Abstract
An innovative approach to identify new conformational antigens of Aβ1–42 recognized by IgG autoantibodies as biomarkers of state and stage in Alzheimer’s disease (AD) patients is described. In particular, through the use of bioinformatics modeling, conformational similarities between several Aβ1–42 forms and other amyloid-like proteins with F1 capsular antigen (Caf1) of Yersinia pestis were first found. pVIII M13 phage display libraries were then screened against YPF19, anti-Caf1 monoclonal antibody, and IgGs of AD patients, in alternate biopanning cycles of a so-called “double binding” selection. From the selected phage clones, one, termed 12III1, was found to be able to prevent in vitro Aβ1–42-induced cytotoxicity in SH-SY5Y cells, as well as to promote disaggregation of preformed fibrils, to a greater extent with respect to wild-type phage (pC89). IgG levels detected by 12III1 provided a significant level of discrimination between diseased and nondemented subjects, as well as a good correlation with the state progression of the disease. These results give significant impact in AD state and stage diagnosis, paving the way for the development not only for an innovative blood diagnostic assay for AD precise diagnosis, progressive clinical assessment, and screening but also for new effective treatments.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia and is a leading cause of morbidity and mortality worldwide
AD is today the main cause of dementia in the population, and it is associated with misfolding and aggregation states of βamyloid
The aggregation states of this peptide are correlated with the onset and progression of disease. β-Amyloid forms insoluble aggregation structures, extracellular plaques, and soluble oligomers
Summary
Alzheimer’s disease (AD) is the most common form of dementia and is a leading cause of morbidity and mortality worldwide. Diagnostic guidelines for Alzheimer disease include three stages: preclinical, mild cognitive impairment (MCI), and dementia. Cognitive impairments are considered the first appearing symptoms and signs of the disease. The preliminary diagnosis of AD is made by a combination of laboratory and clinical criteria, which include neuropsychiatric tests, behavioral history assessments, and neuroimaging techniques.[1−3] In addition, more recent clinical studies have demonstrated biomarkers of “suspected nonAlzheimer disease pathophysiology” (SNAP) causing amnestic type cognitive impairment.[4] other proteinopathies have been associated with substantial cognitive impairment that mimics AD clinical syndrome (i.e., limbic-predominant agerelated TDP-43 encephalopathy, LATE).[5]
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