Alzheimer's disease (AD) is the most prevalent cause of dementia and is primarily associated with memory impairment and cognitive decline, but the etiology of AD has not been elucidated. In recent years, evidence has shown that immune cells play critical roles in AD pathology. In the current study, we collected the transcriptomic data of the hippocampus from gene expression omnibus database, and investigated the effect of immune cell infiltration in the hippocampus on AD, and analyzed the key genes that influence the pathogenesis of AD patients. The results revealed that the relative abundance of immune cells in the hippocampus of AD patients was altered. Of all given 28 kinds of immune cells, monocytes were the important immune cell associated with AD. We identified 4 key genes associated with both AD and monocytes, including KDELR1, SPTAN1, CDC16 and RBBP6, and they differentially expressed in 5XFAD mice and WT mice. The logistic regression and random forest models based on the 4 key genes could effectively distinguish AD from healthy samples. Our research provided a new perspective on immunotherapy for AD patients.
Alzheimer Disease , Cognitive Dysfunction , Mice , Animals , Alzheimer Disease/metabolism , Memory Disorders/metabolism , Memory Disorders/pathology , Gene Expression Profiling , Cognitive Dysfunction/pathology , Hippocampus/metabolism , Disease Models, Animal , Receptors, Peptide/genetics , Receptors, Peptide/metabolism
Exercise has been proposed as an effective non-pharmacological management for Parkinson's disease (PD) patients. Irisin, a recently identified myokine, is increased by exercise and plays pivotal roles in energy metabolism. However, it remains unknown whether irisin has any protective effects on PD. Here, we found that serum irisin levels of PD patients were markedly elevated after 12-week regular exercise, which had a positive correlation with improved balance function scored by Berg Balance Scale. Treatment with exogenous irisin could improve motor function, and reduce dopaminergic neurodegeneration in PD models. Meanwhile, irisin could reduce cell apoptosis by renovating mitochondrial function in PD models, which was reflected in decreased oxidative stress, increased mitochondrial complex I activity and mitochondrial content, increased mitochondrial biogenesis, and repaired mitochondrial morphology. Furthermore, irisin regulated the aforementioned aspects by upregulating downstream Akt signaling pathway and ERK1/2 signaling pathway through integrin receptors rather than directly targeting mitochondria. With the use of small-molecule inhibitors, it was found that irisin can reduce apoptosis, restore normal mitochondrial biogenesis, and improve mitochondrial morphology and dynamic balance in PD models by activating Akt signaling pathway and ERK1/2 signaling pathway. And irisin reduced oxidative stress via activating ERK1/2 signaling pathway. The results revealed that exogenous irisin conferred neuroprotection relieving apoptosis and oxidative stress, restraining mitochondrial fragmentation, and promoting mitochondrial respiration and biogenesis in PD models, and irisin exerted the aforementioned effects by activating Akt signaling pathway and ERK1/2 signaling pathway. Thus, peripherally delivered irisin might be a promising candidate for therapeutic targeting of PD.
Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by cognitive impairment and memory loss, for which there is no effective cure to date. In the past several years, numerous studies have shown that increased inflammation in AD is a major cause of cognitive impairment. This study aimed to reveal 22 kinds of peripheral immune cell types and key genes associated with AD. The prefrontal cortex transcriptomic data from Gene Expression Omnibus (GEO) database were collected, and CIBERSORT was used to assess the composition of 22 kinds of immune cells in all samples. Weighted gene co-expression network analysis (WGCNA) was used to construct gene co-expression networks and identified candidate module genes associated with AD. The least absolute shrinkage and selection operator (LASSO) and random forest (RF) models were constructed to analyze candidate module genes, which were selected from the result of WGCNA. The results showed that the immune infiltration in the prefrontal cortex of AD patients was different from healthy samples. Of all 22 kinds of immune cells, M1 macrophages were the most relevant cell type to AD. We revealed 10 key genes associated with AD and M1 macrophages by LASSO and RF analysis, including ARMCX5, EDN3, GPR174, MRPL23, RAET1E, ROD1, TRAF1, WNT7B, OR4K2 and ZNF543. We verified these 10 genes by logistic regression and k-fold cross-validation. We also validated the key genes in an independent dataset, and found GPR174, TRAF1, ROD1, RAET1E, OR4K2, MRPL23, ARMCX5 and EDN3 were significantly different between the AD and healthy controls. Moreover, in the 5XFAD transgenic mice, the differential expression trends of Wnt7b, Gpr174, Ptbp3, Mrpl23, Armcx5 and Raet1e are consistent with them in independent dataset. Our results provided potential therapeutic targets for AD patients.
Alzheimer Disease/genetics , Alzheimer Disease/immunology , Prefrontal Cortex/immunology , Animals , Female , Gene Expression , Hedgehog Proteins/metabolism , Humans , Ion Transport , Macrophages/metabolism , Male , Mice, Inbred C57BL , Prefrontal Cortex/metabolism
Mitochondria, the centers of energy metabolism, have been shown to participate in epigenetic regulation of neurodegenerative diseases. Epigenetic modification of nuclear genes encoding mitochondrial proteins has an impact on mitochondria homeostasis, including mitochondrial biogenesis, and quality, which plays role in the pathogenesis of neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. On the other hand, intermediate metabolites regulated by mitochondria such as acetyl-CoA and NAD+, in turn, may regulate nuclear epigenome as the substrate for acetylation and a cofactor of deacetylation, respectively. Thus, mitochondria are involved in epigenetic regulation through bidirectional communication between mitochondria and nuclear, which may provide a new strategy for neurodegenerative diseases treatment. In addition, emerging evidence has suggested that the abnormal modification of mitochondria DNA contributes to disease development through mitochondria dysfunction. In this review, we provide an overview of how mitochondria are involved in epigenetic regulation and discuss the mechanisms of mitochondria in regulation of neurodegenerative diseases from epigenetic perspective.
