβ), one of the hallmarks of Alzheimer's disease (AD). This study is to investigate the interactions of Aβ, HNE adducts and responding autoantibodies during the pathogenesis from hyperglycemia to AD. Methods: A total of 239 Taiwanese serum samples from a healthy control group and patients with hyperglycemia, and AD with and without hyperglycemia were analyzed. Aβ was immunoprecipitated from randomly pooled serum in each group and immunoblotted. Synthetic Aβ1-16 and Aβ17-28 peptides were modified with HNE in vitro and verified with LC-MS/MS. The levels of Aβ, HNE adducts, and autoantibody isotypes IgG and IgM against either native or HNE-modified Aβ were determined with ELISA. The diagnostic power of potential biomarkers was evaluated. Results: Increased fasting glucose and decreased high-density-lipoprotein cholesterol in AD groups indicated abnormal metabolism in the pathogenesis progression from hyperglycemia to AD. Indeed, serum Aβ, HNE adducts and most of the autoantibodies recognizing either native or HNE-modified Aβ were increased in the diseased groups. However, HNE adducts had better diagnostic performances than Aβ for both hyperglycemia and AD. Additionally, HNE-Aβ peptide levels were increased, and the responding autoantibodies (most notably IgM) were decreased in hyperglycemic AD group compared to the hyperglycemia only group, suggesting an immunity disturbance in the pathogenesis progression from hyperglycemia to AD. Conclusion: Hyperglycemia increases the level of HNE adducts which may be neutralized by responding autoantibodies. Depletion of these autoantibodies promotes AD-like pathogenesis. Thus, levels of a patient's HNE adducts and associated responding autoantibodies are potential biomarkers for AD with diabetes.
KW - 4-Hydroxynonenal (HNE)
KW - Alzheimer's disease (AD)
KW - Amyloid-beta (Aβ)
KW - Autoantibody
KW - Hyperglycemia
KW - Post-translational modification
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U2 - 10.1016/j.clinbiochem.2021.12.005
DO - 10.1016/j.clinbiochem.2021.12.005
M3 - Article
AN - SCOPUS:85122024066
SN - 0009-9120
VL - 101
SP - 26
EP - 34
JO - Clinical Biochemistry
JF - Clinical Biochemistry
ER -
