UArizona researchers have found a unique approach to tackle both Alzheimer’s disease and diabetes

Researchers at the University of Arizona Health Sciences are investigating the role of cholesterol in both Alzheimer’s disease and type 2 diabetes, identifying small molecules that may help regulate cholesterol levels in the brain, and new therapeutic targets for Alzheimer’s disease. There is a possibility that

There is no known cure for Alzheimer’s disease, which affects more than 5.5 million people in the United States. Over the last decade, scientists have found increasing evidence associated with the underlying causes of type 2 diabetes and Alzheimer’s disease.

Type 2 diabetes occurs when insulin reduces the efficiency of removing glucose from the bloodstream, causing hyperglycemia, which can cause abnormal cholesterol levels. A similar situation occurs with Alzheimer’s disease, but the effects are localized to the brain rather than affecting the entire body.

Alzheimer’s disease and diabetes share many common causes. Our goal was to develop a method to identify compounds that counteract many of the harmful changes that contribute to both Alzheimer’s disease and type 2 diabetes. “

Dr. Gregory Thatcher, Professor of Pharmacology and Toxicology, U Arizona College of Pharmacy, and newly named R. Ken and Donna Coit donate drug discovery chairs

The paper “Discovery of Potential Non-Lipogenic ABCA1-Inducing Compounds in Alzheimer’s Disease and Type 2 Diabetes” was published in the journal ACS Pharmacology and Translation Science..

When cholesterol rises due to insulin resistance or other factors, the body begins a process called reverse cholesterol transport. In this process, certain molecules carry excess cholesterol to the liver and excrete it. Apolipoprotein E (APOE) is one of the proteins involved in the reverse transport of cholesterol.

APOE is the most potent risk factor gene for Alzheimer’s disease and associated dementia, and is also an independent risk factor for type 2 diabetes and cardiovascular disease. Similarly, reduced 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.

“Most people are aware of the so-called” good cholesterol “and” bad cholesterol “that are associated with the risk of heart attack and stroke, but these broad concepts also apply to a healthy brain,” Dr. Thatcher said. Stated. For over 20 years, he has been working on the development of advanced treatments for Alzheimer’s disease. “Move cholesterol to where it’s needed in the body has a positive effect on many physiological processes and helps get rid of accidentally folded proteins that accumulate in the brain.”

Increasing the activity of ABCA1 is expected to have a positive effect on insulin signaling and reduce inflammation in the brain, making it a potential treatment for both type 2 diabetes and Alzheimer’s disease. In this study, Dr. Thatcher and his team designed a way to identify small molecules that improve the function of ABCA1 in the body while avoiding unwanted effects on the liver.

In the March 20th paper of the journal EBioMedicine“A metabolomics analysis of selective ABCA1 producers in obesity-induced challenges provides a rationale for therapeutic development,” said Dr. Thatcher’s team on the ability to stimulate ABCA1 activity, which has a positive effect on the liver. Polished a specific small molecule CL2-57. Plasma triglyceride. The use of this compound showed improved glucose tolerance and insulin sensitivity, as well as reduced weight gain, among other beneficial effects.

Their future research aims to improve the properties of small molecules to raise 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.

“We hear about the increase in deaths in nursing homes during the Covid-19 pandemic. Remember that Alzheimer’s disease and associated dementia are the main causes of elderly people moving to nursing homes. Is important, “said Dr. Thatcher. “It’s good to think about a future with extended healthy life expectancy, especially a healthy brain. Perhaps it’s more important than life expectancy.”