Analysis of mutations in APP1 protein associated with development and protection against Alzheimer's disease - an In silico approach / Análise de mutações na proteína APP1 associadas ao desenvolvimento e proteção contra a doença de Alzheimer - uma abordagem In silico

Abstract

Introduction: Alzheimer's disease (AD) is the dementia with the highest number of cases worldwide, causing great social and economic impact. The amyloid cascade is the most accepted hypothesis to explain the beginning of AD. According to it, neurodegeneration is caused by the accumulation of Aβ peptides and the formation of amyloid plaques in the brain. In familial cases of Alzheimer's, mutations in the APP1 protein lead to increased production of Aβ plaques. Objectives: Analyze in silico the structural and functional impact of missense mutations in APP1 and construct a complete model for the protein. Methods: We generated and validated a theoretical structure of APP1 protein using structural modeling and quality assessment algorithms. We further analyzed the effects of AD-related mutations on APP1 protein and also the neuroprotective mutation A673T by performing functional predictions, evolutionary conservation analysis, and molecular dynamics (MD). Results: The predictive analysis indicated that most mutations occur in conserved regions of APP1 and also present an elevated rate of deleterious predictions, pointing to their harmful effects. The computational modeling generated an unprecedented, accurate and complete model of human APP1, whose quality was corroborated by validation algorithms and structural alignment. The MD simulations of codon 673 variants pointed to flexibility and essential dynamics alterations at the AICD and Aβ domains, which could have strong and non-intuitive consequences on APP1 interactions, including those involved in β-secretase cleavage and, consequently, aβ peptide formation. Conclusions: Flexibility and essential dynamics alterations upon codon 673 variants may have functional implications for APP1, influencing the generation of Aβ peptide, the main responsible for APP1 toxicity in AD.