Abstract

The ultimate goal of this proposal is to test the effectiveness of early-stage treatment with two BACE1 inhibitor candidate drug compounds in genetically-altered mice that mimic signs of Alzheimer’s disease. This would tell us whether the compounds should be taken forward into clinical trials for patients with presymptomatic or mild disease. This study aims to gain proof that these compounds have real potential to slow down or prevent amyloid formation and thus act to modify the course of Alzheimer’s disease. A treatment that prevents or at least reduces the development of amyloid will be of great help to people, potentially giving increased years of higher quality of life, and delaying the onset of the worst symptoms. As there are no drugs currently on the market that actually stop the progression of the disease, a new treatment that can treat the underlying causes of Alzheimer’s disease would be an extremely welcome advance. Since the preliminary evidence is that the compounds have low toxicity, they could be used to treat patients with early-stage disease, identified through increasing improvements in early diagnosis.

Aims

The researchers aim to screen a small library of compounds to see how well they inhibit the activity of BACE1 and the likelihood of side effects. Based on these tests they will select the best two compounds to take forwards for further testing.

The drugs will be profiled for safety, metabolism and measure the changes in their levels with time after dosing. They will be tested for their effects in mice mimicking the early stages of Alzheimer’s disease. These mice develop amyloid plaques, show disruption in brain cells, and develop memory impairments similar to people with Alzheimer’s.
The researchers will test the effects of the drugs on memory formation, signalling between brain cells, plaque formation in the brain, reduction in inflammation, activation of stem cells and the development of new neurons in the brain of the mice. This information will give a clear picture of the effectiveness of the compounds in alleviating the damage to brain functions in Alzheimer’s disease, and the potential to clinical testing of these compounds.