Serum levels of 4-hydroxynonenal adducts and responding autoantibodies correlate with the pathogenesis from hyperglycemia to Alzheimer's disease

Objective: Hyperglycemia leads to lipid peroxidation, producing 4-hydroxynonenal (HNE) adducts which corre-late with the production of amyloid-beta (A beta), one of the hallmarks of Alzheimer's disease (AD). This study is to investigate the interactions of A beta, 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. A beta was immunoprecipitated from randomly pooled serum in each group and immunoblotted. Synthetic A beta 1-16 and A beta 17-28 peptides were modified with HNE in vitro and verified with LC-MS/MS. The levels of A beta, HNE adducts, and autoantibody isotypes IgG and IgM against either native or HNE-modified A beta 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 A beta, HNE ad-ducts and most of the autoantibodies recognizing either native or HNE-modified A beta were increased in the diseased groups. However, HNE adducts had better diagnostic performances than A beta for both hyperglycemia and AD. Additionally, HNE-A beta 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 auto-antibodies. 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.

Automated summary

This study investigates the interactions of A beta, HNE adducts, and responding autoantibodies during the pathogenesis from hyperglycemia to AD. The results suggest that HNE adducts have better diagnostic performances than A beta for both hyperglycemia and AD, and depletion of autoantibodies may promote AD-like pathogenesis.