Novel Hominid-Specific IAPP Isoforms: Potential Biomarkers of Early Alzheimer's Disease and Inhibitors of Amyloid Formation

(1) Background and aims: Amyloidosis due to aggregation of amyloid-β (Aβ₄₂) is a key pathogenic event in Alzheimer's disease (AD), whereas aggregation of mature islet amyloid polypeptide (IAPP₃₇) in human islets leads to β-cell dysfunction. The aim of this study is to uncover potential biomarkers that might additionally point to therapy for early AD patients. (2) Methods: We used bioinformatic approach to uncover novel IAPP isoforms and developed a quantitative selective reaction monitoring (SRM) proteomic assay to measure their peptide levels in human plasma and CSF from individuals with early AD and controls, as well as postmortem cerebrum of clinical confirmed AD and controls. We used Thioflavin T amyloid reporter assay to measure the IAPP isoform fibrillation propensity and anti-amyloid potential against aggregation of Aβ₄₂ and IAPP₃₇. (3) Results: We uncovered hominid-specific IAPP isoforms: hIAPPβ, which encodes an elongated propeptide, and hIAPPγ, which is processed to mature IAPP₂₅ instead of IAPP₃₇. We found that hIAPPβ was significantly reduced in the plasma of AD patients with the accuracy of 89%. We uncovered that IAPP₂₅ and a GDNF derived DNSP₁₁ were nonaggregating peptides that inhibited the aggregation of IAPP₃₇ and Aβ₄₂. (4) Conclusions: The novel peptides derived from hIAPP isoforms have potential to serve as blood-derived biomarkers for early AD and be developed as peptide based anti-amyloid medicine.