Bruce T. Lamb, Ph.D.
Associate Staff, Lerner Research Institute, and Associate Professor, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio, recipient of a 2008 Investigator-Initiated Research Grant and 2005 Zenith Fellows Award
Alzheimer's is a complex disease influenced by multiple genetic and environmental factors. A common denominator is the amyloid precursor protein (APP) and its byproduct, beta-amyloid, which seems to be involved in the initiation of the anatomical and functional changes of Alzheimer's. Beta-amyloid is a protein that goes on to accumulate into large clusters called plaques, one of the hallmarks of the disease. My laboratory uses complementary approaches to help unravel the complexities of Alzheimer's disease and identify factors that contribute to the disease and could be targeted by new drugs and therapies.
Impact of Association funding
In addition to genetic factors, through support from the Alzheimer's Association we have initiated studies to examine the effects of specific environmental factors on the development of Alzheimer's brain changes.
Through generous support from the Alzheimer's Association over the years, including both Investigator-Initiated Research Grants and a Zenith Award, my laboratory has 1) used novel animal models of Alzheimer's to examine the role of genetic and environmental factors that may trigger specific Alzheimer's brain changes, 2) developed more complete animal models of the disease and 3) investigated therapies that might decrease the risk for Alzheimer's. These studies would not have been possible without the support of the Alzheimer's Association.
Using mouse models to study the role of genetic factors
To identify genetic factors that may trigger brain changes, we have used groups of mice that have been genetically engineered to carry different genes or combinations of genes associated with Alzheimer's. Mice with a mutant human Alzheimer's gene show a variety of brain changes, including increased APP and beta-amyloid production, development of plaques, activation of the immune system, behavioral abnormalities and abnormal neuronal changes called cell cycle events (CCEs). Depending on the genes they carry, some mice exhibited all, some, minimal or none of these changes.
Employing a technique called genetic mapping, we have identified the location of several genes in these mice that influence both the production of beta-amyloid and its accumulation into plaques. Our current focus is identifying the specific genes involved in these events.
Using mouse models to study the effects of environmental factors
In addition to genetic factors, through support from the Alzheimer's Association we have initiated studies to examine the effects of specific environmental factors on the development of Alzheimer's brain changes. In particular, we have focused on the effects of high-fat/high-cholesterol diets, as studies in humans have suggested that this may be a risk factor for the development of Alzheimer's.
Our studies have demonstrated that high-fat/high-cholesterol diets similar to those consumed by Western societies increase levels of beta-amyloid in some mouse models of Alzheimer's. The effect of a high-fat/high-cholesterol diet depends entirely on the genetic background of the mice, with some mice being highly sensitive to the effects of diet, others completely resistant to the effects of diet and others falling somewhere in between. These studies suggest that the effects of an environmental risk factor for Alzheimer's depends on the genetic background of the mice. This has implications for 1) human studies examining the rates of Alzheimer's in different populations, 2) recommendations for specific diets to reduce Alzheimer's risk and 3) the development of therapies to counteract the effects of diet.
Developing more complete animal models
My lab has been at the forefront of refining animal models of Alzheimer's. To build an animal model that most closely mimics what happens in humans with Alzheimer's, we have recently undertaken a study to introduce human Alzheimer's genes into mice that have been genetically engineered to lack the mouse counterparts for these genes. This model should provide a better testing ground for new Alzheimer's therapies.
One of the first surprises in this project came in a mouse whose own APP gene had been removed and replaced with a mutant human APP gene that causes Alzheimer's. Substituting the human APP gene actually lessened the brain changes of Alzheimer's. This suggests that the mouse APP gene contributes to the development of the brain changes in the transgenic mouse models of Alzheimer's.
Using mouse models to study the effects of NSAIDs
Finally, we have been examining whether common medications such as nonsteroidal anti-inflammatory drugs (NSAIDS) have a beneficial effect in Alzheimer's mouse models. Notably, we have found that NSAIDs including ibuprofen and naproxen can block inflammation and neuronal CCEs if given before the development of extensive Alzheimer's brain changes. However, if NSAID treatments are begun later in disease progression, it does not reverse neuronal CCEs and other brain changes and has only a minimal effect on other signs of Alzheimer's exhibited by the mice.
These findings are consistent with studies in humans demonstrating that long-term use of NSAIDs for arthritis is associated with a decreased risk for Alzheimer's, while short-term clinical trials with NSAIDs in individuals diagnosed with Alzheimer's have proven largely unsuccessful. These results also suggest that NSAID treatments in humans may need to be initiated as a preventative measure, substantially before the development of extensive brain changes, to be successful.
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