Abstract
The prominent characteristic of Alzheimer’s disease (AD) is the accumulation of amyloid beta (Abeta) proteins in the form of plaques that cause molecular and cellular alterations in the brain. Due to the paucity of brain samples of early-stage Abeta aggregation, animal models have been developed to study early events in AD. Caenorhabditis elegans is a genetically tractable animal model for AD. Here, we used transcriptomic data, network-based protein-protein interactions and weighted gene co-expression network analysis (WGCNA), to detect modules and their gene ontology in response to Abeta aggregation in C. elegans. Additionally, hub genes and their orthologues in human and mouse were identified to study their relation to AD. We also found several transcription factors (TFs) responding to Abeta accumulation. Our results show that Abeta expression in C. elegans relates to general processes such as molting cycle, locomotion, and larval development plus AD-associated processes, including protein phosphorylation, and G-protein coupled receptor-regulated pathways. We reveal that many hub genes and TFs including ttbk-2, daf-16, and unc-49 have human and mouse orthologues that are directly or potentially associated with AD and neural development. In conclusion, using systems biology we identified important genes and biological processes in C. elegans that respond to Abeta aggregation, which could be used as potential diagnostic or therapeutic targets. In addition, because of evolutionary relationship to AD in human, we suggest that C. elegans is a useful model for studying early molecular events in AD.
Highlights
Extracellular senile plaques and neurofibrillary tangles of tau protein are the main hallmarks of Alzheimer’s disease (AD)
We have analyzed transcriptome data produced by Hassan and colleagues in which they used a transgenic C. elegans model expressing amyloid beta (Abeta) in body wall muscle [11]
It is known that C. elegans is a suitable model to study neurodegenerative diseases including AD [26]
Summary
Extracellular senile plaques and neurofibrillary tangles of tau protein are the main hallmarks of Alzheimer’s disease (AD). Senile plaques are composed of amyloid beta (Abeta) peptides with neurotoxic features that lead to synaptic dysfunction, connectome disruption, and neural death. In familial AD, Abeta deposition is related to mutations in either Abeta precursor protein (APP) or catalytic subunits of γ-secretase, presenilin-1 (PS1) or presenilin-2 (PS2) [1]. Similarities between responses to Abeta accumulation in worm and human secretase and β-secretase are membrane-bound proteases that cleave APP to Abeta. Removal of Abeta from cells is achieved via neprilysin (insulin-degrading enzyme) followed by lysosomal degradation (REF). It can be transported into blood vessels and carried away for degradation [1]. Despite the importance of these peptides in AD, it is not possible to monitor the accumulation trends and its impact on human neural cells. The role of Abeta and its accumulation is analyzed in animal model systems of AD
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