The developing brain is subject to many environmental insults. Research in our laboratory has demonstrated that the long-term cognitive deficits imparted by environmental hazards and heavy metals such as PCBs and Pb, respectively, are accompanied by alterations in developmental gene expression. Differential gene expression is mediated by a complex array of specific DNA-binding proteins. Among such factors, which are potential targets for Pb’s action, are the zinc finger family of transcription factors, which play key essential roles during growth/differentiation and are involved in many aspects of eukaryotic gene regulation. Work in our lab has demonstrated that in vivo exposure to Pb and PCBs alters the integrity and function of such factors, their target gene expression, and cellular differentiation. Our lab has worked extensively on the transcription factor Sp1 and its connection to the APP gene that plays a vital role in Alzheimer’s Disease pathogenesis.

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Effects of heavy metals on Alzheimer’s Disease pathogenesis

Our lab has focused on lead (Pb) as a model environmental hazard that is ubiquitous in our daily lives. Despite recent regulations that are meant to curb levels of Pb in the atmosphere, Pb remains a hazard for general populations. Since children are more susceptible to lead toxicity, we have based our model of study on an early exposure scenario and have worked extensively on the Fetal Basis of Adult Disease (FeBAD) hypothesis. Detailed work in our lab has shown that early (infant) exposure to Pb in rats and monkeys caused an increase in the levels of APP and Aβ (the toxic fragment derived from APP) in the aged animals. Therefore, we have provided evidence for a link between early exposure to Pb and a greater risk for developing AD later in life. Current studies are under way using human brain tissue to further substantiate these findings.

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Epigenetics, Pb and AD pathogenesis

In order to determine how early exposure to Pb exerts its latent effect on AD-related genes, our lab is presently studying possible epigenetic effects that may play an important role in modulating this process. The most common form of epigenetic regulation is DNA methylation. It is now known that increased DNA methylation of gene promoter regions leads to a proportional decrease in gene expression. Conversely, decreased DNA methylation is related to increased gene expression. Studies are currently under way in our lab to determine the effect of Pb on APP promoter methylation and early programmatic changes that are imprinted on this gene. In addition, we are also studying the role of reactive oxidative species (ROS) as major players in affecting methylation and regulation of the APP gene. We are presently conducting studies to determine how such oxidative damage may contribute to AD pathogenesis, especially when sustained early in life.

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Pinpointing potential biomarkers of Alzheimer’s Disease

Alzheimer’s Disease (AD) is a neurodegenerative disease that relies on psychological tests rather than a laboratory test for diagnosis. Physiological tests to confirm AD-associated cognitive deficits are inaccurate in fifty percent of diagnoses. The only definitive diagnosis of AD is achieved through post-mortem examination of brain tissue. There is, therefore, a great need to discover reliable biomarkers that can be used to diagnose the onset of AD earlier in life, allowing for more therapeutic intervention and perhaps even for preventative measures. Hallmarks of AD pathology are amyloid plaques (constituted of beta-amyloid, a snippet from the larger Amyloid Precusor Protein) and neurofibrillary tangles (made of the protein Tau). These proteins are believed to contribute to the pathogenesis of AD but their role in peripheral body tissue, such as the blood, is unknown. Considering that there is only one APP gene that can be differentially spliced into many APP isoforms, the hypothesis we have formulated is that Pb induced transcriptional up-regulation of APP will also alter levels of APP and Aβ in neuronal tissue as well as peripheral tissue. Therefore these proteins are suitable for study as potential biomarkers in blood platelets. We are determining the utility of these proteins as biomarkers through manipulation of Pb exposure to mice. Additionally, Pb exposure alters APP expression in the brain; therefore it may also alter expression in other genes. Thus global gene profiling is being used in Pb-exposed animals to identify other possible biomarkers by monitoring gene expression alterations following Pb-exposure both in the blood and the  brain.

 

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A novel class of mechanism-based drugs for the treatment of Alzheimer’s Disease

AD is characterized by chronic and progressive loss of neurons in discrete areas of the brain, causing debilitating symptoms such as dementia, loss of memory, and eventually, premature death. Given the poor performance of existing therapies, there is an increasing need to develop alternative drugs that modify the disease process. We have discovered a novel class of mechanism-based drugs for the treatment of Alzheimer’s disease. We are currently testing these compounds.