Alzheimer's Disease Research - Current Awards 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  Mel B. Feany, M.D., Ph.D.Brigham and Women's Hospital Title: Mitochondrial Pathology in Tauopathy Summary: In this study, Dr. Mel B. Feany and her team use clues from genetic screens to develop a detailed understanding of the mechanisms by which tau becomes toxic to neurons in Alzheimer's disease and related tauopathies. In particular, they are studying the influence of mitochondrial biology on neurotoxicity. These tests, if successful, would pave the way towards consideration of mitochondrial function and dynamics as attractive potential therapeutic targets in Alzheimer's disease, as well as related tauopathies. Program: Alzheimer's Disease  Carl Frieden, Ph.D.Washington University Title: Develop Screening Assays to Differentiate ApoE Isoforms Summary: The primary cause for developing late-onset Alzheimer's disease rests in the properties of one of the ApoE isoforms, specifically a variant called “apoE4.” The screening procedures developed in Dr. Carl Frieden’s experiments are designed to lead to the long term goal of finding therapeutic agents that specifically target ApoE4 without disrupting the physiological function of the “normal” ApoE3, a variant that does not increase risk for Alzheimer’s disease. The hypothesis is that such agents will alter the deleterious effects of ApoE4 and thereby delay or prevent the onset of Alzheimer's disease. Program: Alzheimer's Disease  Nashaat Gerges, Ph.D.Medical College of Wisconsin Title: Beta Amyloid-Induced Synaptic Plasticity Imbalance and Neurogranin Summary: While the application of amyloid beta (a precursor of AD) decreases neurogranin levels and suppresses synaptic transmission, increasing neurogranin in hippocampal neurons was able to reverse the beta amyloid-induced depression in synaptic transmission. We are proposing to understand the mechanism by which neurogranin is capable of such reversal of synaptic function and to explore the possibility that neurogranin may be reversing the synaptic plasticity imbalance. Success of this proposal can open the door for new therapeutic intervention for AD. Program: Alzheimer's Disease  Jason E. Gestwicki, Ph.D.University of California, San Diego Title: Chemical Approaches to Reducing Tau Levels Co-PI(s):
Chad Dickey, Ph.D.
University of South Florida Summary: Tau is a protein that aberrantly accumulates in the brains of patients with Alzheimer's disease. The goal of this proposal by Drs. Jason E. Gestwicki, Chad Dickey, and colleagues is to determine whether newly discovered chemical inhibitors of heat shock protein 70 (Hsp70) will reduce tau accumulation. Such compounds are expected to be potential therapeutics with an under-explored mechanism. Program: Alzheimer's Disease  Karl Herrup, Ph.D.Rutgers University Title: Glutamine as a Neuroprotective Agent in Alzheimer’s Disease Therapy Summary: Glutamine is a simple amino acid that has been clinically proven to provide tissue protection under the stress of chemo or radiation therapy as well as after intestinal surgery. Surprisingly, this effect has never been studied to any degree in the nervous system to determine if neurons can be similarly protected from neurodegeneration, as in Alzheimer's disease. Dr. Karl Herrup and colleagues have developed preliminary data to show that this is likely, and they propose a series of experiments both in tissue culture and in mouse models to move this idea as rapidly as possible towards its application in human beings. Program: Alzheimer's Disease Jeremy Herskowitz, Ph.D.Emory University Title: The role of LR11 intracellular traffic in Alzheimer's disease Mentor:
James Lah, M.D., Ph.D.
Emory University Summary: There are no known therapies for the underlying disease-causing mechanisms of Alzheimer's disease, the leading cause of dementia. The study of LR11, also known as SorLA, a pathogenic factor with multiple influences on Alzheimer's disease susceptibility, will bolster our knowledge of the underlying cellular mechanisms by which LR11 may influence the onset and progress of Alzheimer's disease. Program: Alzheimer's Disease  Bradley T. Hyman, M.D., Ph.D.Massachusetts General Hospital Title: Modeling the Intersection of Tau and Ab in Alzheimer Disease Co-PI(s):
Teresa Gomez-Isla, M.D., Ph.D.
Massachusetts General Hospital Summary: Alzheimer disease starts with neurofibrillary lesions in a special brain area, the entorhinal cortex, which is responsible for memory related brain functions. We propose to make a model of this stage of the disease by genetically engineering a mouse to develop these same lesions in only this brain area; doing so will allow us to study the earliest phase of the disease, and to learn about whether early lesions lead to disease progression. Program: Alzheimer's Disease Joanna Jankowsky, Ph.D.Baylor College of Medicine Title: Separating cell-autonomous from -extrinsic effects of APP/Ab Summary: The amyloid precursor protein and its derivative, amyloid beta, are intimately associated with the onset and progression of Alzheimer's, yet there are still many basic questions about their role in neuronal dysfunction that remain unanswered because we lack appropriate model systems in which to address them. We are investigating a new viral mosaic APP" transgenic mouse model that allows us to tackle fundamental questions about whether APP and amyloid beta act locally in a single cell or exert their effects between cells to alter neuronal structure and function. We are exploring whether their overexpression in the mature brain has distinct effects from those effects that might be seen during early embryological and post-natal development. Answers to these deceptively basic questions will be critical to understanding how APP/amyloid beta contributes to Alzheimer's pathogenesis and determine how best to target its action therapeutically." Program: Alzheimer's Disease  Ksenia V. Kastanenka, Ph.D.Massachusetts General Hospital, Alzheimer's Disease Research Unit Title: Role of Neural Activity in Alzheimer's Disease Mentor:
Brian Bacskai, Ph.D.
Massachusetts General Hospital Summary: Development of therapeutics for Alzheimer’s disease (AD) has been hampered by a lack of clear understanding of the biology governing its progression. Until recently, the scientific community has been focusing predominantly on the nuanced molecular mechanisms leading to the onset of AD. These approaches have often disregarded perturbations of overall function of the neurons that are vulnerable to Alzheimer’s disease. The research proposed by Dr. Ksenia V. Kastanenka and colleagues is designed to provide significant insight into this area of neural activity and contribute greatly to an unexplored aspect of the disease. The results of this study will build a stronger platform for successful therapeutic agent innovation. Program: Alzheimer's Disease Last Review: 04/29/13 |
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