Alzheimer’s disease progresses over time due to the spreading of aggregates of tau protein and amyloid protein from unaffected to affected regions of the brain. At this time, we do not understand how these aggregates spread and how to prevent the spreading. We recently discovered that taking out the USP19 gene in mice with Alzheimer’s-like disease slows the spread of aggregates, results in less inflammation in the brain, less brain atrophy and longer survival.

Our study will determine whether giving a chemical (a possible drug) that inhibits the action of the USP19 protein to the mice with Alzheimer’s like disease will have the same effect as the loss of the USP19 gene in the mice. We will also ask whether this potential drug acts by decreasing the activity of cells that cause inflammation in the brain.

We will give the potential drug or placebo to mice with Alzheimer’s-like disease for several months. We will test whether mice receiving the drug have better memory, less brain atrophy and less spreading of aggregates. We will also treat inflammatory cells isolated from the brain with the potential drug or placebo to see whether drug treated cells have less inflammatory activity. No one has previously studied USP19 or tested its inhibitor in Alzheimer’s disease.

The ability of the drug to prevent spreading of the protein aggregates in the brain and decrease inflammation in the brain will slow or stop the progression of the disease. Giving such a drug to people at high risk or to those in very early stages of the disease will prevent the development of dementia and therefore allow people to remain active with good cognition and independence.

These studies testing a potential drug in a mouse with Alzheimer’s-like disease are a critical step that needs to be accomplished before the potential drug can be tested in humans. Our studies may reveal possible challenges such as duration of action of the drug, ability to enter the brain when given orally, side effects, etc. This very useful information would allow the improvement of the drug before it is tested in human participants.