ApoA1 Identified as a Novel Target for ALS Therapy

Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig’s disease, is a fatal neurodegenerative disorder that affects approximately 350,000 people worldwide.¹ Most cases of ALS have no identified cause, and there is currently no cure for this disease. ALS attacks and damages nerve cells in the brain and spinal cord, leading to loss of muscle control.² Most ALS research focuses on the study and treatment of motor neurons; however, researchers now believe that dyslipidemia—the imbalance of lipids such as cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides—is also an important component of ALS disease pathology.³ Researchers have also observed dyslipidemia in other nervous system disorders, making its study even more important.⁴

Studies have shown that alterations in neurovascular unit function—the relationship between brain cells and blood vessels—are associated with ALS onset, and lipid metabolism plays a major role in vascular maintenance.^5,6,7 “Since there is neurovascular impairment and no one has really touched on neurovasculature in ALS, we thought this could be a novel approach,” said Cesario Borlongan, a professor at the University of South Florida. Borlongan and his team recently published a study in eNeuro showing that Apolipoprotein A1 (ApoA1), a protein that regulates lipid metabolism and is associated with vascular damage prevention, could be a novel target for ALS therapy.^8,9

Borlongan and his team performed in vitro studies by exposing wild-type mouse brain vascular cells to plasma from an ALS mouse model. Plasma exposure killed many of the vascular cells, but when the researchers added ApoA1, vascular cell survival significantly improved. The scientists then co-cultured the ALS plasma-exposed vascular cells with healthy human vascular progenitor cells. They found that co-culture with human cells that naturally express ApoA1 significantly decreased mouse vascular cell death. Overall, the researchers showed that not only does ApoA1 rescue vascular cell death when added exogenously, but it can also reverse cell death when expressed from a nearby progenitor cell. 

For reasons that are hard to explain or hard to understand, actually, we know very little about lipid changes in ALS. 
- Daniela Zarnescu, Penn State University.

These results suggest that researchers could use ApoA1 as a treatment to address the neurovascular defects observed in ALS and perhaps other neurovascular diseases. “For reasons that are hard to explain or hard to understand, actually, we know very little about lipid changes in ALS. Yet, I also think it's one of the areas that perhaps can have the most impact,” said Daniela Zarnescu, a professor at Penn State University who was not involved in the study. “I think using genetic approaches would be really important moving forward. It's a great start into what could be potentially therapeutic strategy.”

“The biggest challenge to me is how can we really put this product from the lab to the clinic,” said Borlongan. “It's a simple type of cell culture system. And whether that's translatable to the clinic, of course, we need to go to the animal model.” In the future, Borlongan and his team also plan to test whether delivering ApoA1 as a drug or via stem cell treatments is more effective at addressing the progressive nature of ALS.