Alzheimer's Disease Research GrantsCurrent Grant AwardsFUNDING PERIOD: APRIL 1, 2007 – MARCH 31, 2010 George R. Jackson, M.D., Ph.D. David E. Kang, Ph.D. James Lah, M.D., Ph.D. Bruce Lamb, Ph.D. Anton Roebroek, Ph.D. Michael R. Sierks, Ph.D. Paul M. Salvaterra, Ph.D. Jashvant D. Unadkat, Ph.D.
CENTENNIAL AWARDS Bradley T. Hyman, M.D., Ph.D. Donald Weaver, M.D., Ph.D.
FUNDING PERIOD: APRIL 1, 2007 – MARCH 31, 2009 Barbara Calabrese, Ph.D. Jungsu Kim, Ph.D. Thomas L. Kukar, Ph.D. Kun Ping Lu, Ph.D., M.D. Enrico Malito, Ph.D. Michael P. McDonald, Ph.D. Robert Alan Nichols, Ph.D. Eric Norstrom, Ph.D. Troy Townsend Rohn, Ph.D. Alejandro F. Schinder, Ph.D. Vijay Sharma, Ph.D. Jane M. Sullivan, Ph.D. Nan Wang, Ph.D. Gregory J. Zipfel, M.D.
FUNDING PERIOD: APRIL 1, 2007 – MARCH 31, 2008 Gary E. Landreth, Ph.D.
FUNDING PERIOD: APRIL 1, 2006 – MARCH 31, 2008 Guojun Bu, Ph.D. David Cribbs, Ph.D. Lee Goldstein, M.D., Ph.D. William Klein, BSc, Ph.D. Jin-Moo Lee, M.D., Ph.D. Alan J. Lerner, M.D. Yueming Li, Ph.D. Steven Mennerick, Ph.D. Ricardo Miledi, M.D. Paul St. John, Ph.D. Brock Schroeder, Ph.D. Gopal Thinakaran, Ph.D. Cheryl Wellington, BSc., Ph.D. Guilian Xu, Ph.D. Riqiang Yan, Ph.D. Li Zhang, Ph.D. Ning Zhong, Ph.D.
FUNDING PERIOD: AUGUST 1, 2004 - JULY 31, 2007 International Award John A. Oates, M.D.
FUNDING PERIOD: APRIL 1, 2005 – MARCH 31, 2007 Gail Anne Breen, Ph.D. In-Young Choi, Ph.D. Mary Konsolaki, Ph.D. Huaxi Xu, Ph.D.
FUNDING PERIOD: APRIL 1, 2004 - MARCH 31, 2006 Yong Shen, Ph.D.
FUNDING PERIOD: APRIL 1, 2007 – MARCH 31, 2010 George R. Jackson, M.D., Ph.D. Neurofibrillary tangles containing tau are a hallmark of Alzheimer’s disease. However, little is known about ways to protect brain cells from degeneration caused by tau. We looked at gene expression in several parts of the brain of mice expressing human tau including a mutation that causes FTD. This was done in combination with testing in the simple fruit fly. We identified several novel modifiers of tau neurotoxicity including the highly conserved protein, puromycin-sensitive aminopeptidase (PSA). Here, we propose further studies of the role of PSA in tauopathy, and plan to validate other genes identified as putative protective or susceptibility genes in the transgenic human tau P301L mouse model. These will involve crossing fruit flies that express tau with other lines that have greater and/or lesser expression of the genes identified in the mouse. Genes that succeed in changing tau toxicity can easily be identified under the microscope by examining the size of the fly eye. Validation and characterization of mechanisms of action of tau modifiers using the fly model will provide a first step toward identifying those modifiers which are most promising as therapeutic targets for AD; these may then be further studied in cell culture and mice.
David E. Kang, Ph.D. Alzheimer's disease (AD) is a progressive and irreversible disease of the brain leading to deterioration of mental function and eventual morbidity and death. The major defining characteristic of AD brains is the excessive accumulation of amyloid plaques, composed of a sticky protein called amyloid b (Ab). Ab is toxic to nerve cells, and this may explain the progressive degeneration seen in AD brains. Ab is formed when “molecular scissors” cut APP into 2 places, resulting in the release of Ab. This is a normal process that also occurs in healthy individuals. However, for reasons we do not understand at present, Ab is either excessively produced or not removed fast enough in AD patients. One obvious way to block Ab formation is to inactivate the “molecular scissors”. However, these proteins also have other important functions, such that blocking the “molecular scissors” can have undesirable side effects. An alternative and perhaps additive design might be to block APP transport inside nerve cells so that it does not reach the sites where the “molecular scissors” reside and are most active. In our studies, we found that a protein called LRP normally promotes Ab generation by directing the transport of APP inside cells to compartments where the “molecular scissors” are most active. More than 80% of Ab production is dependent on the presence of LRP. Remarkably, we found that a very small region of LRP (LRP-C37) by itself is sufficient to mimic LRP in robustly increasing Ab generation. In addition, we identified new proteins that physically interact with the C37 domain and modify the cuts made in APP. At present, how LRP-C37 by itself or in the context of the full protein increases Ab production is not known. Furthermore, it is not known how the two new proteins we identified alter APP processing and Ab generation. We hypothesize that the LRP-C37 domain plays a critical role in transporting LRP and APP to compartments where Ab is normally generated. In this application, we propose to characterize the mechanistic basis of the LRP-C37 domain in LRP and APP transport inside cells and Ab generation. In addition, we will determine the role of the two new LRP-C37 interacting proteins in these processes. These studies are expected to form the basis of designing a novel therapeutic approach to block Ab generation.
James Lah, M.D., Ph.D. Because of the strong association between aging and Alzheimer's disease, it is becoming an increasingly important public health concern as life expectancies increase and the number of affected individuals grows. Despite rapid growth in our scientific understanding of Alzheimer’s disease, current treatments are relatively ineffective. In earlier studies, we discovered a novel association between a receptor called LR11 (also known as SorLA) and Alzheimer's disease. LR11 levels were consistently reduced in the brains of patients with AD compared to normal individuals. Additional research findings indicate that changes in LR11 may occur early in the disease process and that LR11 may play an important role in regulating the levels of amyloid-beta peptide, which is believed to play a central role in causing Alzheimer's disease. The evidence emerging from our study of LR11 suggests that it represents an important new therapeutic target for Alzheimer’s disease. We hypothesize that LR11 will be a good target for discovery of candidate compounds that can modulate amyloid-beta through interactions with LR11. We propose to initiate a search for LR11-interacting compounds, which will produce leads in the development of new therapeutic agents. To accomplish this, we will combine our scientific expertise with the capabilities of the NIH-funded Emory Molecular Libraries Screening Center to develop tools to identify and evaluate candidate compounds that interact with LR11. In Aim 1, we will develop high throughput assays to screen a library of small compounds for those capable of interacting with specific portions of LR11. In Aim 2, we will develop cell-based assays to identify relevant LR11-interacting compounds. In Aim 3, we will test the ability of LR11-interacting molecules to modulate amyloid-beta levels to refine the list to the most promising compounds and expedite future efforts to develop LR11-based therapeutic agents. The long-term goal of these studies is to exploit our understanding of LR11 to develop new treatments that can slow or prevent the development of Alzheimer's disease.
Bruce Lamb, Ph.D. Alzheimer's disease (AD), the most common dementing disorder of late life, is now the fourth major cause of death in the developed world. A definitive diagnosis of AD requires examination of brain tissue for the presence of distinctive AD pathological alterations including filamentous inclusions (termed neurofibrillary tangles) and extracellular deposits of the ß-amyloid peptide (Aß, termed senile plaques). In addition, while there is considerable data that suggests there is a marked activation of the immune system within the AD brain, there is little evidence that altered inflammation plays a direct role in the observed neurodegeneration. It was recently demonstrated that alterations in inflammation within the brain, through genetically engineered mutations in the chemokine receptor, CX3CR1, can directly result in increased neuronal cell loss in three different mouse models of neurodegeneration. The focus of the current proposal is to determine the role of CX3CR1 plays in activation of the immune system, neuronal cell death and Aß deposition in two different mouse models of AD as well as to gain insight into the mechanisms involved. The long-term goal of this project is to gain insight into the role inflammation play in AD and thus provide potential new avenues of therapeutic intervention.
Anton Roebroek, Ph.D. Alzheimer’s Disease (AD) is caused by the increasing appearance of abnormal structures in the brain of AD patients, named senile plaques. These plaques consist mainly out of aggregates of a small peptide, Ab, which arises from cleavage from a larger protein. Ab is also present in the brain of healthy people, but for some reason the amount of Ab in the brain goes strongly up and it is deposited in the senile plaques in AD patients. It seems that the normal balance between production and breakdown of Ab, in scientific terms Ab metabolism, is disturbed. Recent scientific investigations revealed that a receptor, LRP1, present on the outside of the cells in the brain might be involved at the same time in both production and breakdown of Ab. Lately, the applicant of the research project generated mice and cells with a modified LRP1, which can be used to clarify the double role of LRP1 in Ab metabolism. It is the strong believe of the applicant that this scientific research will result in essential additional knowledge on the role of LRP1 in the balance of production and breakdown of Ab. This could eventually contribute to new approaches for a treatment for AD.
Michael R. Sierks, Ph.D. Alzheimer's Disease (AD) is characterized by the presence of neuritic plaques and neurofibrillary tangles. The role of Aß in AD is still controversial, an issue that has been complicated greatly by the multiple lengths and morphologies of Aß. A wealth of literature suggests the various lengths and morphologies have different effects on neuron viability and memory. In order to reliably assess the roles of Aß and anti-Aß vaccination strategies in AD, highly specific and very well-defined reagents such as single chain antibody binding variable domains (scFvs) that target individual Aß forms and morphologies are needed. Using a novel technology combining antibody diversity and microscopic imaging techniques, scFvs against specific Aß morphologies can be isolated. The isolated scFvs can be affinity matured to have extremely high specificity for the target ligands. The hypothesis of this proposal is that highly specific and well defined scFvs to specific oligomeric morphologies of Aß can be isolated by useful therapeutics for treating AD. The long term goal is to use the pool of morphology specific scFvs to probe the roles of the various Aß morphologies in AD and to test the value of these scFvs as potential diagnostic and therapeutic agents.
Paul M. Salvaterra, Ph.D. Chronic and progressive dying neurons are the major feature of Alzheimer's disease that can best explain the clinical symptoms. More than 20 years of intensive research has implicated two toxic peptides generated from a larger normal protein as playing an important role in the disease process. It is not known, however, if these peptides are a cause of the disease or just an effect of some other problem in brain cells. Our work is designed to investigate the role of these peptides, both alone and in combination, as direct causes of chronic brain cell death. We will accomplish this by using a simplified genetically controlled model organism. We also believe that our preliminary observations indicate a new cellular pathway that may be responsible for Alzheimer's related cell death. We will thus try and prove this hypothesis using genetic and drug based experimental strategies in our model system. If this new pathway is indeed responsible for cell death in Alzheimer's disease our work could lead to the identification of new treatment and prevention strategies.
Jashvant D. Unadkat, Ph.D. P-glycoprotein (P-gp) is an export pump that is highly active at the barrier that separates brain tissue from blood (called the blood brain barrier or BBB). P-gp can transport amyloid-β (Aβ), a compound that accumulates in the brain of people with Alzheimer’s disease (AD). We believe that reduced activity of P-gp at the BBB results in accumulation of Aβ in the brain of patients with AD. In the proposed study we will compare P-gp activity at the BBB in patients with AD and in age-matched volunteers without AD, using a method called positron emission tomography (PET). The proposed studies are particularly relevant to Alzheimer’s disease for a number of reasons. For the first time, our studies will test the idea that P-gp activity at the BBB is compromised in AD. If it is, we will test in future studies if compounds that are known to increase P-gp activity in the human intestine, such as rifampin or St. John’s Wort, can increase P-gp activity at the BBB. If both or one of these compounds do increase P-gp activity at the BBB, they can be tested for their effectiveness in stopping progression of Alzheimer’s disease.
CENTENNIAL AWARDS Bradley T. Hyman, M.D., Ph.D. Dr. Hyman and his collaborators are studying different forms of a protein that is associated with Alzheimer’s disease. One form of the protein dramatically increases the risk of developing the disease, while another form protects against it. By studying the different forms of this protein, Dr. Hyman’s team hopes to identify features of its molecules that might be used as targets of future medicines. The close collaboration among Dr. Hyman and his co-investigators at Stanford University and Washington University is an excellent example of the scientific synergy key to new discoveries.
Donald Weaver, M.D., Ph.D. Currently, there are no drugs that stop or reverse the progression of Alzheimer’s disease. The drugs that are available treat the symptoms but not the cause of this disease. Dr. Weaver and his collaborators are investigating small molecules that can disrupt the protein buildup that damages the brains of Alzheimer’s patients. By disrupting these proteins, they hope to stop their aggregation and in turn, prevent brain cell death. The ultimate goal of Dr. Weaver’s research is to discover new and useful drug treatments for Alzheimer’s disease.
FUNDING PERIOD: APRIL 1, 2007 – MARCH 31, 2009 Barbara Calabrese, Ph.D. Barbara Calabrese, Ph.D. of the Scripps Research Institute, proposes studying in rat hippocampal neurons how the amyloid beta (Aβ) peptide, a key trigger of Alzheimer’s disease pathology, induces early changes at synapses - the specialized connections between neurons that are essential for learning and memory. Research suggests that in early stages of Alzheimer’s disease cognitive disruption reflects significant loss in the numbers and/or function of synapses. The soluble forms of Aβ have been found to induce memory impairments in animal models. However, it is still not understood how soluble Aβ alters the structure and function of synapses, especially in early stages of the disease. Dr. Calabrese hypothesizes that exposure of neurons to low levels of soluble Aβ results in definable changes in the numbers, shape, and stability of synapses. Pharmacological and gene transfer manipulations of synaptic Aβ targets will be used in combination with high resolution live cell imaging to test this hypothesis. These studies may provide novel insights to treat the earliest stages of AD, during which intervention is likely to be most effective. The hope is that by understanding soluble. Aβ-induced synaptic destabilization we can improve upon therapies that prevent synapse loss or restore synapse function.
Jungsu Kim, Ph.D. Alzheimer's disease (AD) is the most common cause of dementia. Mutations in specific genes (APP, PSEN1, and PSEN2) cause rare forms of familial AD. While these mutations have been very useful, >99% of AD (late-onset) does not appear to be due to these mutations. Defects in clearance of Abeta from brain could underline many cases of sporadic AD. There is only one proven genetic risk factor for both early and late-onset AD, one's APOE genotype. ApoE4 is associated with an increased risk and apoE2 is associated with a decreased risk for AD. A large amount of evidence suggests that apoE is likely to influence risk for AD by acting as a molecular chaperone for Abeta and influencing Abeta fibrillogenesis and clearance. The hypothesis being tested is that different human apoE isoforms and lipidation states of apoE alters apoE and Abeta clearance in the CNS. We further hypothesize that the perturbation in regulation of apoE metabolism will then influence Abeta metabolism and will alter both the time course and amount of Abeta depostion in brain. Results from these experiments may provide insights into normal apoE metabolism in the CNS as well as clarify why APOE isofom genotype influences risk for AD.
Thomas L. Kukar, Ph.D. Understanding the factors responsible for Alzheimer's disease (AD) is critical for the development of therapeutic strategies for this debilitating neurodegenerative disease. Intriguingly, epidemiological studies suggest that chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) protects from the development of AD. We have shown that certain NSAIDs selectively lower production of the 42 amino acid form of the amyloid beta peptide (Aβ42). Based on evidence that the accumulation of Aβ42 in the brain leads to AD, it has been hypothesized that this unique property may contribute to the protective effect of some NSAIDs. These compounds not only selective lower Aβ42 but also increase the levels of shorter Aβ peptides such as Aβ34, 37, and 38. Studies have shown that Aβ42 is much more prone to form amyloid than shorter fragments. Based on these results, we hypothesized that the elevations in shorter Aβ peptides induced by some NSAIDs further enhances their anti-amyloidogenic effect. Experiments will directly investigate the effects of smaller Aβ peptides on Aβ aggregation and fibril formation in vitro. Most importantly a unique technology to rapidly and specifically increase the levels of these short Aβ peptides in the brains of mice will be used to see if they protect from Aβ plaque formation.
Kun Ping Lu, Ph.D., M.D. Alzheimer’s disease is the most common form of dementia and its pathological hallmarks are tangles made of a protein called tau and plaques comprising small peptides called Aβ peptides generated from its precursor protein called APP. We have recently identified a new enzyme, Pin1 that regulates the structure and function of certain proteins such as tau and APP. Moreover, Pin1 is pivotal for protecting against tangle formation, Aβ accumulation and neurodegeneration. Notably, Pin1 is inhibited by various mechanisms in Alzheimer’s patients. These results suggest that Pin1 deregulation is an important factor in Alzheimer’s development, although its molecular targets and mechanisms are not fully elucidated. Our hypothesis in this proposal is that Pin1 might also regulate the function of presenilin 1, an essential component of the enzyme responsible for Aβ production, and that this regulation might be disrupted by some Alzheimer’s mutations in presenilin 1. To test this hypothesis, we will determine whether Pin1 regulates presenilin 1 structure in a test tube, whether manipulating Pin1 function affects PS1 activity in cell culture and animal models, and whether this Pin1-dependent regulation is disrupted by presenilin 1 mutations. These studies would provide new insight into Alzheimer’s development and might have important therapeutic implication.
Enrico Malito, Ph.D. Accumulation in the brain of a specific protein in the form of insoluble plaques is a critical event in Alzheimer’s disease pathology. The imbalance between production of this protein and its degradation is the critical event responsible for its accumulation. Investigating the defects of enzymes that degrade this protein is an essential effort for a better understanding and for the treatment of Alzheimer’s disease. Insulin degrading enzyme (IDE) is among the enzymes responsible for the degradation of the peptide that then accumulates in the brain in an insoluble form, and IDE deficiency is correlated with a significant net increase in accumulation of insoluble plaques in the brain. Consequently, IDE represents a new target for the development of drugs for the treatment of Alzheimer’s disease. Our structural studies of IDE allowed us to understand the basic features of this important enzyme. Starting from these observations we can now modify IDE in order to obtain a decrease of accumulated insoluble plaques. We propose to further investigate the molecular mechanism by which IDE exerts its function, with the final aim of finding a hyperactive form of IDE able to more effectively degrade the protein responsible for the onset of Alzheimer’s disease. These studies will provide valuable insights into the design of IDE-based therapeutics against Alzheimer’s disease.
Michael P. McDonald, Ph.D. Alzheimer's disease is characterized by the accumulation of plaques in the brain, widespread neurodegeneration, and cognitive decline. We have shown that by eliminating an enzyme called GD3S we are able to reduce plaque formation, block cell death, and prevent memory deficits in a mouse model of Alzheimer's disease. This suggests that blocking GD3S may useful in treating Alzheimer's disease. However, in these mice the mutation that blocked GD3S was made before birth, and the enzyme plays an important role in many processes that are important for normal brain development. Thus it's important to test the therapy in adult mice, after they've gone through normal brain development. This is analogous to what a genetic therapy will be like for Alzheimer's patients, i.e., the treatment begins in adulthood. A new technique, called siRNA, allows us to simply and efficiently suppress the expression of the GD3S gene in live mice. We propose to use siRNA to suppress GD3S expression in a mouse model of Alzheimer's disease. Consistent with our previous results, we expect that this novel genetic therapy will significantly reduce plaque formation and completely block the memory deficits normally exhibited by these mice.
Robert Alan Nichols, Ph.D. Alzheimer’s disease is a relentlessly progressive degenerative disorder for which there is currently only limited treatment. Early in the disease memory deficits occur, followed later by disruption of many facets of thinking and even language. Eventually, patients can no longer recognize anyone, including family members, and cannot care for themselves. Thus, it would appear that the disease results from a number of brain functions going awry at different times over its course, involving multiple pathological entities. One entity in particular is a small, sticky peptide known as beta amyloid, which accumulates in the brains of aging adults and eventually forms large, dense deposits (otherwise known as plaques). What free beta amyloid is doing in the brain in the first place is completely unknown, but its accumulation into deposits is one of the first signs in the course of the disease. It is largely produced from nerve endings where they make contacts with and signal to other nerve cells. Normally, this signaling from nerve endings to nerve cells is the primary way that communication occurs within the brain and we are hypothesizing that the free beta amyloid, accumulated at pathological levels, disrupts this basic communication. At present, one particular hope is to identify individuals at risk for heavy accumulation of the beta amyloid, using brain imaging techniques, and then to remove the free beta amyloid. In animal models where beta amyloid is artificially expressed in the brain, early removal of accumulating free beta amyloid prevents the memory deficits that result from the presence of beta amyloid; however, removal from the brain has required vaccination against beta amyloid and to date that has been problematic, though still remains an important and hopeful avenue. Another approach is to disrupt beta amyloid’s pathological actions, potentially preserving its normal function. In order to address this idea, it is essential to understand beta amyloid’s normal function. This project is aimed at understanding its physiological role. Using a defined nerve cell system in culture, we can express target protein receptors for beta amyloid and then examine the functional consequence via several techniques. We can also introduce mutations into the receptors or make deletions to define precisely the molecular components targeted by beta amyloid. Finally, we can explore derivatives of beta amyloid as potential means to disrupt beta amyloid’s action
Eric Norstrom, Ph.D. Alzheimer's disease is an incurable neurodegenerative disease characterized by the accumulation of amyloid plaques - deposits of protein in the brain whose main constituent is the Ab peptide, which is itself derived from the metabolism of a larger protein called APP. Reducing the Ab load in the brain is a major goal of Alzheimer’s research, and to accomplish this, many strategies aim to inhibit the metabolism of APP. Thus, understanding which proteins APP interacts with is important because 1) this aids in the design of small molecule drugs, and 2) if APP metabolism is to be inhibited, an understanding of its natural function is critical. Although many studies have investigated the metabolism of APP in cultured cells, confirmation of these results in animal studies has not yet been achieved. Thus, we aim to generate a transgenic mouse that expresses APP containing a peptide tag. By using this tagged APP as”bait" in the living animal, we can subsequently purify it and those proteins with which it is bound. Analyzing the purified material and comparing it to a protein database will confirm binding partners identified by cell culture studies and identify new binding partners with new specific targets for drug therapy.
Troy Townsend Rohn, Ph.D. Introduction: Recent studies have suggested that proteolytic cleavage of tau by caspases may be an important event linking beta-amyloid with neurofibrillary tangles in Alzheimer's disease (AD). These studies suggest that caspase activation may play an important role in driving AD disease pathology and simply do not represent end-stage events associated with this disease. Hypothesis: Direct, functional evidence for the involvement of caspases in driving AD pathology is currently lacking. The current proposal will test directly the role of caspases in AD by blocking caspase activation in an AD transgenic mouse model and examining whether such inhibition prevents the pathology associated with these animals.
Long-term goals: Direct evidence indicating a causative role for caspases in AD may stimulate the development of caspase inhibitors for their potential in treating this disease. In addition, results from this pilot study will provide the necessary feasibility and data for the development of a more comprehensive proposal examining all pathological aspects of these novel AD mice.
Alejandro F. Schinder, Ph.D. The complexity of the human brain can be easily conceived if we think about 1011 neurons connected by 1015 synapses. Those connections are highly dynamic. Synapses are continuously formed and eliminated in a manner that depends on the activity of brain circuits. Activity-dependent remodeling of neuronal networks is essential for higher brain functions. Its impairment has been associated with mental retardation syndromes and may also play an important role in neurodegenerative disorders. Alzheimer’s disease (AD) has been associated with amyloid plaques, neurofibrillary tangles and neuronal death, which were thought to be the cause of cognitive decline. Recently, animal models of AD have taught us that amyloid-beta (Ab) peptides can impair synaptic transmission in the absence of plaques or tangles, but the specific effects and sites of action of Ab remain unknown. Does Ab impair neuronal communication and/or synapse formation and elimination? Our goal is to study the effects of Ab on synapse formation and function in the hippocampus of adult mice in vivo. We are using a novel strategy based on the fact that new neurons are continuously generated in the adult hippocampus and go through an intense period of synapse formation. We manipulate the genetic information of those adult-born neurons to increase their levels of Ab and analyze their development and maturation using electrophysiology and microscopy. Addressing these questions will contribute to the better understanding of the early changes underlying cognitive impairment in AD and other neurodegenerative diseases.
Vijay Sharma, Ph.D. Alzheimer’s Disease (AD) patients demonstrate loss of neurons in regions of the brain responsible for learning and memory (hippocampus) and the presence of distinct protein aggregates, commonly known as amyloid plaques. Emerging new models for occurrence of the disease indicate that pathways in disease progression are likely mediated by transporters prevalent in the brain. Among these transporters, P-glycoprotein (Pgp) known to block penetration of numerous drugs or cytotoxins into brain may likely be involved in buildup of amyloid plaques within the brains of AD patients. We hypothesize that natural function involving Pgp mediating efflux of amyloid plaques out of the CNS may likely be compromised in diseased patients compared with the normal ones and the process initiates prior to appearance of symptoms for the disease. Thus, ultrasensitive-diagnostic agents capable of evaluating that novel risk factor in terms of individual variations in Pgp transport would likely assist in patient stratification and guide therapeutic choices. Herein, we propose to evaluate the potential of lead Pgp-targeted agent to act as noninvasive probe to detect those defects in brains of mouse models via PET imaging. Additionally, our strategy is amenable to kit formulation with potential for widespread deployment of a test for managing AD.
Jane M. Sullivan, Ph.D. The earliest manifestations of Alzheimer’s disease are deficiencies in cognitive function, specifically problems with memory. These earliest symptoms of the disease are most likely caused by abnormal synaptic transmission. As the disease progresses and dementia becomes more severe, neurons will die, but the earlier changes, those that are hypothesized to be caused by more subtle effects on the way that synapses operate before neurons die, have not been well studied. This is because these changes are occurring in patients that are still alive, and they cannot be investigated with existing techniques. In order to understand what changes are taking place at synapses before neurons die, a model system must be used. This model system must replicate the changes that are thought to be taking place in the brains of patients with early Alzheimer’s disease. This grant proposal describes a series of pilot studies that will develop such a model system using brain cells from mice. Identifying specific changes in synaptic function produced by mutant presenilin, a protein strongly implicated in the inherited form of Alzheimer’s disease, will provide molecular targets for novel therapies to improve cognitive function and delay further neurodegeneration in patients with early Alzheimer’s disease
Nan Wang, Ph.D. Recent studies suggest that cholesterol balance in the brain may affect development of Alzheimer's disease. Increased cholesterol is associated with increased risk of Alzheimer's disease while decreased cholesterol appears to reduce it. Recently, we have identified two membrane transporters that are involved in cholesterol transport in cells. These transporters are highly expressed in the brain. Now we have evidence suggesting that increased activity of these transporters enhances generation of Abeta, the molecule aberrant elevation and deposition of which is considered to be the major cause of Alzheimer's disease. Importantly, deficiency of the transporters appears to decrease Abeta production in the brain. ABCG4, one of two transporters, is mainly expressed in the brain and studies with mouse models of ABCG4 deficiency suggest that ABCG4 deficiency does not affect animal development and no impaired physiological functions have been identified in these mice. Therefore, ABCG4 may represent a novel drug target for treatment of Alzheimer's disease.
Gregory J. Zipfel, M.D. Cerebral amyloid angiopathy (CAA) involves deposition of a protein called amyloid-β (Aβ) into brain blood vessels. It is almost universally found in patients with Alzheimer's Disease (AD). CAA can lead to stroke and dementia, likely by causing blood vessel dysfunction and lowering blood flow to the brain. We hypothesize that treating CAA with an anti-Aβ antibody (an antibody directed against the Aβ protein) will improve blood vessel function and blood flow to the brain. If true, this would prove that Aβ deposits are the reason why CAA leads to blood vessel dysfunction and reduced brain blood flow. It would also mean that these antibodies may represent a new treatment for CAA and AD. The specific aims of this project are as follows:
The long-term goals of this research are to determine how CAA causes stroke and dementia and to discover effective treatments for CAA and AD.
FUNDING PERIOD: APRIL 1, 2007 – MARCH 31, 2008 Gary E. Landreth, Ph.D. Alzheimer's disease is characterized by the deposition of b amyloid (Ab) within the brain and there is good biological evidence that that therapies that reduce Ab deposition and enhance its clearance from the brain will be beneficial. This application investigates the ability of a new class of drug that activate a transcription factor, termed peroxisome proliferator-activated receptor gamma (PPARg). Importantly, drugs that activate PPARg are already in clinical use and have been shown to result in enhanced learning and memory in AD patients. The central problem is that we do not know how the drugs work to elicit the behavioral improvement and this application is focused on establishing the mechanism of drug action. We show that treatment of animal models of AD with PPARg stimulators lead to lower levels of plaque deposition. Moreover, we show that this is likely due to the ability of the drug to stimulate Ab degradation, reducing brain levels of amyloid. We think that PPARg activation works to stimulate the production of factors that allow cellular proteases to cut the amyloid peptides into pieces too small to be deposited. This research provides an explanation for why the present generation of drug that PPARg are beneficial and will inform the development of the next generation of drugs that target this receptor.
FUNDING PERIOD: APRIL 1, 2006 – MARCH 31, 2008 Guojun Bu, Ph.D. Amyloid β-peptide (Aβ) accumulation in the brain is a pathological hallmark of Alzheimer’s disease (AD). Recent studies have shown that aggregated forms of Aβ is toxic to neurons and contribute to memory loss in AD. The toxic Aβ is derived from sequential cleavage of a larger protein called the amyloid precursor protein, or APP. Increased APP cleavage can directly cause AD. APP is a dynamic molecule that moves among different compartments within cells. The general hypothesis is that APP cycling between cell surface and inside the cells increases its chance to be cleaved to Aβ. Dr. Bu has identified three important molecules called LRP, LRP1B, and sorting nexin 17 (SNX17), each interacts with APP and modifies its cycling speed. Specifically, the preliminary studies found that LRP and SNX17 facilitate and LRP1B inhibits APP cycling. The goal of this proposal is to analyze in brain-derived neurons whether their effects on APP cycling also translate into changes in Aβ production. If the results are confirmed, drugs can be designed to increase LRP1B levels or decrease LRP and SNX17 levels to benefit AD patients.
David Cribbs, Ph.D. The focus of this proposal is on immunotherapy (vaccine) as an experimental approach to treat Alzheimer's disease. Dr. Cribbs plans to directly delivery specific antibodies to the central nervous system to attack the toxic amyloid peptide that accumulates in the brain. The antibodies will be delivered by the patient's own stem cells which will be isolated from their bone marrow. These stem cells will be genetically modified to make the antibodies, and then they will be injected into the brain where they will go to the sites of brain inflammation and secrete the therapeutic antibodies.
Lee Goldstein, M.D., Ph.D. A major roadblock in AD research, treatment and drug development is the lack of a safe and reliable diagnostic test. Definitive diagnosis currently involves analysis of brain tissue after death. A sensitive early diagnostic test would greatly speed testing of new drugs in animal and human treatment trials. Building on his exciting recent discoveries (Goldstein et al., Lancet, 2003) that Alzheimer's disease (AD) can be detected in the lens of the eye, Dr. Goldstein’s team has developed new optical tests that can potentially diagnose and monitor the disease from the beginning stages. AD involves the accumulation of a protein called beta amyloid in the brain which also accumulates in the lens of the eye as unusual cataracts in patients with AD. These cataracts are different from those associated with aging. Dr. Goldstein has been able to non-invasively detect these special AD cataracts in humans and in an AD mouse model. His technique uses quasi-elastic light scattering (QLS) to detect cataract formation. This instrument is the most sensitive technology available to detect the very early stages of cataracts. He has also developed a complementary diagnostic technology called fluorescence ligand scanning (FLS). In this approach, he uses special eye drops that contain fluorescent image enhancing molecules that bind to beta amyloid in the lens. If beta amyloid molecules are present, the fluorescing molecules light up and are detected by the instrument. The FLS test is now undergoing evaluation in laboratory animals. The diagnostic tests will accelerate preclinical drug discovery, streamline clinical testing, and facilitate early clinical intervention. Patient care will be greatly enhanced by an objective means to establish early diagnosis, monitor disease progression, and assess treatment response.
William Klein, BSc, Ph.D. Memory formation begins at synapses, and it appears likely that destruction of memory formation is due to synapse failure. This proposal investigates the molecular cause of this failure. It focuses on a new neurotoxin, called ADDLs, that was discovered and characterized by this group over the past several years. Dr. Klein previously showed that ADDLs accumulate in AD brains, so it is important to know how they act. His most recent work established that ADDLs attack synapses, a fact that gives very strong support to the idea that AD is a synapse failure. He now wants to discover what type of structural and molecular damage ADDLs cause to synapses after they bind. The preliminary evidence strongly indicates that ADDLs rapidly change the geometry of synapses into a shape often seen in mental retardation. Evidence also indicates that the neurotransmitter receptor molecules required for information storage are removed from synapses. Dr. Klein plans to verify and extend these preliminary results by new experiments using state-of-the-art experimental models to study synapse biology and the impact of ADDLs. The experiments in the long run will determine how the ADDLs attack on synapses could result in the catastrophic memory failure suffered in early Alzheimer's disease.
Jin-Moo Lee, M.D., Ph.D. One of the major abnormalities found in the brains of patients with Alzheimer's disease (AD) are clumps of abnormally aggregated protein, called amyloid plaques. These proteins (amyloid-beta peptide) have a remarkable propensity to self-aggregate into long chains of protein known as amyloid fibrils, which are thought to be very resistant to breakdown and clearance. Thus, it is believed that the plaques accumulate in the brains of patients with Alzheimer's disease, contributing to brain degeneration and leading to dementia. Dr. Lee has recently found an enzyme, matrix metalloproteinase-9 (MMP-9), capable of degrading amyloid fibrils in test tube experiments. He has also found that MMP-9 degrades amyloid plaques in brain slices from a mouse model of AD. Furthermore, he finds that this enzyme is found in cell surrounding amyloid plaques in this mouse model, suggesting that it may play a role in regulating the growth of plaques. In this grant application, Dr. Lee proposes to study the role of MMP-9 in degrading amyloid plaques in a mouse model of Alzheimer's disease. He plans to use genetically altered AD mice that lack MMP-9 to examine the formation of amyloid plaques, asking the question: “Is plaque formation accelerated in AD mice that lack MMP-9?” Furthermore, this research will determine if MMP-9 limits the size of amyloid plaques once they are formed. Dr. Lee hopes to gain further insight into mechanisms that regulate the growth and degradation of amyloid plaques in Alzheimer's disease
Alan J. Lerner, M.D. Studies have suggested that low cognitive performance and low activity level in youth may be associated with an increased risk for dementia in adulthood. However, we know little about the mechanism(s) underlying the associations. Experiences occurring in mid- and late-life could mediate the influence of cognitive ability and activity level in youth on cognitive function in adulthood. Or, the effects of early life factors on AD could be independent of mid- and late-life experiences. In this project, Dr. Lerner will examine the relationships between teen IQ and activity level, and a genetic risk factor for AD (APOE e4), on the development of AD over time. Subjects will be 1940s graduates of the same high school who had normal cognition in 2002. Subjects will undergo two follow-up evaluations to detect transitions to dementia. IQ test scores and activity levels, gathered from sources at the school, will be used as predictor variables in statistical models. Dr. Lerner predicts that lower IQ and activity level, and the high-risk APOE gene will each increase AD risk, and that mid- and late-life factors will directly and indirectly contribute to this effect. These findings will contribute to knowledge about pathways leading to AD and may identify modifiable risk factors.
Yueming Li, Ph.D. The long term objective of the proposed studies is to gain a better understanding of the function of y-secretase and to develop specific y-secretase inhibitors for treatment of Alzheimer’s disease (AD). y-Secretase cleaves the amyloid precursor protein (APP) to generate the C-termini of Aβ peptides (Aβ40 and Aβ42), in the final step of amyloid production. Aβ, the major constituent of amyloid plaques found in AD, is believed to play a critical role in the neuropathogenesis of AD. It is known that Aβ42 is more prone to aggregation than Aβ40 and increased Aβ42 production may accelerate the pathological cascade leading to AD. Mutations in PS1 and PS2 that lead to familial early-onset AD (FAD) cause an increased ratio of Aβ42/Aβ40. The precise mechanism by which these mutations result in the increased ratio of Aβ42/Aβ42 is unknown. The hypothesis that the dynamics of the PS1- and PS2-associated y-secretase complexes regulate the production of Aβ40 and Aβ42 and that deregulation of this process leads to production of excessive Aβ42. Dr. Li will investigate the complex dynamics through integrated approaches incorporating biochemistry, cell biology and chemical biology. The proposed studies will help to uncover the regulation and function of y-secretase, thereby facilitating the development of selective inhibitors for AD therapy.
Steven Mennerick, Ph.D. Aβ is a protein of unknown function that is secreted by brain cells normally but accumulates in toxic forms outside of brain cells in the progression of Alzheimer's disease. It is known that eventual accumulation of toxic Aβ is related to the levels of released Aβ throughout life, but the processes governing Aβ release from cells are poorly understood. Better understanding could lead to early intervention in the disease, before toxic accumulation can occur. Inversely, exploring the effects of released Aβ protein on the function of brain cells should lead us to better understand what goes awry in neuronal signaling during disease progression. The goals of the proposed studies are to test a negative feedback hypothesis of Aβ release and effects. Neurons normally communicate by releasing chemical messenger (transmitter) from tiny, membrane-bound packages, or vesicles, by fusion of these vesicles with the cell membrane. These packages are re-used by a process of membrane retrieval from the cell surface. Preliminary results demonstrate that somehow the process of vesicle use and retrieval (normal neuronal communication) causes the appearance of more Aβ outside of brain cells. The first aim is to test the idea that vesicle retrieval is directly important for Aβ release from neurons. This result would support a general hypothesis by which the process of membrane retrieval, driven by neuronal communication, normally retrieves the precursor for Aβ along with vesicle membrane. The precursor gets sorted into a compartment inside the cell separate from the vesicle, and the precursor, when in this intracellular compartment, is cleaved to Aβ. The Aβ is then secreted by the cell from this separate compartment. The idea that neuronal communication itself indirectly drives Aβ release may influence strategies for slowing the release of Aβ and preventing toxic Aβ formation. The second aim explores the general question "Once Aβ is released, what does it do?" Dr. Mennerick will test the hypothesis that Aβ feeds back to dampen the ability of brain cells to communicate with each other. If so, this could directly cause neuronal dysfunction during disease progression. Aβ regulation of neuronal communication could have a normal function, which turns pathological in the presence of excessive Aβ levels. Go to Top
Ricardo Miledi, M.D. All the functions of the brain, sensations, memory etc. depend on the transmission of signals across the myriads of synapses that interconnect the billions of neurons of the brain. In the synaptic process neurotransmitter substances, released from one neuron, act on receptor proteins embedded in the membrane of neighboring neurons. Alzheimer’s is a synaptic disease accompanied by neuronal loss. Nevertheless, very little is known about the neurotransmitter receptors of the Alzheimer’s brain. Dr. Miledi will study the structure and function of these receptors, using a method that he developed to micro-transplant receptors from the human brain to frog oocytes. Membranes, isolated from brains frozen post-mortem, are injected into oocytes. These membranes, carrying the original receptors from the Alzheimer’s brain, and still embedded in their original membrane, fuse with the oocyte membrane. Remarkably, the receptors are still functional and can be subjected to detailed structural and functional analyses. Receptors from Alzheimer’s brains will be compared with those from non-Alzheimer’s brains, focusing on the receptors to GABA and Glutamate: the main inhibitory and excitatory neurotransmitters in the human brain. The effects of Amyloid beta will also be studied. All this will help determine the cause of Alzheimer’s disease and help to develop new treatments.
Paul St. John, Ph.D. Alzheimer's disease (AD) is a debilitating brain disease marked by often severe cognitive disorders. Existing evidence suggests that amyloid-beta (Aβ) peptides can cause or contribute to AD, but how they do so is not clear. A significant problem in this area is that Aβ peptides spontaneously aggregate to generate several distinct "assembly forms" that can differ in their biological properties. However, which form or forms cause AD is not known. This proposed research will test a two-part hypothesis: 1) Assembly forms of Aβ differ in their potency for inducing programmed cell death (apoptosis) in central nervous system neurons, and 2) a particular subtype of neurotransmitter receptor on such neurons mediates the triggering of cell death by Aβ. The Specific Aims will test each part of this hypothesis. Aim 1: Quantify and compare the ability of different Aβ assembly forms to induce apoptosis in cultured CNS neurons; Aim 2: Determine whether normal functioning of the receptor subtype in question is necessary for Aβ to induce apoptosis in CNS neurons. The completed work will set up subsequent studies to test treatments to prevent the apoptotic effects of Aβ, with the focus on directly interfering with Aβ binding to CNS neurons.
Brock Schroeder, Ph.D. Dysfunction at synapses in the brain may underlie many of the deficits present in Alzheimer's disease. Factors that influence the health of synapses are thus vital areas of research focus. The proposed research will be focused on a protein which has shown promise as a protective factor in other models of neurodegeneration, but which has not been examined in Alzheimer's Disease models. The objective is to elucidate whether this protein (known as WLDs) is functionally useful as a protective factor in an Alzheimer's disease model. Given the protective effect that the WLDs protein has had in other models, the working hypothesis is that the protein will attenuate synaptic dysfunction Alzheimer's disease models. Dr. Schroeder will first determine the effects of the WLDs protein on synaptic transmission and learning deficits known to exist in Alzheimer's disease models. In the second part of this proposal, he will examine the effect of the WLDs protein on known structural and synaptic protein expression changes in Alzheimer's disease models. In the long-term, he hopes that the potential protective effects of the WLDs protein will serve to clarify the mechanism of synaptic dysfunction in Alzheimer's disease as well as lead to therapeutic options for treating synaptic dysfunction.
Gopal Thinakaran, Ph.D. Alzheimer’s disease (AD) is the major cause of dementia in the elderly. Mutations in genes encoding Presenilins and Amyloid Precursor Protein (APP) cause early onset AD. These mutant proteins increase the production of toxic beta-amyloid peptides (Aβ), which accumulate in the brains of individuals with AD. Production and accumulation of Aβ are central events in AD pathogenesis. This proposal seeks to investigate the regulation of Aβ production. Aβ is released from truncated APP by the action of “y-secretase”, composed of Presenilins and three other proteins. Specialized microdomains of cellular membranes, called lipid rafts, seem to play important role in Aβ production. Dr. Thinakaran seeks to investigate how y-secretase complex is selectively targeted to lipid rafts. He also proposes to examine the regulation of y-secretase complex and APP by a variety of molecular and cell biological approaches. A better understanding of the relationship between y-secretase and lipid rafts will shed more light on the mechanisms involved in Aβ production. Information stemming from the biochemical, molecular and cellular investigations will likely be critical in developing novel and rational strategies for therapeutic intervention for AD aimed at reducing Aβ burden.
Cheryl Wellington, BSc., Ph.D. Cholesterol is increasingly recognized to play a role in Alzheimer's Disease (AD), suggesting that genes that regulate cholesterol may affect the process of AD. Down Syndrome (DS) is a genetic disease caused by inheritance of an extra copy of chromosome 21. A prominent feature of DS is the inevitable development of AD by the mid-late 30s, decades earlier than the general population. Notably, chromosome 21 contains a gene known as ABCG1 that is highly expressed in brain and that is involved in cholesterol metabolism. Dr. Wellington shows that ABCG1 increases the production of Abeta peptides, which are the toxic species that accumulate in AD and DS brains. This result suggests that ABCG1 may connect cholesterol with the acceleration of AD in DS. In this proposal, Dr. Wellington will evaluate whether ABCG1 accelerates AD pathology in a mouse model and study exactly how ABCG1 works in a cell culture model system. She will also initiate studies of ABCG1 in human and mouse brain tissue as a first step in translating the results into applications for human health. This research will determine whether eventual therapies for AD may be based on ABCG1, which will be applicable for both the general and DS populations.
Guilian Xu, Ph.D. There is substantial evidence to suggest that the deposition of beta-amyloid (small fragments of a protein called the amyloid precursor protein) triggers a cascade of events that ultimately causes the symptoms of Alzheimer’s disease. The life-long accumulation of amyloid peptide in the brain is determined by the rate of its generation versus clearance. A large number of studies have provided evidence that a protein called the low-density lipoprotein receptor-related protein (LRP) may play a pivotal role in regulating the production or clearance of amyloid peptides. This study will use transgenic mouse models to study the roles of LRP in modulating amyloid pathology. Dr. Xu will use a genetic system, called Cre/lox, to eliminate LRP expression in specific types of cells in the forebrains of mice and then assess how this manipulation has altered amyloid deposition. It has been suggested that the binding of LRP to proteins involved in amyloid peptide production and clearance is the mechanism of action. If so, then it may be possible to identify drugs that modulate LRP binding to these proteins and thus influence its role in the formation of amyloid pathology.
Riqiang Yan, Ph.D. The etiology of Alzheimer’s disease (AD) is still unclear, and many factors appear to affect AD pathogenesis. Hence, it is imperative that every approach be considered in the effort to stem this disease. Neuritic plaques (or called senile plaques) and neurofibrillary tangles are two well known pathological features in patients’ brains. Neuritic plaques that are predominantly seen in brains of Alzheimer's patients are due to the presence of amyloid depositions surrounded by dystrophic neuritis, reactive astrocytes and activated microglia. In this proposal, Dr. Yan proposes to study a molecule called Nogo Receptor 2 (NgR2) and its role in the formation of neuritic plaques. The information gained from this study will be used for developing therapeutic agents to prevent and/or treat Alzheimer's patients.
Li Zhang, Ph.D. Alzheimer’s disease (AD) is a progressive age-related neurodegenerative disorder and the most common cause of dementia among the elderly. The pathological development of AD is characterized by progressive impairment of memory and cognitive functions and is accompanied by amyloid plaques and neurofibrillary tangles. While synaptic loss appears to correlate well with the early emergence of cognitive dysfunction in AD patients, the neural basis for the cognitive impairment, in terms of structural and functional properties of cortical circuitry, remains largely unknown. In this project Dr. Zhang will explore the neural basis for AD-related cognitive impairment in a mouse model of AD and determine how the pathological development of AD is accompanied with specific and progressive changes of functional organization of sensory cortices. Fourier intrinsic optical imaging technique will be applied to study functional organization in sensory cortices. This imaging method detects the intrinsic deoxyhemoglobin signals which indicate brain activity (with a spatial resolution of 30-50 micrometers), and allows to locate cortical regions activated by specific sensory stimuli within a large-scale cortical area. Therefore, by applying various sensory stimuli, Dr. Zhang can visualize how cortical representation of these stimuli is topographically organized. In addition, Fourier-based analysis allows a rapid acquisition of results. In fact, a similar paradigm used in this technique can also be extended to functional MRI for imaging human cortex, since both detect similar intrinsic signals. This project represents an initial effort in investigating the neural basis underlying the cognitive impairment in AD. By comparing cortical functional organization between AD and normal aging sensory cortex, and by monitoring changes of cortical functional organization during the pathological development of AD, a better understanding can be established of the neural basis underlying the functional deficits caused by AD. This study may also have impact on early diagnosis of AD.
Ning Zhong, Ph.D., Alzheimer’s disease (AD), a devastating neurodegenerative disease, is the most common form of dementia among older people. Aside from age, the greatest known risk factor for AD is the gene for one of three apolipoprotein (apo) E isoforms: apoE4. ApoE4 is associated with 40–60% of cases of AD. In contrast, apoE3 appears to offer some protection against AD, and apoE2 is even more protective. ApoE3 and apoE4 differ by only a single amino acid in their protein sequence. As a result of domain interaction, apoE4 has a more compact structure than the other forms of apoE, and this property likely contributes to its adverse effects in neurobiology. ApoE4 is also the least stable isoform of apoE, causing it to more readily form a molten globule state. Molten globules are associated with several pathological conditions. Since the structure of a protein often determines its function, an apoE4 molten globule is an intriguing potential mechanism to explain the pathological functions of apoE4 in various diseases. Dr. Zhong will aim to learn the correlation between apoE4 isoform-specific structural properties and synaptic pathology, one of the major manifestations of AD. The structural specificity of apoE4 suggests an intriguing strategy for developing AD therapies: convert apoE4 into a molecule that more closely resembles apoE3 or apoE2.
FUNDING PERIOD: AUGUST 1, 2004 - JULY 31, 2007 John A. Oates, M.D. This study focuses on the effects of an enzyme, cyclo-oxygenase, on amyloid beta, the protein fragment that aggregates into plaques in the brains of Alzheimer's patients. The process by which amyloid beta accumulates and clumps together to create plaques is not well understood, but scientists think it is central to the development of Alzheimer's disease. The study may shed light on how non-steroidal anti-inflammatory drugs (NSAIDs) like aspirin and ibuprofen are thought to lower the risk of developing Alzheimer's disease. NSAIDs are known to inhibit the actions of cyclo-oxygenases, and the scientists believe that if they can succeed in creating a more powerful compound to block cyco-oxygenase activity, it could lead to a drug that would actually halt the disease. Current Alzheimer's drugs treat the symptoms, but no drug has been found yet to stop the progression of Alzheimer's disease.
FUNDING PERIOD: APRIL 1, 2005 – MARCH 31, 2007 Gail Anne Breen, Ph.D. A reduced rate of brain metabolism is one of the best documented abnormalities in Alzheimer’s disease (AD). Since abnormalities in mitochondrial energy production appear to play a major role in pathophysiology of AD, Dr. Breen plans to test the hypothesis that the proteins of the mitochondrial oxidative phosphorylation system are decreased or modified in the brains of AD patients. If data using a mouse model of AD demonstrate differences in the levels of the proteins of the oxidative phosphorylation system in AD versus control brains, then future studies will be directed towards examining these proteins in human AD brains. Identification of the factors involved in the etiology and/or progression of AD may lead to the development of treatments to improve neuropsychological function in AD patients or delay the onset of the disease.
In-Young Choi, Ph.D. Oxidative stress plays an important role in age-related pathophysiology such as Alzheimer’s disease. However, the effects of oxidative stress in the living brain with Alzheimer’s disease have not been clearly described. The objective of Dr. Choi’s project is to measure a molecule in the brain called Glutathione (GSH), which reflects the antioxidant defense system, and its regional variation in the living human brain to explain the role of oxidative stress in Alzheimer’s disease. The identification of an important biomarker in the living brain tissue will be particularly valuable for evaluating the effects of antioxidant therapy in patients with Alzheimer’s disease in the future.
Mary Konsolaki, Ph.D. Although progress has been made in understanding the basic pathology of Alzheimer’s disease, the currently available therapies can only address the symptoms of the disease and fail to reverse its causes. In order to be able to design therapies that effectively combat this devastating disease, it is necessary to gain a better understanding of the mechanisms that lead to neuronal death in affected individuals. Aβ peptides have been shown to be toxic to neurons, but the specific mechanisms of such toxicity remain to be further elucidated. Dr. Konosolaki intends to isolate and characterize genes that play a role in Aβ-associated toxicity, using genetic screens in flies. These screens will lead to the identification of novel factors associated with Aβ neurotoxicity and will contribute to the understanding of pathways that mediate Aβ effects. This knowledge may contribute to future design of appropriate therapies for Alzheimer’s.
Huaxi Xu, Ph.D. The identities of “AD genes” are largely unknown. Identification of these genes is one of the most challenging tasks neuroscientists need to address in order to understand the mechanisms underlying the genesis of AD and to find a cure for it. To identify these genes, laboratories have adopted a new technology called “microarray” to compare the gene expression patterns. Searching for the genes expressed differentially in certain types of neuron cells, requires use of a newly developed technology called Laser Capture Microdissection (LCM), to isolate individual types of neurons in the brain region that controls cognitive activity. Dr. Xu plans to identify the genes that govern AD susceptibility at a cellular level by using LCM together with microarray analyses. The potential results of this research will enhance our understanding of the molecular mechanisms underlying pathogenesis of AD and provide crucial information for developing effective therapies.
FUNDING PERIOD: APRIL 1, 2004 - MARCH 31, 2006 Yong Shen, Ph.D. Scientists have discovered that the brain changes constantly throughout life, generating new neurons and connections. This process, called plasticity, offers a possible mechanism through which the brain might be induced to repair itself after injury or disease. Dr. Shen’s research is expanding upon previous studies by isolating neural precursor cells from rapidly autopsied elderly brains with Alzheimer’s disease. The location and function of neural precursor cells in the normal aged brains are being compared to those in Alzheimer’s brains with the goal of determining how amyloid beta peptide (Aß), a small-sized protein, affects the differentiation of neural precursor cells into neurons. The long-term goal of Dr. Shens’s research is to provide an advanced understanding of the foundation of the innate healing capacity of diseased brains and to provide an avenue for physicians to deliver drugs in the future that would stimulate the brain to replace its own cells and thereby rebuild its damaged circuits.
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