Lipid Metabolism Mechanisms in Neurodegenerative Diseases: A New Study on Multiple Sclerosis

Multiple Sclerosis (MS) is a common inflammatory autoimmune demyelinating disease of the central nervous system (CNS). As the disease progresses, patients gradually experience neurological damage and disability. Although there have been advances in the treatment of relapsing forms of Multiple Sclerosis in recent years, effective therapeutic methods to slow the neurodegenerative process for patients with later-stage progressive Multiple Sclerosis (PMS) are still lacking. Due to the complexity of its pathological mechanisms, current treatments find it difficult to specifically protect neural cells and slow further deterioration of neurological functions. Therefore, understanding the key pathogenic mechanisms in PMS and developing new therapeutic targets presents a significant challenge for academia.

Research Background and Team

To explore the metabolic mechanisms behind the neurodegenerative changes in the brains of PMS patients, researchers Rosana-Bristena Ionescu, Alexandra M. Nicaise, Angelo D’Alessandro, and others conducted an innovative study. This study was published in the November 2024 issue of the journal “Cell Stem Cell” and was a collaborative effort from multiple international research teams, including the University of Cambridge’s Department of Clinical Neurosciences and the University of Colorado School of Medicine. The research unveiled how neural progenitor cells in PMS patients lead to neurotoxicity through metabolic alterations, thus providing new insights for lipid metabolism-targeted therapies for PMS.

Research Methods and Process

This study generated induced Neural Stem Cells (iNSCs) from the skin fibroblasts of PMS patients through direct reprogramming to study their senescence phenotype in vitro. These cells exhibited significant signs of aging, activated inflammatory signaling, and a high metabolic state. The research process included the following major steps:

1. Cell Reprogramming and Phenotype Detection
   The research team reprogrammed the skin fibroblasts of PMS patients into iNSCs and used immunocytochemistry to detect their characteristic markers. The iNSCs of PMS displayed an upregulation of senescence-associated gene expression, such as CDKN2A, indicating an inflammatory-related senescence-associated secretory phenotype (SASP).

2. Metabolic Pathway Analysis
   Using mass spectrometry, researchers analyzed the metabolites of PMS iNSCs. The results showed notably active glycolysis and lipid metabolism pathways in these cells, leading to lipid droplet accumulation. These metabolic activities were mediated by HMG-CoA reductase (HMGCR), promoting the synthesis of cholesterol and fatty acids. Key metabolites in this process, like glucose and glutamine, were rapidly converted to lipid precursor molecules within the cells and formed large amounts of lipid droplets in the cytoplasm.

3. Effect of SASP on Neurotoxicity
   The study demonstrated that the SASP of PMS iNSCs drives neurotoxicity through cholesterol-dependent transcription factors. Experiments revealed that secretions from these senescent iNSCs could induce a neurotoxic reaction in mature neurons, characterized by dendritic shortening and increased apoptosis. Further integrative omics analysis indicated that this neurotoxic effect was related to various secretory factors, including matrix metalloproteinase (MMP2) and fibronectin (FN1).

4. Drug Intervention Trials
   To explore the possibility of drug intervention, researchers used the FDA-approved drug simvastatin, an HMGCR inhibitor. The experimental results showed that simvastatin effectively inhibited cholesterol synthesis, significantly reduced the SASP level of PMS iNSCs, and mitigated their neurotoxic effects. Post-treatment with simvastatin not only reduced the accumulation of lipid droplets in iNSCs but also restored some protective properties of the cells, alleviating their neurotoxicity.

Research Results

The main findings of this study include:

1. High Metabolic Phenotype of PMS iNSCs
   PMS iNSCs exhibited a unique high metabolic phenotype, significantly increasing metabolic activity in glycolysis, cholesterol synthesis, and fatty acid synthesis. These metabolic activities resulted in the accumulation of large lipid droplets, which is commonly associated with cell aging and activation of inflammatory signals.

2. Cholesterol-Dependent Neurotoxic SASP
   The SASP of PMS iNSCs induced neurotoxic secretions through cholesterol-dependent pathways, leading to a neurotoxic response in mature neurons. Integrative omics analysis revealed that the secretions from the SASP are related to several biological processes, including extracellular matrix remodeling, axon guidance, and ROS detoxification.

3. Potential Protective Effects of Simvastatin
   Drug intervention trials showed that simvastatin can remodel the SASP of PMS iNSCs by inhibiting HMGCR activity and reducing neurotoxicity. By regulating intracellular cholesterol levels, simvastatin can restore some protective properties of the cells, providing a new direction for the clinical treatment of PMS patients.

Research Significance and Potential Applications

This study is the first to reveal the pathological changes in metabolism and secretions in PMS iNSCs, highlighting the central role of cholesterol synthesis in the pathogenesis of PMS. This finding has significant scientific and clinical implications:

1. Scientific Significance
   The research shows that metabolic reprogramming in the neural progenitor cells of PMS patients leads to lipid accumulation and an enhanced SASP, a change commonly seen in cell models of aging and neurodegenerative diseases. This study enriches our understanding of the cell biological mechanisms in PMS and provides a new perspective on the metabolic pathology in PMS and other neurodegenerative diseases.

2. Clinical Application Potential
   The intervention trials with simvastatin provide a foundation for future development of cholesterol metabolism-regulating treatments for PMS. By controlling the metabolic phenotype of PMS iNSCs, this method could potentially slow disease progression in clinical settings, protecting neural cells from damage. Further studies could evaluate the potential of simvastatin or other cholesterol inhibitors in treating neurodegenerative diseases.

Research Highlights and Innovations

• Innovative Methods: This study utilized direct reprogramming techniques to generate neural progenitor cells with senescence characteristics from patient fibroblasts, maintaining the senescence phenotype and making the research closer to the real disease state.
• Metabolic Regulation Mechanisms: This study was the first to clarify the critical role of cholesterol metabolism in PMS iNSCs, indicating that metabolic reprogramming is a key factor leading to neurotoxic SASP.
• New Directions for Drug Intervention: The discovery that simvastatin can effectively reverse the SASP of PMS iNSCs and reduce neurotoxicity provides a potential for developing new PMS treatment methods in the future.

Conclusion and Outlook

Through the study of the metabolic characteristics of neural progenitor cells in PMS patients, this research revealed the relationship between cholesterol synthesis and neurotoxicity, proposing a treatment strategy targeting cholesterol metabolism. In the future, researchers can further explore the impact of other metabolic pathways on PMS and evaluate the efficacy of different cholesterol inhibitors in clinical treatments. Additionally, this study provides a cautionary note for future patient-specific stem cell therapy strategies; when using autologous cells for stem cell therapy, potential pathological characteristics inherent in the cells may need further processing.