A researcher from the University of Arizona Health Sciences studied the role of cholesterol in both Alzheimer’s disease and type 2 diabetes to identify a small molecule that can help regulate cholesterol levels in the brain, making it a potential new one makes therapeutic target for Alzheimer’s disease.
There is no known cure for Alzheimer’s disease, which affects more than 5.5 million people in the United States. Over the past decade, scientists have found increasing evidence linking the underlying causes of type 2 diabetes and Alzheimer’s disease.
Type 2 diabetes occurs when insulin removes glucose from the bloodstream less efficiently, resulting in high blood sugar that can lead to abnormal cholesterol levels. A similar situation occurs with Alzheimer’s disease, but instead of affecting the entire body, the effects are localized in the brain.
Alzheimer’s and diabetes have many common causes. Our goal was to find a way to identify compounds that counteract many of the harmful changes that contribute to both Alzheimer’s and type 2 diabetes. “
Gregory Thatcher, PhD, Professor of Pharmacology and Toxicology, UArizona College of Pharmacy and the renamed R. Ken and Donna Coit Endowed Chair of Drug Discovery
The paper “Discovery of Non-lipogenic ABCA1-Inducing Compounds with Potential for Alzheimer’s Disease and Type 2 Diabetes” was published in the journal ACS Pharmacology and Translational Science.
When cholesterol levels rise due to insulin resistance or other factors, the body starts a process known as reverse cholestrol transport, in which certain molecules move excess cholesterol into the liver for excretion. Apolipoprotein E (APOE) is one of the proteins involved in the reverse transport of cholesterol.
APOE is also the strongest risk factor gene for Alzheimer’s disease and related dementia, as well as an independent risk factor for type 2 diabetes and cardiovascular disease. Similarly, decreased activity of another cholesterol transporter, the ATP-binding cassette transporter A1 (ABCA1), correlates with an increased risk of cardiovascular disease, type 2 diabetes and Alzheimer’s disease.
“While most people are familiar with the so-called ‘good cholesterol’ and ‘bad cholesterol’ that are linked to the risk of heart attack and stroke, these broad concepts apply to a healthy brain,” said Dr. Thatcher We have been developing advanced therapeutics for Alzheimer’s for more than 20 years. “Moving cholesterol to where it’s needed in the body has beneficial effects on many physiological processes and can help clear out misfolded proteins that build up in the brain.”
Increasing the activity of ABCA1 is expected to positively affect insulin signaling and reduce inflammation in the brain, making it a potential therapy for both type 2 diabetes and Alzheimer’s disease. In this study, Dr. Thatcher and the research team found a way to identify small molecules that improve the way ABCA1 works in the body while avoiding undesirable effects on the liver.
In an article in the journal EBioMedicine on March 20, “The metabolomic analysis of a selective ABCA1 inducer in obesogenic exposure provides a justification for the therapeutic development”, investigated Dr. Thatcher’s team identified a specific small molecule, CL2-57, for its ability to stimulate ABCA1 activity with beneficial effects on liver and plasma triglycerides. The use of this compound showed, among other things, improved glucose tolerance and insulin sensitivity and reduced weight gain.
Your future research will aim to improve the properties of the small molecules to increase levels in the brain. Your long-term goal is to understand which patients suffering from the cognitive and neuropsychiatric symptoms of Alzheimer’s and dementia will benefit from treatment.
“During the Covid-19 pandemic, we hear of increasing deaths in nursing homes and it’s important to keep in mind that Alzheimer’s and related dementia are a leading cause of elderly people moving to nursing homes,” said Dr. Thatcher. “It would be good to think of a future where health spans have been extended, especially a healthy brain. Maybe that’s more important than lifespan.”
University of Arizona Health Sciences
Aissa, MB et al. (2021) Discovery of non-lipogenic ABCA1-inducing compounds with potential for Alzheimer’s and type 2 diabetes. ACS Pharmacology & Translational Science. doi.org/10.1021/acsptsci.0c00149.