Bioinformatic analysis of Amyloid-beta Precursor Protein (APP) and gene mutations related to Alzheimer's disease

Abstract

Introduction: Alzheimer’s disease is the most common form of dementia and is the only top 10 cause of death in the United States that lacks disease altering treatments It is a complex disorder with environmental and genetic components. There are two major types of Alzheimer’s disease, early onset and the more common late onset [1]. There are nearly 47 million people living with dementia worldwide, which is predicted to double every 20 years, increasing to more than 131 million by 2050. Alzheimer’s disease (AD) is the best characterized among them, and it accounts for 50–60% of all dementia cases. This common neurodegenerative disease is clinically characterized by a progressive and gradual cognitive impairment, synapse loss, and substantial loss of neurons in later stages. [2]. The prevalence of dementia in the Western world in people over the age of 60 has been estimated to be greater than 5%, about twothirds of which are due to Alzheimer’s disease. [3]. Methods: In this study, APP protein information was collected through NCBI, Uniprot and CATCH databases. Also, the mutations reported for APP gene of Alzheimer's disease were obtained through NCBI and Uniprot databases. Then, using SIFT and Polyphen site, the effects of these mutations on the disease were investigated separately, and finally, the common mutations were extracted and displayed in the form of statistically. Finally, we used NCBI to detect where the most regions had mutation. Results: To advance our understanding of how APP and DR6 function together to initiate downstream signaling controlling axon pruning and synapse elimination, we determined the crystal structure of the APP/DR6 complex. The complex between the APP E2 domain and the ECD of DR6 was crystallized, and its structure was determined at 2.2 Å resolution, as described in the Materials and Methods. Consistent with previous studies, DR6 contains four CRD modules composed mostly of strands and loops of various lengths, with either two or three pairs of disulfide bonds stabilizing each CRD module [4]. Based on SIFT, we found about 200 single nucleotide polymorphisms (SNPs) with a score between 0.999-1 that were deleterious and had pathogenicity records in the UniProt database, and by analyzing the data by polyphen, the degree of damage in substitution We obtained amino acids with each other. The results showed that most of them were malignant and only 2 benign samples were found. Conclusions: In this research, APP protein and gene mutations and their pathogenicity were investigated. APP, a well-investigated protein for AD development, is widely expressed across many tissues, including skeletal muscle. APP metabolism and its function in muscles are crucial for synapse development and maintenance at the NMJ. However, the molecular mechanisms that link muscular APP to the brain’s pathology and function remain elusive. Identification of the role of APP in muscles will alsoestablish the link between sarcopenia and neurodegenerative diseases. These may lead to insights into muscle brain crosstalk and suggest potential contributions to age-related degeneration [5].