Key Genes and Biochemical Networks in Various Brain Regions Affected in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is one of the most complicated progressive neurodegenerative brain disorders, affecting millions of people around the world. Ageing remains one of the strongest risk factors associated with the disease and the increasing trend of the ageing population globally has significantly increased the pressure on healthcare systems worldwide. The pathogenesis of AD is being extensively investigated, yet several unknown key components remain. Therefore, we aimed to extract new knowledge from existing data. Ten gene expression datasets from different brain regions including the hippocampus, cerebellum, entorhinal, frontal and temporal cortices of 820 AD cases and 626 healthy controls were analyzed using the robust rank aggregation (RRA) method. Our results returned 1713 robust differentially expressed genes (DEGs) between five brain regions of AD cases and healthy controls. Subsequent analysis revealed pathways that were altered in each brain region, of which the GABAergic synapse pathway and the retrograde endocannabinoid signaling pathway were shared between all AD affected brain regions except the cerebellum, which is relatively less sensitive to the effects of AD. Furthermore, we obtained common robust DEGs between these two pathways and predicted three miRNAs as potential candidates targeting these genes; hsa-mir-17-5p, hsa-mir-106a-5p and hsa-mir-373-3p. Three transcription factors (TFs) were also identified as the potential upstream regulators of the robust DEGs; ELK-1, GATA1 and GATA2. Our results provide the foundation for further research investigating the role of these pathways in AD pathogenesis, and potential application of these miRNAs and TFs as therapeutic and diagnostic targets.

Tissue-Specific Metabolomic Reprogramming Determines the Disease Pathophysiology of Sars-Cov-2 Variants in Hamster Model

“…The balance between neural excitation and inhibition is essential for proper brain function, and its disruption contributes to neuronal disorders like AD ( 70, 71 ). Dysregulation of the GABAergic synapse pathway and decreased levels of GABA found in this study have also been reported in Alzheimer’s brain ( 72 ). Overall, our findings in the SARS-CoV-2 infected hamster brains indicate the presence of multiple molecular markers associated with the development of neurodegenerative disorders.…”

Fingolimod effects on the brain are mediated through biochemical modulation of bioenergetics, autophagy, and neuroinflammatory networks

“…Retrograde eCB signaling is one of the major altered pathways in several neurodegenerative diseases such as AD, PD, and MS [ 34 , 35 , 36 ]. Recently a meta‐analysis on transcriptomics datasets from five brain regions of AD patients including hippocampus, CB, temporal cortex, entorhinal, and FC highlighted retrograde eCB signaling as a key altered pathway in AD patients [ 37 ]. Retrograde signaling is the main mechanism by which eCBs regulate short‐ and long‐term forms of plasticity at both excitatory and inhibitory synapses [ 35 ].…”

Gender differences in microRNA expression in levodopa-naive PD patients

“…[16]. Recently, Stefanik et al found that hippocampal expression of miR-34a-5p was sexdependent [24]. MiR-34a-5p is abundantly expressed in the brain and emerging evidence support its involvement in different neurodegenerative diseases as Alzheimer's disease and PD [13].…”