The goal of this project is to identify cells that are both most vulnerable and most resistant to Alzheimer’s disease in order to develop drugs that will protect the most vulnerable.
At the early stages of Alzheimer’s disease (AD), neurofibrillary tangles (NFT) and neurodegeneration occur only in very specific regions, while many regions remain virtually unaffected. Paul Greengard’s lab at the Rockefeller University recently developed a new procedure to compare the molecular profiles of very specific cell types inside the brain. They will apply this technology to mice in order to compare vulnerable regions with more resistant regions that don’t show any pathology until late stages of the disease. They will establish the molecular profiles of the different regions of interest, try to find genes that are common to all vulnerable regions or to all resistant regions and verify the region-specific expression of these genes in human brain tissue. Important differences between vulnerable and resistant cells might not be obvious at a normal physiological state,
but might become obvious only in a pathological environment. They will apply the bacTRAP technology (a platform to identify novel targets in specific cell types) to different AD mouse models, and study the molecular profile of the different regions in an AD-like environment. Then they will try to find genes that are modulated region-specifically in the context of AD and verify their findings in brain tissue of patients at different stages of AD.
These comparisons will yield lists of vulnerability genes that could potentially explain why vulnerable cells are vulnerable, or why resistance genes protect resistant cells from the pathology. By comparing these genes with AD susceptibility genes, they have the potential to identify genes that are crucial for AD pathogenesis. In future studies, they will modulate the expression level of the best candidates in neurons, and test the vulnerability of the cells thereafter. If these genes are indeed vulnerable or resistance genes, they could be very good drug targets aimed at protecting vulnerable cells.
The goal of this project is to develop genetically modified human neural progenitor cells that can replicate Alzheimer’s disease pathology in in vitro and in vivo conditions in order to develop and test Alzheimer disease drugs in human brain cells.
This work represents a potential major breakthrough in the use of stem cells for Alzheimer’s research. Various therapeutic applications are under development in many laboratories to treat this tragic disease. However, the lack of fast and reliable Alzheimer’s disease model system slows down the validation of laboratorial trials that could lead to the final clinical stage. Current Alzheimer disease mouse models fail to fully replicate the disease pathology, possibly due to lack of human-specific physiological pathways of the brain.
Dr. Doo Yeon Kim and his team plan to develop Alzheimer’s disease models based on human neural progenitor cells. Human neural progenitor cells are multipotent stem cells that can differentiate to brain cells in in vitro and in vivo conditions. Recent reprogramming technology makes it possible to generate human neural progenitor cells easily from skin cells of normal and Alzheimer’s disease patients. In this study, they will develop genetically modified human neural progenitor cells that can replicate Alzheimer’s disease pathology in in vitro and in vivo conditions. Their study will provide a novel Alzheimer’s disease model system that can be used to develop and test Alzheimer’s disease drugs in human brain cells and it will provide a human Alzheimer’s disease model for basic researchers.
The goal of this project is to test whether the strategy of stimulating endogenous stem cells in the AD brain is safe in order to find treatment for Alzheimer’s patients.
Recent evidence shows the adult brain contains discrete populations of stem cells that retain the capacity to generate new neurons through the process of neurogenesis. Dr. Se Hoon Choi will test whether the strategy of stimulating endogenous stem cells in the AD brain is safe and effective ultimately to find treatment for Alzheimer’s patients.
A collaboration of members of the Research Consortium, a member of the Cure Alzheimer’s Fund Science Advisory Board and non-Cure Alzheimer’s Fund-affiliated researchers hypothesizes that an abnormal increase in levels of synaptic Abeta and, particularly, Abeta oligomers may lead to synaptic dysfunction, cognitive decline and eventually dementia. This highly innovative collaborative project will address how Abeta oligomers are formed and which types detrimentally impact synaptic dysfunction and neuronal survival in the brain.
As a result of promising results from the first year of work, the original members of the collaborative were re-funded for a second year in August, 2007. Two more researchers, Sam Gandy of Mount Sinai Medical School and Tae-Wan Kim of Columbia University, joined the Oligomer Collaborative and were also funded in August.
The project has grown in the third year to include a broader view of the Abeta synaptic feedback loop.
Abeta Oligomers in Mouse Models of AD – Lee $300,000
Mouse Models of Abeta Oligomers and Vasculopathy – Gandy $100,000
Effects of Abeta Oligomers on Neurotransmisson Across the Neuronal Synapse – Greengard and Tanzi - $150,000
Role for Phosphoinositides in Abeta Oligomer-associated Synaptic Dysfunction – Kim $100,000
Role of Oligomeric Abeta in AD – Glabe $200,000
The Role of Oligomeric Abeta in Synaptic Transmission and Plasticity – Greengard $200,000
Role of Synaptic Activity and Neurotransmitter Modulation in the Dynamic Regulation of Inter-stitial Fluid Amyloid and Oligomer Formation – Holtzman $200,000
Molecular Analysis of *56 Structure and Function – Sisodia $200,000
Specificity and Mechanism of Abeta OligomerAction Through Prion Protein – Strittmatter $100,000
Cure Alzheimer's Fund is part of a funding consortium supporting collaborative biomarker investigation of the elevation of tau and decreased concentrations of Amyloid beta 42 in the Central Spinal Fluid as evidence of the presence of the Alzheimer's disease pathology.
Investigating the increasingly documented link between TBI/stroke and Alzheimer’s disease is aimed not only at developing effective interruptions of that linkage but also a contribution to an understanding of the basic Alzheimer’s disease mechanism.
The hypothesis of this proposal is that a method can be developed to measure tau levels in the extracellular space of the brain (interstitial fluid–ISF) and that assessment of ISF tau in both normal mice as well as a variety of animal models that develop AD pathology will provide new insights into tau metabolism and the relationship between Aβ and tau in AD. If this method development is successful, it has a chance to tell us more about the pathophysiology of AD as well as a provide a novel way to screen for new AD treatments.
The goal of this project is to determine which types of cells and factors in the brain influence excess Abeta deposition in Alzheimer’s patients, using animal models of the disease.
Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by impairments in memory and cognition, neuronal loss and deposition of Abeta peptides that are derived from larger amyloid precursor proteins (APP). Rare, familial, early-onset autosomal dominant forms of Alzheimer’s disease (FAD) are caused by mutations in genes encoding APP, presenilin-1 (PS1) and presenilin-2 (PS2), polypeptides that are expressed ubiquitously in all central nervous system cell types and in peripheral organs. Transgenic animal (mouse) models for Alzheimer’s recapitulate the histological, synaptic and memory deficits that are classically associated with the human disorder. The goal of this project is to employ genetic and molecular strategies to test for the effects of FAD mutations in specific types of cells in the brains of Alzheimer’s animal models. The hypothesis is that deposition of Abeta in the brain can be influenced by various factors that are secreted not only by nerve cells, but other cells, e.g. glial cell in the neighborhood of the nerve cells. If they can identify which cell populations influence Abeta deposition, future studies will be aimed at identifying the exact factors that mediate Abeta deposition in animal models of Alzheimer’s disease. These factors then could guide novel drug discovery efforts to treat and prevent Alzheimer’s disease.