Irisin inhibits microglial senescence via TFAM-mediated mitochondrial metabolism in a mouse model of tauopathy.

BACKGROUND: The accumulation of senescent microglia has been highlighted as a critical contributor to the progression of tauopathies. Irisin, a muscle-derived hormone produced by the proteolytic cleavage of Fibronectin-domain III containing 5 (FNDC5), mediates the pleiotropic effects of exercise on the physical body. Herein, we investigate the potential role of irisin in microglial senescence in tauopathies. METHODS: To model tauopathies both in vivo and in vitro, we utilized P301S tau transgenic mice and tau K18 fibril-treated microglia BV2 cells, respectively. We first examined the expression of the irisin expression and senescence phenotypes of microglia in tauopathies. Subsequently, we investigated the impact of irisin on microglial senescence and its underlying molecular mechanisms. RESULT: We observed a reduction in irisin levels and an onset of premature microglial senescence both in vivo and in vitro. Irisin administration was found to counteract microglial senescence and ameliorate cognitive decline in P301S mice. Mechanistically, irisin effectively inhibited microglial senescence by stimulating the expression of mitochondrial transcription factor A (TFAM), a master regulator of mitochondrial respiratory chain biogenesis, thereby enhancing mitochondrial oxidative phosphorylation (OXPHOS). Silencing TFAM eliminated the inhibitory effect of irisin on microglial senescence as well as the restorative effect of irisin on mitochondrial OXPHOS. Furthermore, the SIRT1/PGC1α signaling pathway appeared to be implicated in irisin-mediated upregulation of TFAM. CONCLUSION: Taken together, our study revealed that irisin mitigated microglial senescence via TFAM-driven mitochondrial biogenesis, suggesting a promising new avenue for therapeutic strategies targeting tauopathies.

AMPK-mediated autophagy pathway activation promotes ΔFosB degradation to improve levodopa-induced dyskinesia.

BACKGROUND: Parkinson's disease patients on chronic levodopa often suffer from motor complications, which tend to reduce their quality of life. Levodopa-induced dyskinesia (LID) is one of the most prevalent motor complications, often characterized by abnormal involuntary movements, and the pathogenesis of LID is still unclear but recent studies have suggested the involvement of autophagy. METHODS: The onset of LID was mimicked by chronic levodopa treatment in a unilateral 6-hydroxydopamine (6-OHDA) -lesion rat model. Overexpression of ΔFosB in HEK293 cells to mimic the state of ΔFosB accumulation. The modulation of the AMP-activated protein kinase (AMPK)-mediated autophagy pathway using by metformin, AICAR (an AMPK activator), Compound C (an AMPK inhibitor) and chloroquine (an autophagy pathway inhibitor). The severity of LID was assessed by axial, limb, and orofacial (ALO) abnormal involuntary movements (AIMs) score and in vivo electrophysiology. The activity of AMPK pathway as well as autophagy markers and FosB-ΔFosB levels were detected by western blotting. RT-qPCR was performed to detect the transcription level of FosB-ΔFosB. The mechanism of autophagy dysfunction was further explored by immunofluorescence and transmission electron microscopy. RESULTS: In vivo experiments demonstrated that chronic levodopa treatment reduced AMPK phosphorylation, impaired autophagosome-lysosomal fusion and caused FosB-ΔFosB accumulation in the striatum of PD rats. Long-term metformin intervention improved ALO AIMs scores as well as reduced the mean power of high gamma (hγ) oscillations and the proportion of striatal projection neurons unstable in response to dopamine for LID rats. Moreover, the intervention of metformin promoted AMPK phosphorylation, ameliorated the impairment of autophagosome-lysosomal fusion, thus, promoting FosB-ΔFosB degradation to attenuate its accumulation in the striatum of LID rats. However, the aforementioned roles of metformin were reversed by Compound C and chloroquine. The results of in vitro studies demonstrated the ability of metformin and AICAR to attenuate ΔFosB levels by promoting its degradation, while Compound C and chloroquine could block this effect. CONCLUSIONS: In conclusion, our results suggest that long-term metformin treatment could promote ΔFosB degradation and thus attenuate the development of LID through activating the AMPK-mediated autophagy pathway. Overall, our results support the AMPK-mediated autophagy pathway as a novel therapeutic target for LID and also indicate that metformin is a promising therapeutic candidate for LID.

Analysis and experimental validation of necroptosis-related molecular classification, immune signature and feature genes in Alzheimer's disease.

Necroptosis, a programmed cell death pathway, has been demonstrated to be activated in Alzheimer's disease (AD). However, the precise role of necroptosis and its correlation with immune cell infiltration in AD remains unclear. In this study, we conducted non-negative matrix factorization clustering analysis to identify three subtypes of AD based on necroptosis-relevant genes. Notably, these subtypes exhibited varying necroptosis scores, clinical characteristics and immune infiltration signatures. Cluster B, characterized by high necroptosis scores, showed higher immune cell infiltration and was associated with a more severe pathology, potentially representing a high-risk subgroup. To identify potential biomarkers for AD within cluster B, we employed two machine learning algorithms: the least absolute shrinkage and selection operator regression and Random Forest. Subsequently, we identified eight feature genes (CARTPT, KLHL35, NRN1, NT5DC3, PCYOX1L, RHOQ, SLC6A12, and SLC38A2) that were utilized to develop a diagnosis model with remarkable predictive capacity for AD. Moreover, we conducted validation using bulk RNA-seq, single-nucleus RNA-seq, and in vivo experiments to confirm the expression of these feature genes. In summary, our study identified a novel necroptosis-related subtype of AD and eight diagnostic biomarkers, explored the roles of necroptosis in AD progression and shed new light for the clinical diagnosis and treatment of this disease.

Identification of metabolism-related subtypes and feature genes in Alzheimer's disease.

BACKGROUND: Owing to the heterogeneity of Alzheimer's disease (AD), its pathogenic mechanisms are yet to be fully elucidated. Evidence suggests an important role of metabolism in the pathophysiology of AD. Herein, we identified the metabolism-related AD subtypes and feature genes. METHODS: The AD datasets were obtained from the Gene Expression Omnibus database and the metabolism-relevant genes were downloaded from a previously published compilation. Consensus clustering was performed to identify the AD subclasses. The clinical characteristics, correlations with metabolic signatures, and immune infiltration of the AD subclasses were evaluated. Feature genes were screened using weighted correlation network analysis (WGCNA) and processed via Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Furthermore, three machine-learning algorithms were used to narrow down the selection of the feature genes. Finally, we identified the diagnostic value and expression of the feature genes using the AD dataset and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) analysis. RESULTS: Three AD subclasses were identified, namely Metabolism Correlated (MC) A (MCA), MCB, and MCC subclasses. MCA contained signatures associated with high AD progression and may represent a high-risk subclass compared with the other two subclasses. MCA exhibited a high expression of genes related to glycolysis, fructose, and galactose metabolism, whereas genes associated with the citrate cycle and pyruvate metabolism were downregulated and associated with high immune infiltration. Conversely, MCB was associated with citrate cycle genes and exhibited elevated expression of immune checkpoint genes. Using WGCNA, 101 metabolic genes were identified to exhibit the strongest association with poor AD progression. Finally, the application of machine-learning algorithms enabled us to successfully identify eight feature genes, which were employed to develop a nomogram model that could bring distinct clinical benefits for patients with AD. As indicated by the AD datasets and qRT-PCR analysis, these genes were intimately associated with AD progression. CONCLUSION: Metabolic dysfunction is associated with AD. Hypothetical molecular subclasses of AD based on metabolic genes may provide new insights for developing individualized therapy for AD. The feature genes highly correlated with AD progression included GFAP, CYB5R3, DARS, KIAA0513, EZR, KCNC1, COLEC12, and TST.

Common mechanisms underlying axonal transport deficits in neurodegenerative diseases: a mini review.

Many neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are characterized by the accumulation of pathogenic proteins and abnormal localization of organelles. These pathological features may be related to axonal transport deficits in neurons, which lead to failures in pathological protein targeting to specific sites for degradation and organelle transportation to designated areas needed for normal physiological functioning. Axonal transport deficits are most likely early pathological events in such diseases and gradually lead to the loss of axonal integrity and other degenerative changes. In this review, we investigated reports of mechanisms underlying the development of axonal transport deficits in a variety of common neurodegenerative diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease and Huntington's disease to provide new ideas for therapeutic targets that may be used early in the disease process. The mechanisms can be summarized as follows: (1) motor protein changes including expression levels and post-translational modification alteration; (2) changes in microtubules including reducing stability and disrupting tracks; (3) changes in cargoes including diminished binding to motor proteins. Future studies should determine which axonal transport defects are disease-specific and whether they are suitable therapeutic targets in neurodegenerative diseases.

ONO-2506 Can Delay Levodopa-induced Dyskinesia in the Early Stage.

BACKGROUND: Levodopa-induced dyskinesia (LID) is a common motor complication of levodopa (L-DOPA) treatment for Parkinson's disease (PD). In recent years, the role of astrocytes in LID has increasingly attracted attention. OBJECTIVE: To explore the effect of an astrocyte regulator (ONO-2506) on LID in a rat model and the potential underlying physiological mechanism. METHODS: Unilateral LID rat models, established by administering 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle through stereotactic injection, were injected with ONO-2506 or saline into the striatum through brain catheterization and were administered L-DOPA to induce LID. Through a series of behavioral experiments, LID performance was observed. Relevant indicators were assessed through biochemical experiments. RESULTS: In the LID model of 6-OHDA rats, ONO-2506 significantly delayed the development and reduced the degree of abnormal involuntary movement in the early stage of L-DOPA treatment and increased glial fibrillary acidic protein and glutamate transporter 1 (GLT-1) expression in the striatum compared to saline. However, there was no significant difference in the improvement in motor function between the ONO-2506 and saline groups. CONCLUSIONS: ONO-2506 delays the emergence of L-DOPA-induced abnormal involuntary movements in the early stage of L-DOPA administration, without affecting the anti-PD effect of L-DOPA. The delaying effect of ONO-2506 on LID may be linked to the increased expression of GLT-1 in the rat striatum. Interventions targeting astrocytes and glutamate transporters are potential therapeutic strategies to delay the development of LID.