Question: What is the role of the DGAT2 enzyme in microglial lipid metabolism and Alzheimer's?

 Question: What is the role of the DGAT2 enzyme in microglial lipid metabolism and Alzheimer's?

Answer: The DGAT2 enzyme plays a critical and multifaceted role in microglial lipid metabolism and significantly impacts the progression of Alzheimer's disease.

Here's a breakdown of its function:

 

• Conversion of Free Fatty Acids into Triacylglycerols: DGAT2 is identified as a key enzyme that converts free fatty acids into triacylglycerols. Triacylglycerols are the main components of lipid droplets, which are intracellular storage units for fat.

 

• Facilitating Lipid Droplet Formation in Microglia: In the context of Alzheimer's disease, when microglia are chronically exposed to amyloid-beta (Aβ) plaques, they initially accumulate toxic free fatty acids. With the assistance of the DGAT2 enzyme, these free fatty acids are subsequently converted into triacylglycerols and stored within lipid droplets inside the microglia.

 

• Correlation with Disease Pathology: Studies have shown that in both mouse models of Alzheimer's and post-mortem human brain samples from patients with late-stage Alzheimer's, microglia located near amyloid plaques exhibit high DGAT2 expression. These microglia are often "bloated with lipid droplets," particularly in the hippocampus, a brain region crucial for memory. Researchers observed a direct correlation where "the closer they are [microglia] to plaques, the fatter they get," indicating that proximity to plaques correlates with lipid droplet size.

 

• Impairing Microglial Function: This DGAT2-mediated lipid build-up disrupts the microglia's ability to effectively engulf and digest more Aβ. Essentially, the microglia "sacrifice their protective immune function in exchange for lipid safety". This means that their crucial role of clearing waste products and toxic proteins like Aβ is compromised.

 

• Contribution to Alzheimer's Progression: The impairment of microglial function due to DGAT2-driven fat accumulation leads to a detrimental cycle: more plaques result in more fat accumulation, which in turn leads to more microglial dysfunction. This "trade-off may be a key step in Alzheimer’s progression," exacerbating the disease by allowing harmful proteins to accumulate further. This destruction in the brain can begin years, even decades, before symptoms appear.

 

• Therapeutic Potential: Research has demonstrated that blocking DGAT2 activity – either through a pharmacological inhibitor or a custom-designed PROTAC-like degrader specific to microglia – reduces fat accumulation in microglia. Crucially, this intervention restores their ability to clear amyloid plaques. Even a short, one-week treatment drastically reduced plaque burden by over 50% and significantly reduced neuronal damage markers in aged mice with severe pathology. This highlights DGAT2 as a promising therapeutic target for Alzheimer's.

 

• Considerations for Targeting DGAT2: While promising, it's noted that DGAT2 is expressed in many cell types throughout the body, so systemic targeting could lead to unwanted side effects. Therefore, the development of a microglia-specific DGAT2 degrader represents a significant and promising step towards a cell-selective therapy.