Repurposing CETP inhibitors for the treatment of Alzheimer’s disease
Alzheimer’s disease is the most common cause of dementia. We now understand that the first changes of Alzheimer’s disease occur in the brain 15-30 years before clinical symptoms appear. We therefore need treatments that prevent or arrest the progression of Alzheimer’s disease in these early stages. At a molecular level, protein fragments called amyloid-beta aggregate in the brain, resulting in large amyloid deposits (plaques) that are the defining pathologic feature of Alzheimer’s disease. Conditions that elevate amyloid-beta production are contributing to Alzheimer’s disease, whereas interventions that reduce amyloid formation may help to prevent the disease. A protein called CETP promotes increased blood cholesterol, an established risk factor for Alzheimer’s disease. Impaired CETP function seems to relate to healthy brain aging or even protection from Alzheimer’s disease. However, CETP has never been investigated in the context of Alzheimer’s disease. Interestingly, drugs were developed to block CETP function. In this proposal, we will investigate if such drugs enter the brain and if they may indeed ameliorate Alzheimer’s disease in a mouse model. If our project is successful, we hope to suggest to use those existing drugs for a new purpose: for the treatment of Alzheimer’s disease.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
There is currently no effective treatment available to prevent, halt or stop Alzheimer’s disease. The fast identification of a therapeutic intervention is therefore desirable, which can be best achieved with a pharmacological strategy called drug repurposing. Here, an already existing drug used for other diseases is ‘simply’ repurposed for the treatment of Alzheimer’s disease, because research has proven its beneficial effects in Alzheimer’s disease. In this project, we investigate CETP blockers for their effect on Alzheimer’s disease. If our study is successful, we will have a drug in hands that could indeed help millions of Alzheimer’s patients worldwide.
We anticipate to observe that CETP blockers enter the brain and block CETP function in the brain. We expect that mice treated with this blocker will generate less amyloid-beta peptides in the brain and maintain good cognitive functions in memory tests.