Mouse model shows promise for treatment of Alzheimer’s disease
Wednesday, February 28, 2018
More than 5 million Americans suffer from Alzheimer's disease, and treatments are needed for this devastating condition. One strategy researchers have been examining is to shrink the buildup of amyloid beta in the brains of those suffering the disease.
With this in mind, a type of genetically engineered mouse was studied recently under the direction of Riquiang Yan, Ph.D., the vice chair of neuroscience of the Cleveland Clinic Lerner Research Institute. The mice did not have an enzyme that was hypothesized to cause the amyloid beta clumping in the brain, which contributes to the symptoms and expression of Alzheimer's disease.
To create a mouse model that might parallel a human, the researchers developed a genetic mouse absent the beta-secretase enzyme (BACE1) then bred the mouse with another mouse model, and the resultant mouse was one that did not demonstrate the absent expression of BACE1 until after development.
This enabled the researchers to study the deposition of amyloid in the mouse and the impact of BACE1 on the amyloid after the expression of the absence of BACE1. The mouse showed a reversal of amyloid deposits, demonstrating that sustained BACE1 inhibition can reverse deposits.
This was good news as BACE inhibitor drugs are being studied for the treatment of Alzheimer's disease. Some forms have been tried and abandoned — such as solanezumab through Eli Lilly, bapineuzumab with both Johnson & Johnson and Pfizer, and verubecestat by Merck for patients diagnosed with Alzheimer's disease.
Merck was still looking at verubecestat in patients before they are diagnosed with prodromal symptoms, but they announced earlier this month that they were no longer pursuing the research. Eli Lilly, in collaboration with AstraZeneca, is still moving forward with their investigation into treating Alzheimer's disease with a BACE inhibitor.
Attention needs to be paid to the potential side effects of any drug, and the mice in the study did suffer side effects, including neural development abnormalities. The studies undertaken earlier by Eli Lilly had shown aspects of liver toxicity.
But a strategy that prevents or reduces the amount of amyloid in the brain is worth pursuing. Higher levels of circulating amyloid are associated with early symptoms, including depression.
The location and density of plaques are known to have a relationship with symptoms of Alzheimer's disease, but other factors including the location and density of the brain neurofibrillary tangles, another type of brain deposit associated with Alzheimer's disease, correlate the closest to the severity of cognitive impairment. Drug strategies to reduce the burden of tangles are also underway as well as additional novel approaches.
While the mouse model demonstrating the clearance of amyloid from the brain with inhibition of BACE type enzymes shows promise in using BACE inhibitors to treat Alzheimer's disease, many have tried and many have failed. The research continues.
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