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Can targeting brain inflammation lead to decreased beta-amyloid in Alzheimer's as a potential therapy?
Enza Lacivita
University of Bari, Department of Pharmacy
Bari, Italy
Background
Alzheimer's is characterized by the accumulation of the protein fragment beta-amyloid in the brain. Specialized immune cells that live in the brain called microglia stimulate response to remove beta-amyloid, by releasing inflammatory molecules. Under normal circumstances, this inflammatory response is turned off by a group of proteins called specialized pro-resolving mediators (SPM). In Alzheimer's, however, the levels of SPM are decreased so the inflammatory response to beta-amyloid is not turned off. The resulting chronic state of inflammation in a brain with Alzheimer's contributes to a further increase in beta-amyloid levels and this may lead to nerve cell damage and death.
Previous work in microglia cells grown in a laboratory dish and studies in animals have shown that one of these SPM molecules called LXA4, can reduce inflammation, reduce beta-amyloid levels and protect nerve cells. These studies suggested that SPMs could be used as potential therapies against chronic brain inflammation in Alzheimer's. However, LXA4 is quickly broken down in the body and removed before reaching the brain.
Research Plan
Dr. Enza Lacivita has convened a team that includes experts at University of Bari, Polish Academy and Aachen University. Together, Dr. Lacivita will design small molecules similar to LXA4 that will reduce inflammation in the brain and can also reach the brain. They will first determine how quickly these small molecules move throughout the body and are removed from the system. The team will also confirm that these molecules can cross from the bloodstream to the brain.
The most promising small molecules from these initial experiments will then be examined to narrow down those that may be developed into a potential therapeutic for Alzheimer's.
To do this, the research team will mix the promising molecules with microglia cells grown in a dish to determine the effect on cell health and the production of factors that cause inflammation. The candidate molecules that pass these tests will be used to treat genetically engineered Alzheimer's-like mice to examine the effect on brain inflammation, as well as memory and learning.
Impact
Dr. Lacivita and team are exploring a novel set of molecules and the related underlying biology. If successful, the study results could help identify a novel approach to develop therapies for Alzheimer's.
This project is sponsored by the Alzheimer's Association, Colorado Chapter.
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