Will targeting impaired brain metabolism and inflammation help improve brain changes related to Alzheimer’s disease?
Aida Adlimoghaddam, Ph.D.
St. Boniface General Hospital
Specialized structures inside cells, known as mitochondria, are the powerhouse of energy generation for the cells. Mitochondria typically keep themselves healthy, in part, through a quality control process known as mitophagy, in which damaged mitochondria are identified and removed. Studies suggest that this process of mitophagy becomes dysfunctional early on in Alzheimer’s and other brain diseases which can lead to a reduced energy production (metabolism) in brain cells. Such build-up may negatively impact brain function and lead to various dementia-related brain changes, including beta-amyloid plaques and tau tangles (two hallmark brain changes of Alzheimer’s) and increased inflammation in the brain.
Identifying ways to improve the process of mitophagy and other clearance mechanims are potential therapeutic targets for Alzheimer’s and other brain diseases. Nilotinib is a therapy currently approved for the treatment of a specific type of blood cancer and has recently shown benefit in patients with Alzheimer’s. Studies have shown this drug is able to help clear beta-amyloid plaques and tau tangles and also stimulates mitophagy. Dr. Adlimoghaddam has also shown that nilotinib can help improve energy production in the brain cells of genetically engineered Alzheimer’s-like mice. In addition to nilotinib, Lithium is a drug that has been shown to reduce inflammation, and enhance the brain's ability to clear unwanted proteins, such as beta-amyloid and tau tangles. Dr. Adlimoghaddam and team will study if combining nilotinib and lithium could help improve energy production and reduce Alzheimer’s related brain changes.
Dr. Adlimogghaddam and colleagues will study the effects of nilotinib and lithium on brain metabolism, inflammation, and other brain changes . Lithium and nilotinib will be given to older genetically-engineered Alzheimer’s-like mice for 4 weeks. A group of cognitively unimpaired mice will also receive the drug combination and be included in the study for comparison. After those 4 weeks all mice will undergo a set of experiments to assess the effect of both nilotinib and lithium on memory and cognitive function. They will also perform brain scans on the mice to assess the drug’s effect on metabolism. Finally, they will analyze brain tissue to evaluate if the drugs played a role in improving mitophagy, reducing inflammation, and removing Alzheimer’s-related brain changes.
If the combination of lithium and nilotinib is successful in reducing Alzheimer’s related brain changes, it could lead to studying this combination of drugs in larger animals and ultimately lay the groundwork for human clinical trials. These drugs are both already FDA approved and known to be safe to use in humans, which will allow for an easy transition into clinical trials.
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