Title: Arrest of Amyloid Fibril Formation Associated to Type II Diabetes: Structural and Functional Links to the Mechanism of Alzheimers β- Amyloid Fibrillization
Volume: 2
Issue: 2
Author(s): Ehud Gazit
Affiliation:
Keywords:
alzheimers disease, amyloid formation, islet amyloid polypeptide, type II diabetes, prion disease, protein misfolding, p-stacking
Abstract: Pancreatic amyloid deposits composed of the islet amyloid polypeptide (IAPP) are found in nearly all type II diabetes patients. These fibrillar deposits are cytotoxic and their production is clearly associated with the progression of pancreatic βcells death. Such progressive formation of cytotoxic amyloid fibrils by IAPP in Type II diabetes is parallel in many ways to the process of cerebral amyloid fibril formation by the βamyloid polypeptide in the case of Alzheimers disease. Another line of parallelism between Alzheimers disease and Type II diabetes is the occurrence of a mutation within the IAPP gene that is correlated with an early onset of Type II diabetes in the Asian population. This finding resembles the occurrence familial mutations within the βamyloid polypeptide that are correlated with early onset of Alzheimers disease. Biochemical and biophysical analysis demonstrated an increased amyloidogenic potential as well as cytotoxicity for the altered IAPP protein. Arrest of amyloid formation by IAPP therefore seems to be significant to halt the deterioration in βcell function of Type II diabetes patients and maybe used as a treatment to delay onset for parts of the population with predisposition for this disease. Extensive studies by several academic and industrial groups already resulted in lead molecules that can inhibit amyloid fibril formation by IAPP. Some of these lead molecules are based of the same methodologies that were successfully used for the development of potential drugs that inhibit formation of amyloid fibrils by the βamyloid polypeptide.
