Revealing the Molecular Mechanisms of Alzheimer’s Disease Based on Network Analysis

Abstract

The complex pathology of Alzheimer’s disease (AD) emphasises the need for comprehensive modelling of the disease, which may lead to the development of efficient treatment strategies. To address this challenge, we analysed transcriptome data of post-mortem human brain samples of healthy elders and individuals with late-onset AD from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) and Mayo Clinic (MayoRNAseq) studies in the AMP-AD consortium. In this context, we conducted several bioinformatics and systems medicine analyses including the construction of AD-specific co-expression networks and genome-scale metabolic modelling of the brain in AD patients to identify key genes, metabolites and pathways involved in the progression of AD. We identified AMIGO1 and GRPRASP2 as examples of commonly altered marker genes in AD patients. Moreover, we found alterations in energy metabolism, represented by reduced oxidative phosphorylation and ATPase activity, as well as the depletion of hexanoyl-CoA, pentanoyl-CoA, (2E)-hexenoyl-CoA and numerous other unsaturated fatty acids in the brain. We also observed that neuroprotective metabolites (e.g., vitamins, retinoids and unsaturated fatty acids) tend to be depleted in the AD brain, while neurotoxic metabolites (e.g., β-alanine, bilirubin) were more abundant. In summary, we systematically revealed the key genes and pathways related to the progression of AD, gained insight into the crucial mechanisms of AD and identified some possible targets that could be used in the treatment of AD.

Review of Current Human Genome-Scale Metabolic Models for Brain Cancer and Neurodegenerative Diseases

“…GEM is an in silico representation of the metabolism where the interactions between metabolites and the biochemical reactions are formulated in a sparse stoichiometric matrix and the relationship between genes and reactions by Boolean rules (GPR rules). Moreover, GEM is used to simulate the role of the microbiome in the development of PD [ 70 , 71 ] or to study psychiatric diseases [ 72 ] and AD [ 73 ] in humans and PD-like phenotypes in mice [ 74 ]. However, brain metabolism has specific properties that must be considered before applying CBM.…”

A Personalized Metabolic Modelling Approach through Integrated Analysis of RNA-Seq-Based Genomic Variants and Gene Expression Levels in Alzheimer’s Disease

“…Additionally, propanoate, inositol phosphate, glycerophospholipid and biotin metabolic pathways were identified to be perturbed in both variant and non-variant models of the same dataset. Propanoate metabolite is known to be neuroprotective and associated with brain-gut axis (Bayraktar, et al, 2021). A study showed that changes in the levels of inositol phosphate metabolic enzymes were correlated with amyloid beta peptide formation and tau hyperphosphorylation in AD (Stygelbout, et al, 2014).…”

Integrated multi-omics analysis of Alzheimer’s disease shows molecular signatures associated with disease progression and potential therapeutic targets

“…Previous studies have shown low levels of B 6 , B 12 , or folate lead to elevated levels of Aβ aggregates in neurons of transgenic mice models of Alzheimer’s disease 30 , 31 , 73 . B 6 is a cofactor that is involved in dopaminergic, and GABAergic synapse function 74 . The cholinergic synapses are also deregulated in Alzheimer’s disease 75 .…”