In late July of each year the Alzheimer’s Association, the largest private funder of Alzheimer’s research in the world, announces research awards for new projects. We are very excited that three local researchers were among the recipients of these prestigious awards. Together, the three awards are in excess of $500,000 in support for local research projects. Below are descriptions of the three researchers and their projects:

Kelly T. Dineley PhD, UTMB in Galveston

Amyloid and Nuclear Factor Kappa B

Kelly T. Dineley PhD, Assistant Professor in the Department of Neurology at UTMB in Galveston, is one of the recipients of this year’s grants. Her two-year study, funded by the Alzheimer’s Association, will investigate the relationship between beta amyloid (a hallmark of Alzheimer’s Disease - AD) and nuclear factor kappa B (a compound significant in the body’s inflammatory response). Using genetically modified mice, Dr. Dineley hopes to identify the important interactions between these two compounds, with the ultimate goal of new Alzheimer’s treatment options. Dr. Dineley, in reflecting on her work, wanes philosophical “I like working on Alzheimer’s Disease and hope to answer a few important questions during my lifetime.”

Dr. Dineley received her BA and MS degrees from University of the Pacific in Stockton, CA, but came to Texas as soon as she could to work on her PhD in Neuroscience at Baylor College of Medicine in Houston, TX. After completing her PhD in 1998, Dr Dineley completed her Post-doctoral fellowship at Baylor in the Department of Neuroscience, and then worked as an instructor for several years before accepting her current position at UTMB in Galveston.

Below is a more technical explanation of Dr. Dineley’s work on Alzheimer’s Disease:

Nuclear factor kappa B (NF- k B) is an ubiquitous rapid response transcription factor in cells exposed to inflammatory assaults such as exposure to b -amyloid (A b ). The specific Aims of this proposal will test the hypothesis that elevated A b triggers an NF- k B inflammatory signaling axis. This hypothesis is the foundation of our model that elevated A b triggers an NF- k B-mediated inflammatory response that then proceeds to contribute to and exacerbate neuron and memory function. During the course of the disease, the particular forms of the NF- k B signaling axis that are key will likely be in flux. Hence our interest in tracking the components at several ages in our animal model that represent specific cognitive effects of A b exposure in vitro. Upon completion, this project will have determined the particular forms of NF- k Bs that are perturbed in association with cognitive decline in our animal model as well as determined the upstream mediators and downstream consequences of such perturbations. This will likely result in several candidate points of intervention in Alzheimer’s Disease as well as contribute substantially to the molecular etiology of the disease.

Eric Klann PhD, Baylor College of Medicine

Oxidative Stress and Alzheimer’s Disease

Eric Klann PhD, Associate Professor in the Department of Molecular Physiology and Biophysics, at Baylor College of Medicine, is another recipient of an Alzheimer's Association research grant. His area of study is the role of oxidative stress with plaque accumulation and memory impairments. His 3-year, $240,000 grant, will study this relationship using two strains of genetically altered mice - one that models AD and one that reduces brain oxidative stress. Through this study Dr. Klann expects to gain an understanding of the impact of reducing oxidative stress on the accumulation of plaques in AD, and predicts "that decreased plaque accumulation will correlate with improved cognitive function."

Dr. Klann received his BS in Chemistry from Gannon University in Erie, PA in 1984. He received his PhD degree in 1989 from Medical College of Virginia and Virginia Commonwealth University in Richmond, VA. Dr. Klann worked as a Post-doctoral fellow at Baylor College of Medicine in the Department of Neuroscience from 1989 – 1994. After working ‘abroad’ for 7 years at the University of Pittsburgh, PA, he returned to Baylor College of Medicine where he serves as Director of Graduate Program in the Department of Molecular Physiology & Biophysics with a joint appointment in the Translational Biology and Molecular Medicine Graduate.

Below is the more technical description of his research study:

Oxidative damage is a key feature in the brain of Alzheimer’s Disease (AD) patients. However, it is not known whether oxidative damage is a result of AD pathologies such as amyloid plaques or whether amyloid plaques cause the oxidative damage. In one well-studied mouse model of AD, Tg2576 mice that overexpress a double mutant form of amyloid precursor protein (APP), amyloid plaque deposition was shown to be associated with oxidative damage. In addition, these AD model mice exhibited diminished long-term potentiation (a cellular model of learning and memory) and impaired hippocampus-dependent memory. However, it is not known whether prevention of production of oxidants can alleviate either amyloid plaque formation, LTP deficits, or memory impairments in the Tg2576 mouse model of AD. Because of evidence that mitochondrial dysfunction results in oxidative stress in a number of neurodegenerative diseases, including AD, we plan to determine whether scavenging mitochondrial superoxide by overexpression of mitochondrial superoxide dismutase (SOD-2) can prevent the aforementioned abnormalities. More specifically, we will determine:

• Whether Tg2576 mice crossed to SOD-2 transgenic mice exhibit formation of amyloid plaques.
• Whether Tg2576 mice crossed with SOD-2 transgenic mice exhibit decreased hippocampal long-term potentiation.
• Whether Tg2576 mice crossed to either SOD-2 transgenic mice exhibit impairments in hippocampus-dependent memory function.

The results of these experiments should provide crucial information concerning the source of oxidative stress in AD. Such information should be useful in developing pharmacological and therapeutic strategies for treatment of not only AD, but also other neurodegenerative diseases that involve oxidative stress.

Juan Botas PhD, Baylor College of Medicine

Genetic Pathways of Alzheimer’s Disease

Juan Botas PhD, Associate Professor in the Department of Molecular and Human Genetics at Baylor College of Medicine, is one of the three Southeast Texas' Alzheimer's grant recipients this year. Dr. Botas is studying AD using the fruit fly as disease model. Fruit flies were originally studied in order to understand normal embryonic development, but Dr. Botas finds them an efficient model for gaining understanding of the genetic factors involved in the development and progression of AD. Surprisingly, the genetically modified fruit flies Dr. Botas uses in his studies develop plaques and tangles in their neurons and lose cognitive function. "I believe the fruit fly will provide a key to unlocking the mysteries of AD and ultimately an effective therapeutic intervention," says Dr. Juan Botas. During his 3-year, $240,000 Alzheimer's Association-funded study, Dr. Botas hopes to identify the genes which slow neurodegeneration in AD, and gain insight into the genetic mechanisms of the most promising suppressors of AD.

Dr. Botas received his BS and PhD degrees from the Autonomous University of Madrid, Spain. After completing his PhD in 1986, Dr Botas worked as a Post-doctoral fellow at Stanford University Medical School in the Departments of Developmental Biology and Biochemistry. Following his fellowship, he joined the faculty at Baylor College of Medicine in the Department of Molecular and Human Genetics and Molecular and Cellular Biology.

Below is a brief summary his research study:

We have generated a new model system of Alzheimer’s Disease (AD) by introducing in Drosophila (fruit fly) two genes responsible for the formation of plaques and tangles in humans; i.e., beta-amyloid (Abeta-42) and wild-type Tau. Using this new model system we found that Abeta-42 induces changes in wild-type Tau that lead to AD-like neuronal dysfunction.

This Drosophila AD model will allow us to search the genome and identify genes that are capable to modify AD pathogenesis. These modifier genes will likely define key steps in the cascade of events that leads to neuronal death during AD progression.

This new model system may prove useful for determining genetic risk factors, as well as the genetic pathways and molecular mechanisms underlying neuronal degeneration in AD. Perhaps more importantly, identifying novel suppressor genes may suggest new approaches for AD therapy.

The Alzheimer’s Association is proud of these researchers and their commitment of helping find answers to the mysteries of Alzheimer’s Disease. Please join us in congratulating them on their grant award, and wish them success in their research.