Alzheimer's Disease Research - Current Awards Steven E. Arnold, M.D.University of Pennsylvania Title: Effect of Insulin Sensitizer Metformin on Alzheimer’s Disease Biomarkers Summary: Previous studies and Dr. Steven Arnold’s laboratory work have shown that the brain in Alzheimer's disease is resistant to the healthy growth effects of insulin and that re-sensitizing brain cells to insulin may be a useful therapeutic strategy. Dr. Steven Arnold and colleagues have identified the anti-diabetes drug, metformin, as a safe medicine that enters the brain and re-sensitizes insulin receptors. This proposal seeks to conduct an efficient clinical trial with metformin in people with mild cognitive impairment and early dementia due to Alzheimer's disease to determine its effect on cognitive functioning and physiological and biochemical biomarkers of Alzheimer's disease. Program: Alzheimer's Disease  Narayan Bhat, Ph.D.Medical University of South Carolina Title: Role of a Stress Kinase in AD Pathogenesis Summary: The project investigates the role of a key cell signaling pathway commonly involved in cell stress and inflammatory responses i.e., p38 MAP kinase in multiple pathogenic processes of Alzheimer's disease (AD) including neuroinflammation, tau phosphorylation, amyloid deposition and synaptic dysfunction. The approach uses a genetic conditional knockout strategy to cell-specifically delete the kinase in microglia and forebrain neurons in a mouse model of AD. The outcome will provide mechanistic insight into AD-associated pathogenic processes and define the signaling pathway as a versatile treatment target for AD. Program: Alzheimer's Disease  Kurt R. Brunden, Ph.D.University of Pennsylvania Title: In Vivo Testing of Novel Tau Fibrillization Inhibitors Summary: The accumulation of insoluble fibrils of tau protein within neurons is a hallmark pathological feature of the Alzheimer's disease brain. A body of evidence suggests that these tau fibrils are pathogenic and contribute to the neuron loss observed in Alzheimer's disease. The research proposed here is to further characterize novel drug-like inhibitors of tau fibril formation, and the results of these studies will provide important information about the therapeutic potential of such compounds for the treatment of Alzheimer's disease. Program: Alzheimer's Disease  Biju K. Chandu, Ph.D.The University of Texas Health Science Center at San Antonio Title: iPS-Derived Microglia-Based Gene Therapy for Alzheimer's Co-PI(s):
Senlin Li, M.D. (Mentor)
University of Texas Health Science Center Robert A. Clark, M.D. (Mentor)
University of Texas Health Science Center Mentor:
Multiple mentors, listed above.
Summary: Extracting bone marrow cells requires surgery, which may be strenuous or impossible for older patients. To meet large-scale demand for bone marrow cells in clinical trials for the treatment of Alzheimer's disease, we will generate bone marrow cells from blood, which we in turn will genetically modify to secrete drugs once these cells migrate to the brain. This new approach is expected to contribute to the development of an important therapy for Alzheimer's. Program: Alzheimer's Disease  John R. Cirrito, Ph.D.Washington University Title: Endocytic Trafficking in Synaptic Amyloid-Beta Generation Co-PI(s):
Jin-Moo Lee, M.D., Ph.D.
Washington University Summary: Amyloid-beta peptide aggregation and accumulation appears to be the initial step that sets off a cascade of factors that lead to Alzheimer's disease (AD). Two proteins, PICALM and Bin1, have recently been identified in genetic studies as risk factors for AD. Drs. John Cirrito, Jin-Moo Lee, and colleagues will determine the cellular mechanisms by which these proteins act and interact to mediate amyloid-beta generation in living mice. Program: Alzheimer's Disease  Catherine Clelland, Ph.D.Columbia University Title: The Role of miR-138 in Alzheimer’s Disease Dendritic Spine Pathology Summary: We will test if dysregulation of the miR-138 controlled pathway contributes to dendritic spine pathology in a murine tauopathy model. We believe this project is highly innovative because if successful, this study will be one of the first to directly link the dysregulation of a miRNA regulated pathway to the in vivo dendritic spine pathology seen in a mouse model of human tauopathy. Program: Alzheimer's Disease  Colin K. Combs, Ph.D.University of North Dakota School of Medicine Title: Novel Approach for Attenuating Microgliosis in Alzheimer’s Disease Summary: The main goal of this project is to determine whether a specific protein is responsible for most of the inflammation that occurs in the brain during Alzheimer's disease. Dr. Colin Combs and colleagues propose two novel approaches, intended not only to identify this protein but also to test specific strategies for interfering with its function, using a mouse model of the disease. This interference should be able to decrease the inflammation in the brain and decrease behavioral decline. Program: Alzheimer's Disease  Marta Cortes-Canteli, Ph.D.Rockefeller University Title: Role of Fibrinogen in AD Neuronal and Synaptic Loss Summary: The association between fibrinogen and Abeta affects normal hemostasis. Determining if fibrinogen also influences the neuronal and synaptic loss present in Alzheimer's disease is substantially important as it will support the design of therapeutic strategies aimed at blocking that association. Program: Alzheimer's Disease  Pritam Das, Ph.D.Mayo Clinic Jacksonville Title: Cytokine Modulation Of Amyloid Beta Associated Pathologies In APP Mouse Models Of Alzheimer's Disease Summary: The experiments proposed here will establish an experimental template to study potential disease modifiers, their roles in modulating Alzheimer’s disease (AD) like pathologies and their use in the future design of potential AD therapeutics. Program: Alzheimer's Disease  Michael DeTure, Ph.D.Mayo Clinic Jacksonville Title: Restoration of the 3R:4R Tau Equilibrium as a Tauopathy Therapy Summary: Tau polymerization into neurofibrillary tangles is a central pathological feature of Alzheimer's disease as the abundance of these lesions correlates positively with neuronal loss and cognitive decline in these patients. Tau based neurodegeneration may be caused directly by altering the normal equimolar 3R to 4R tau ratio; and indeed, different silent mutations in tau have been shown to lead to the preferential expression and accumulation of either 3R or 4R tau with resulting neuronal loss and cognitive decline in FTDP-17. Together these results suggest that therapeutic interventions aimed at returning the tau isoform ratios to their normal balance may benefit tauopathy patients including AD patients which also exhibit locally enriched 3R or 4R tau deposits. Program: Alzheimer's Disease Last Review: 04/29/13 |
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