Cholesterol may be key to new therapies for Alzheimer’s disease, diabetes

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A University of Arizona health science researcher examined 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 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. In the last decade, scientists have found more and more evidence linking the underlying causes of type 2 diabetes and Alzheimer’s disease.

Type 2 diabetes occurs when insulin becomes less effective in removing glucose from the bloodstream, resulting in high blood sugar that can cause abnormal cholesterol levels. A similar situation occurs with Alzheimer’s disease, but instead of affecting the body as a whole, the effects are localized in the brain.

“Alzheimer’s disease and diabetes have many common causes,” said Dr. Gregory Thatcher, Professor of Pharmacology and Toxicology at the Faculty of Pharmacy in UArizona and newly appointed R. Ken and Donna Coit in charge of the Department of Drug Discovery. “Our goal was to develop a way to identify compounds that would counteract the many harmful changes that contribute to both Alzheimer’s disease and type 2 diabetes.”

The article “Detection of non-lipogenic ABCA1 inductive compounds with potential in Alzheimer’s disease and type 2 diabetes” was published in the journal ACS Pharmacology and Translation Sciences.

When cholesterol rises, due to resistance to insulin or other factors, the body begins a process known as reverse transport of cholesterol, during which certain molecules carry excess cholesterol to the liver to be excreted. 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, and 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 aware of the so-called ‘good cholesterol’ and ‘bad cholesterol’ associated with the risk of heart attack and stroke, these broad concepts are also applicable to a healthy brain,” said Dr. Thatcher, who has been working on the development of advanced therapy for Alzheimer’s disease for more than 20 years. “Moving cholesterol where it is needed in the body has a positive effect on many physiological processes and can help clean up misfolded proteins that accumulate in the brain.”

Increasing ABCA1 activity 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 devised a way to identify small molecules that improve ABCA1 function in the body, while avoiding side effects on the liver.

In the March 20 magazine EBioMedicine, “Metabolomic analysis of selective inducer ABCA1 in obesogen challenge provides an explanation for therapeutic development”, team dr. Thatcher perfected a specific small molecule, CL2-57, because of its ability to stimulate ABCA1 activity with positive effects on liver and plasma triglycerides. The use of this compound has shown improved glucose tolerance and insulin sensitivity, as well as reduced weight gain, among other beneficial effects.

Their future research will seek to improve the properties of small molecules to increase levels in the brain. Their long-term goal is to understand which patients suffering from cognitive and neuropsychiatric symptoms of Alzheimer’s disease and dementia will benefit from treatment.

“During the COVID-19 pandemic, we hear about an increase in deaths in nursing homes, and it’s important to remember that Alzheimer’s disease and related dementia are a major cause of the relocation of the elderly to nursing homes,” said Dr. Thatcher. “It would be good to think about a future where life expectancy has been extended, especially a healthy brain; maybe that’s more important than life expectancy.”

A potential target of diabetes-related Alzheimer’s disease

More information:
Manel Ben Aissa et al., Detection of non-lipogenic ABCA1 inducing compounds with potential in Alzheimer’s disease and type 2 diabetes, ACS Pharmacology and Translation Sciences (2021). DOI: 10.1021 / acsptsci.0c00149

Provides the University of Arizona on health sciences

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