Exploring the Mechanism of Action of GM-CSF (Leukine®) in Alzheimer’s Disease
People with rheumatoid arthritis have an ~8-fold reduced risk of developing Alzheimer’s disease. After testing several protein cytokines upregulated in blood from rheumatoid arthritis patients, Dr. Potter’s team identified granulocyte-macrophage colony-stimulating factor (GM-CSF) as a candidate, whose upregulation may explain the reduced risk of Alzheimer’s disease in people with rheumatoid arthritis. They then found that treatment with GM-CSF reduced AD pathology and completely reversed the cognitive impairment in a mouse model of Alzheimer’s disease. And they later discovered that GM-CSF improved cognition in bone marrow transplant patients. This led to the design of the ongoing clinical trials with Leukine® (recombinant human GM‑CSF), from which samples will be obtained to examine the impact of GM-CSF on various metrics of immune system function. We are also using the most advanced animal models of Alzheimer’s disease to investigate the mechanism of action of GM-CSF. The innovation of this project resides on the fact that, unlike therapeutic strategies focused on reducing amyloid burden in Alzheimer’s disease, GM-CSF could become the first Alzheimer’s disease therapy that targets the accompanying immune processes.
Investigating Type 3 Diabetes in Alzheimer’s Disease
In addition to losing many brain cells as their disease progresses, Alzheimer’s disease patients show a decreasing ability to use blood sugar (glucose) to feed their remaining brain cells. This Alzheimer’s disease-associated problem with blood sugar regulation has been called “Type 3 Diabetes.” However, the reasons for this problem have remained relatively unexplored. Through our research at the RMADC, we have uncovered an important cause of this defect linked to the key Alzheimer’s disease protein amyloid-beta and the microtubule-dependent motor protein Kinesin-5. As a result of this problem, neurons are unable to detect insulin and import blood sugar, which is required for their essential functions. We are targeting this mechanism to develop novel drugs that can reverse the Type 3 diabetes of Alzheimer’s disease, with the goal of protecting against brain cell loss.
Understanding Chromosome Mis-segregation in Alzheimer’s Disease and Other Neurodegenerative Disorders
When chromosomes fail to segregate properly during cell division, the resulting daughter cells will have an abnormal number of chromosomes and are called “aneuploid.” When neurons become aneuploid, they are prone to degeneration. We and others have found that the death of aneuploid neurons likely underlies most of the neurodegeneration and nerve cell loss in both Alzheimer’s disease and frontotemporal dementia. In Alzheimer’s disease, the neuronal cell death is caused by the amyloid-beta protein itself, which inhibits the activity of Kinesin-5, a microtubule-dependent motor protein required for mitosis and other cellular functions. We are currently analyzing aneuploidy in other forms of neurodegenerative disease and are testing novel drugs capable of preventing chromosome mis-segregation defects in cell culture and animal models of Alzheimer’s disease.
Understanding the Role of ApoE in Alzheimer’s Disease
Besides age, inheritance of the ApoE4-encoding form of the apolipoprotein E (APOE) gene is the most important risk factor for developing Alzheimer’s disease. We have discovered a mechanism by which ApoE works to promote Alzheimer’s disease: it binds to the amyloid-beta peptide and converts it into toxic species that kill neurons and cause neurodegeneration, with the ApoE4 form being the most detrimental. We are using complementary approaches to identify drugs that prevent ApoE from promoting this neurodegenerative pathway in Alzheimer’s disease.
Environmental Enrichment, Exercise, and Rolipram Studies
Research from our group and others has shown that environmental enrichment and exercise can lead to enhanced cognition in a mouse model of Alzheimer’s disease, and increasing evidence suggests that similar benefits are likely to occur in humans. We have discovered and published our finding that a known drug, called Rolipram, can mimic the benefits of environmental enrichment in a mouse model of Alzheimer’s disease. We believe this unique approach has great potential to translate into applications for people with Alzheimer’s disease.
Caffeine and Melatonin Studies
Both caffeine and melatonin, two safe over-the-counter remedies, have been shown by us and others to prevent and/or reverse Alzheimer’s disease cognitive deficits in mouse models of the disease. We are continuing to investigate these findings using additional complementary models of Alzheimer’s disease, before initiating clinical trials.