The Yassine Lab uses this innovation to study how APOE4 affects brain lipids and inflammation. He is studying the role lipids in the brain might play in brain health.
APOE4 also impacts how fats and other nutrients, which are important for correct maintenance of the brain, are delivered to the brain. It has been revealed that APOE4, for example, can lead to break down of fatty acids, such as omega-3, which might describe why APOE4 carriers with Alzheimers lack certain omega-3 fatty acids in the brain and might not respond to supplements as soon as dementia establishes. By comprehending the variety of methods APOE4 may initiate the process of system failures in the brain, Yassine hopes to find methods to intervene long prior to neurons pass away, preventing the advancement of Alzheimers and other dementias.
Yassine Lab. Credit: USC
USC endocrinologist takes Alzheimers disease research study in new directions.
A USC Keck School of Medicine scientist discovers possible brand-new methods to avoid cognitive decline by studying the APOE4 gene and its effect on brain inflammation and fat metabolism.
For decades, the considering Alzheimers illness has been dominated by the so-called amyloid hypothesis which proposes that an unusual build-up of amyloid-beta plaques in different parts of the brain is the primary chauffeur of a cascade of events, resulting in the loss of synapses and the death of neurons causing deficits in cognition and memory.
As the search for a reliable treatment continues, some scientists have actually begun exploring brand-new ways of thinking about Alzheimers illness in the hope of discovering brand-new, more appealing methods to avoid and treat this and other types of dementia.
Family pet image of the brain of an APOE4 target replacement mouse model injected with a radioactive arachidonic acid tracer established with Kai Chen, PhD/USC Radiology. The Yassine Lab utilizes this technology to study how APOE4 impacts brain lipids and swelling.
One such researcher is Hussein Yassine, MD, an endocrinologist who treats clients with diabetes and lipid conditions. Lipids are natural compounds that are insoluble in water, such as fats and oils, and they serve various functions in the body. He is studying the role lipids in the brain may play in brain health.
” There is considerable factor to believe it is not only the accumulation of amyloid which there are lots of other methods people can develop Alzheimers illness and other kinds of dementia,” stated Hussein Yassine, MD, associate professor of medication and neurology at the Keck School of Medicine of USC. “The system that keeps the brain healthy is complex and there are numerous methods that it can stop working.”
The APOE4 gene and its link to system failures in the brain
Yassine has actually invested the past years studying the function of a particular variation of the apolipoprotein E (APOE) gene, which is included in lipid metabolic process. APOE is a protein that makes lipids soluble in the blood and carries lipids in the body as high-density lipoprotein (HDL).
The variant, called APOE4, is a recognized threat factor for developing Alzheimers and is present in as much as 50% of all people with Alzheimers dementia. The APOE gene has various functions in the brain and APOE4 is linked to several different types of system failure, all of which can put a person at risk of developing Alzheimers illness.
” In APOE4 carriers, it seems that when the system is stressed, a variety of things can fail. The blood vessels can become leaky, swelling can persist longer, the brain may not be getting the energy it needs from the remainder of the body,” stated Yassine. “APOE4 is also associated with low grade inflammatory processes within the brain, which was as soon as believed to be an outcome of Alzheimers illness but is now acknowledged to be one of the drivers. There are lots of methods the system can get struck and we do not believe it is just something that can cause Alzheimers. Some individuals with APOE4 might never get this disease, but with more hits, the system in APOE4 providers begins to stop working.”
APOE4s impact on fatty acids in the brain
APOE4 also impacts how fats and other nutrients, which are essential for proper maintenance of the brain, are provided to the brain. It has been shown that APOE4, for instance, can cause break down of fatty acids, such as omega-3, which may describe why APOE4 carriers with Alzheimers lack certain omega-3 fats in the brain and may not react to supplements as soon as dementia develops. By comprehending the variety of ways APOE4 may initiate the procedure of system failures in the brain, Yassine hopes to discover ways to step in long prior to nerve cells pass away, avoiding the development of Alzheimers and other dementias.
” We want to comprehend how APOE4 changes the brain from age 20 to 80 due to the fact that a lot is happening in midlife that impacts the aging brain,” stated Yassine. “By the time individuals develop symptoms, it is far too late for intervention, so we require to understand what modifications are taking place long before neurons start to die.”
One focus of Yassines lab is understanding the mechanisms behind faulty lipid metabolic process and neuroinflammation, in the hopes of determining brand-new treatment targets to avoid the development of Alzheimers. Yassines lab just recently recognized a protein understood as cPLA2, which is associated with the advancement of neuroinflammation, that is activated in brains of APOE4 carriers who developed dementia.
The search for brand-new treatments
Yassines team is teaming up with colleagues at the USC School of Pharmacy, and the Departments of Computational and quantitative Biology and Chemistry at USC Dornsife College of Letters, Arts and Sciences to find drugs that might inhibit cPLA2. An effective cPLA2 inhibitor could be a possible treatment to curb neuroinflammation and enhance the brain uptake of fatty acids in APOE4 carriers.
They have actually likewise introduced a scientific trial, called PREVENTE4, to check whether giving people with APOE4 high doses of omega-3 fatty acid supplements can prevent or cut cognitive decrease prior to Alzheimers illness establishes.
It has been shown that APOE4 oxidizes omega-3s which low levels of the long-chain omega-3 fatty acids DHA and EPA increase the danger of Alzheimers disease. In earlier research studies, Yassines team discovered that cognitively healthy individuals who took omega-3 supplements had 200 percent more DHA in their blood compared to the control group and 28 percent more in the cerebrospinal fluid, a measure of brain uptake. APOE4 carriers had lower increases in brain DHA and EPA than non-carriers after supplements.
In addition, Yassine is studying HDL particles, the so-called good cholesterol, which physicians consistently test for in clients blood, however not in the brain. Yassines team assisted establish an assay to determine HDL in the brain and found that it associates with cognitive function. They have considering that identified a protein that increases HDL in blood and are attempting to determine if reengineering this protein can result in a brand-new treatment to increase the formation of brain HDL.
Yassine also integrates his proficiency as an endocrinologist with his interest in Alzheimers disease to explore the connection in between diabetes and Alzheimers illness. Most recently, he released an evaluation on the usage of a class of diabetes drugs understood as glucagon-like peptide 1 receptor agonists, which, appear to have considerable neuroprotective effects and are being evaluated as treatments for Alzheimers disease.
Yassine is starting a center for dementia prevention in the Department of Neurology at the Keck School that will concentrate on APOE4 providers and others at high danger for dementia. Yassine will use his clinical background in endocrinology and nutrition to assist patients with tailored suggestions on diet, way of life, lipids, high blood pressure, and sugar control with the objective of promoting vascular health and brain health.
Ultimately, he intends to develop a Center for Personalized Brain Health with distinct expertise in APOE4 education, training and research, and scientific trials. The center would also offer carriers of APOE4 with customized, tailored scientific care through the course of their adult lives that might potentially help prevent Alzheimers illness.
” There is a lot more research that needs to be done, but we are making tremendous development,” said Yassine. “There is absolutely reason to be enthusiastic. And the more research we do, the more we are going to have the ability to establish brand-new treatments to assist APOE4 providers prevent developing this ravaging illness.”
