Pathological implications of APP clustering and its effect on β-Secretase cleavage

Abstract

Alzheimers disease(AD) is one of the most prevalent and debilitating neurodegen- erative diseases. One of the indicators of AD pathology is the presence of Amyloid Beta(Aβ) plaques in different regions of the brain. Aβ molecules aggregate to form plaques due to the excess production or improper clearance of Aβ. It is therefore of paramount importance to study the reactions involved in the production of Aβ. Aβ is formed when Amyloid Precursor Protein (APP), a transmembrane protein found abun- dantly in neurons is sequentially cleaved by β- and γ-Secretase.This project focuses on the interactions between APP and β-Secretase. From experimental data, we know that APP forms clusters on the synaptic membrane.Motivated by experimental obser- vations of clustering and localization of APP, we use a Monte-Carlo based spatially realistic model to recreate these APP interactions.We also systematically reproduce a range of aberrant biophysical properties observed in AD, quantify its consequences and discuss its effects on APP cleavage. Our calculations inferred that differential APP clustering and affinities to β-Secretase can modulate the Aβ produced.As APP cleav- age is the penultimate step in the production of Aβ, understanding the details of its synaptic localization and its processing can provide valuable insights into Aβ pathol- ogy.