Neuronal AMPK Regulates Microglial Lipid Droplet Accumulation in Tauopathy Brain
Accumulation of Lipid Droplets in Microglia is Regulated by Neuronal AMPK
Background and Research Question
Alzheimer’s Disease (AD) is a common type of dementia characterized by neurofibrillary tangles and β-amyloid plaques. However, beyond these classical pathologies, changes in lipid metabolism are increasingly recognized as closely associated with the development of AD and other age-related neurodegenerative diseases. Lipid droplets (LDs), essential organelles for intracellular lipid storage, play a critical role in regulating cellular metabolism and responding to oxidative stress. In the brains of AD patients, particularly in neurons associated with tau pathology, abnormal accumulation of lipid droplets has been repeatedly observed. However, the specific cellular and molecular mechanisms underlying this phenomenon remain unclear.
Research Origin
This research was conducted by Yajuan Li, Daniel Munoz-Mayorga, Yuhang Nie, and others from multiple departments at the University of California, San Diego (UCSD), including the Departments of Bioengineering, Neurosciences, and Pediatrics. The study was published in the journal Cell Metabolism on June 4, 2024, under the title “Microglial Lipid Droplet Accumulation in Tauopathy Brain is Regulated by Neuronal AMPK.”
Research Methods
To explore the mechanisms of lipid droplet accumulation in tauopathy, the research team first employed label-free Stimulated Raman Scattering (SRS) microscopy. SRS imaging technology allows direct in situ observation of the distribution and dynamic changes of lipid droplets in brain tissues, avoiding potential cellular damage from traditional fluorescent dyes. The team also used deuterium oxide (D2O) labeling to track the metabolic pathways of newly synthesized lipids within cells.
The experiments involved mouse, fly, and neuron models derived from induced pluripotent stem cells (iPSCs), all expressing tau protein mutations to simulate tauopathy. Through SRS imaging and D2O labeling, the research team meticulously recorded and analyzed the formation, distribution, and dynamic changes in lipid metabolism in these models.
Additionally, the study used genetic and pharmacological approaches to investigate the role of AMP-activated protein kinase (AMPK) in neurons and glial cells, and evaluated its impact on lipid droplet accumulation and neuroinflammation in tauopathy brains.
Research Results
Lipid Droplet Accumulation in Microglia: SRS imaging of the brains of mice expressing the P301S tau mutation (PS19 mice) revealed that, compared to wild-type mice, tauopathy mice exhibited substantial lipid droplet accumulation in the hippocampus, a phenomenon particularly prominent in older mice. Further experiments indicated that these lipid droplets mainly accumulated in microglia and astrocytes, while the proportion in neurons was relatively low.
Lipid Metabolism Impairment in Tauopathy Neurons: Using a fly model, the study found that the brains of flies overexpressing human tau protein showed significantly increased lipid droplet formation and inefficient lipid metabolism. Neurons generated from iPSCs with the tau mutation (V337M) displayed similar characteristics of lipid droplet accumulation and metabolic dysfunction.
Lipid Transfer Between Neurons and Microglia: In vitro co-culture experiments demonstrated that tauopathy neurons could transfer excess unsaturated lipids to microglia via Neuronal Conditioned Media (NCM), leading to lipid droplet accumulation, increased oxidative stress, and impaired phagocytosis in microglia. D2O labeling further confirmed this direct lipid transfer phenomenon.
AMPK Regulation of Lipid Droplet Accumulation: The study found that activating AMPK in neurons could reduce lipid synthesis and promote lipophagy, thereby decreasing lipid transfer to microglia. Conversely, reducing AMPK expression in neurons resulted in severe lipid droplet accumulation, exacerbating neuroinflammation and neurotoxicity.
Research Significance
This study, for the first time, visually demonstrated the accumulation of endogenous lipid droplets in tauopathy brains using label-free SRS imaging technology, revealing the crucial role of neuronal AMPK in regulating brain lipid homeostasis. This discovery offers a new perspective on the pathological mechanisms of tauopathy, particularly in the metabolic communication and mutual influence between neurons and microglia. This understanding not only clarifies the pathogenesis of neurodegenerative diseases but also provides a theoretical foundation for developing novel therapeutic strategies targeting lipid pathology. For instance, enhancing AMPK activity to regulate lipid metabolism in neurons and glial cells could potentially alleviate neuroinflammation and related neuronal damage.
Research Highlights
- Innovation in Observation Methods: For the first time, the study applied label-free SRS imaging technology, avoiding potential cellular damage from traditional dyes, and combined it with D2O labeling to accurately track lipid metabolic dynamics.
- Revealing Metabolic Communication Between Neurons and Microglia: The study discovered that tauopathy neurons transfer lipids to microglia through conditioned media, leading to lipid droplet accumulation and functional impairment in microglia.
- Clarifying the Critical Role of AMPK in Regulating Lipid Metabolism: The study elucidated how AMPK reduces lipid droplet accumulation and mitigates neuroinflammation by inhibiting lipid synthesis and promoting lipophagy.
Summary
This study made breakthrough progress in elucidating the relationship between lipid metabolism abnormalities and microglial dysfunction in tauopathy. Using the latest label-free imaging technology and multiple model systems, the research team clarified the important role of neuronal AMPK in regulating brain lipid homeostasis. This research not only expands the understanding of the pathological mechanisms of neurodegenerative diseases like Alzheimer’s but also provides new ideas and technical support for the development of future therapeutic strategies.