Insights from microcanonical thermostatistics into amylinanalogues and amyloid-βcross-seeding

Growing evidence from population studies and clinical observations strongly suggests a complexconnection between major proteinopathies, to know, Type 2 diabetes (T2D) and Alzheimer's disease (AD).People with T2D face a significantly higher risk of developing AD compared to those without diabetes.These two conditions share several key features, such as inflammation, oxidative stress, metabolic dys-function, and the buildup of certain proteins known as beta-amyloid (A beta 42) and pancreatic islet amyloidpolypeptide (IAPP or amylin). In AD, the brain develops characteristic senile plaques mainly composedof A beta 42. Similarly, in individuals with T2D, the pancreas shows deposits of a protein called human amylin(hIAPP). The accumulation of these aggregated proteins in both the brain and pancreas has been associ-ated with impaired cell function and even cell death. To gain molecular insight in the outset of such complexscenario, we perform microcanonical thermostatistics analysis of Monte Carlo simulations of A beta 42 cross-seeded by hIAPP, or its biotechnological therapeutic analogous as Pramlintide. We find that while A beta 42is quite prone to cross-seed with hIAPP, and then to aggregate around that critical nuclei, this can beabolished for some of its analogues, which may possibly lead to alternative therapeutic approaches to T2Dand AD