Alzheimer's Disease Research GrantsFUNDING PERIOD: APRIL 1, 2004 - MARCH 31, 2006 Robert P. Brendza, Ph. D. Ian A. D’Souza, Ph.D. Michael D. Ehlers, Ph.D. Joseph B. El Khoury, M.D. Ralph J. Greenspan , Ph.D. Annat F. Ikin, Ph.D. Pravat K. Mandal, Ph. D. Ian V. J. Murray, Ph. D. Marco Prado, D.Sc. Melanie Pritchard, Ph. D. Tingyu Qu, M.D., Ph. D. Agueda Rostagno, Ph.D. Timothy J. Seabrook, Ph. D. Sangram Sisodia, Ph.D. *Yong Shen, Ph.D. John D. Sweatt, Ph.D. Gopal Thinakaran, Ph.D. Christopher H. van Dyck, M.D.
FUNDING PERIOD: APRIL 1, 2004 - MARCH 31, 2006 Robert P. Brendza, Ph. D. In AD, the appearance of dystrophic or degenerating neuritis, which are thought to disrupt neuronal function, correlates with the clinical severity of dementia. However, it remains unknown whether the damage to these neuronal structures is static, dynamic or possibly reversible. Dr. Brendza is analyzing neuritic plaques in the brains of living transgenic mice that develop amyloid plaques and AD-like pathology. Amyloid-associated dystrophic neurites, as well as unaffected neuron structures, can be visualized in these animals by their inherent fluorescence. Dr. Brendza is using this system to investigate whether dystrophic neurites undergo dynamic changes over time and to determine if treatments that remove amyloid will reverse the neuronal damage. It is hoped that this research will yield new insight into the dynamic nature of amyloid toxicity and help scientists understand whether removing existing amyloid or sequestering diffusible toxic forms of amyloid-beta peptide is a valid target for the treatment of Alzheimer’s disease.
Ian A. D’Souza, Ph.D. Dementia affects more than 20 million people worldwide and more than 4 million people in the United States. Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are two of the most common forms of dementia. Toxic, insoluble aggregates of tau protein, called neurofibrillary tangles (NFTs) are pathological signatures in AD and FTD. The amount of tau accumulation correlates with disease severity, but its role in the initiation of the disease is unknown. The objective of Dr. D’Souza’s research is to understand the mechanism for tau gene expression during normal development, normal aging, and disease development in cell cultures and mouse neuronal systems. Mice bred to express the human tau genomic construct will be a powerful system to study tau gene expression during brain development and aging, and could help identify new candidates for therapeutic interventions.
Michael D. Ehlers, Ph.D. A significant amount of early memory deficit in Alzheimer’s disease (AD) is caused by abnormal communication between nerve cells in the hippocampus, a brain region dedicated to memory formation. Such communication occurs at excitatory synapses, specialized cell-cell contact sites where the neurotransmitter glutamate is released and detected. A prominent form of AD-associated synapse dysfunction is the impairment of synaptic plasticity by beta-amyloid (Aß), the protein fragment that accumulates in the brains of Alzheimer’s patients. A newly recognized mechanism for changing synaptic strength is the removal of neurotransmitter receptors that detect the neurotransmitter glutamate by a process called endocytosis. Dr. Ehlers has found that Aß peptides cause a selective activation of endocytosis molecules with a simultaneous loss of glutamate receptors at hippocampal synapses. Using his preliminary data, Dr. Ehlers is working to define the underlying cellular mechanism of the Aß-dependent disturbance of endocytosis and to identify molecular signals that restore normal synapse function in the amyloid-exposed brain.
Joseph B. El Khoury, M.D. Data from humans with Alzheimer’s disease and animal models of the disease indicate that the accumulation of microglia (inflammatory cells) in senile plaques contributes significantly to neural degeneration. Previous research from both Dr. El Khoury’s laboratory and from other scientists indicates that beta-amyloid activates local microglia and astrocytes to produce chemokines, which then attract additional microglia to the plaque. The recruited microglia bind to the already deposited beta-amyloid and become activated to produce neurotoxins and other inflammatory mediators that cause neuronal damage. With prior support from ADR, Dr. El Khoury found that a small protein, called MCP-1, is necessary for the recruitment of microglia to sites of beta-amyloid deposition, and he has hypothesized that this protein may play a role in the recruitment of microglia to senile plaques in Alzheimer’s disease. He is now working to build upon this data by investigating the specific mechanisms of recruitment, activation, and retention of microglia in senile plaques.
Ralph J. Greenspan , Ph.D. Understanding the functions of genes related to disease is an important step towards identifying new drug targets, assessing their likelihood of a new drug’s success, and augmenting the effectiveness of existing drugs. Through a knowledge of genes and their network of interactions, one can obtain clues to new drug targets as well as potential interactions that might result in side effects. One of the genes involved in Alzheimer’s disease, low-density lipoprotein-related protein (LRP), is present in the fruit fly Drosophila, and there are fly strains available that carry mutant forms of the gene. Dr. Greenspan has developed a method of testing systematically for interactions between Drosophila’s version of LRP and its other genes. Dr. Greenspan’s research is designed to determine the network of LRP’s relationships with other genes from the large number of existing mutants and genetic strains in the fruit fly. Knowing more about the normal function of these genes could create a new strategy for identifying new and potentially more effective drug targets.
Annat F. Ikin, Ph.D. Alzheimer’s disease (AD) is believed to be caused by the excess accumulation of amyloid beta (Aß) in the brain. It is well known that Aß is derived through the processing of a larger molecule, the amyloid precursor protein (APP). Determining the function of APP will further an understanding of the pathological events leading to AD and should help to identify therapeutic targets that do not disrupt normal brain functions. Dr. Ikin believes that proteins that bind to APP could potentially modify its function. One such protein is the cytosolic adapter FE65. Dr. Ikin has already shown that APP and FE65 both localize in a region of neuronal growth cones along with mena, which regulates membrane motility and is required for normal neural development. This suggests that a constellation of factors involving APP and FE65 may play a role in growth cone motility. In this project, Dr. Ikin is testing the hypothesis that APP, FE65, and one or more additional proteins form a complex involved in the regulation of growth cone movement and neurite outgrowth. The function of this complex may have direct implications for AD, since the loss of neural connections and neuronal sprouting are prominent features of Alzheimer’s disease pathology.
Pravat K. Mandal, Ph. D. Amyloid plaques and tangled bundles of fiber (neurofibrillary tangles or NFTs) are thought to play an important role in the pathogenesis of Alzheimer’s disease (AD). Scientists have found that the amyloid plaques are associated with a type of molecule called gangliosides in the brains of Alzheimer’s patients. There are five main gangliosides in the human brain, and research shows that some gangliosides increase while others decrease with aging. Dr. Mandal has already demonstrated through nuclear magnetic resonance (NMR) studies that one ganglioside is capable of preventing the toxic precipitant in an experimental environment. His current goal is to understand the role of these “good” and “bad” gangliosides in the formation of toxic amyloid plaques. This research could lead to the design of new drugs that could slow or halt the symptoms of AD and could also contribute to the development of a noninvasive way to test for Alzheimer’s disease using magnetic resonance spectroscopy.
Ian V.J. Murray, Ph. D. Patients with Alzheimer’s disease experience a gradual loss of memory, problems with reasoning, disorientation, loss of language skills, and behavioral problems. The major cause of the disease is thought to be the misfolding of a specific protein within the brain. Many researchers hypothesize that oxidation and free radical damage to the brain predates the protein misfolding and the clumping of protein fragments into plaques. Dr. Murray is investigating the interactions of oxidation and free radical damage with the brain lipids and misfolded proteins. It is hoped that the resulting knowledge will assist in the development of new treatment methods for Alzheimer’s and possibly other neurodegenerative diseases.
Marco Prado, D.Sc. Early cognitive symptoms of Alzheimer’s disease can be improved by drugs that slow the breakdown of an important brain messenger called acetylcholine. Researchers have known that neurons that secrete acetylcholine are vulnerable in Alzheimer’s disease, but so far, they have been unable to understand specifically how a lack of acetylcholine influences behavior. However, recent advances in scientific methodologies make it possible to generate mouse models that have specific mutations. Dr. Prado has hypothesized that these methodologies can now be used to selectively impair or decrease acetylcholine secretion in certain brain regions of the mouse. Certain behaviors can now be studied in these mice and their performance correlated with the levels of acetylcholine secretion in different brain regions. This research will provide fundamental knowledge on how a deficit of acetylcholine contributes to some of the symptoms associated with Alzheimer’s disease.
Melanie Pritchard, Ph. D. All individuals with Down’s syndrome (DS) develop AD-like neurological pathology. Dr. Pritchard’s efforts to identify genes with the potential to cause the brain anomalies observed in Down’s syndrome led to the discovery of a gene called Intersectin 1 (ITSN-1). In neurons in the brain, a specialized process called endocytosis is part of the synaptic transmission, and it is essential for neurons to communicate with one another. Evidence suggests that ITSN-1 is one of the genes involved in the uptake of signaling molecules into neurons. This fact, together with its location on chromosome 21 (the chromosome triplicated in DS), plus its increased expression in the developing DS brain, makes ITSN-1 a prime candidate for contributing to the early endocytic anomalies reported in both DS and AD brains. It is hoped that Dr. Pritchard’s research will provide new insights into the functioning of the endocytic pathway in neurons by examining the role of ITSN-1 in edocytosis in animal models. The data from this study have the potential to provide new targets for drug design that will target the earliest neuropathological events in both DS and Alzheimer’s disease.
Tingyu Qu, M.D., Ph. D. Cholinergic neurons, which are closely associated with memory function, selectively degenerate in Alzheimer’s disease (AD). Dr. Qu’s previous research has demonstrated that transplanted human neural stem cells (hNSCs) migrate to the proper sites and differentiate into the proper cell types to replace lesioned cholinergic neurons in the brain. Therefore, the transplantation of hNSCs may be a good candidate as a cholinergic cell replacement therapy for AD. Dr. Qu has found that transplanting hNSCs to aged (24-month-old) rats improved behavioral impairment as measured in the Morris water maze. He was also able to show that neurons and glia derived from the transplanted cells were present in several areas of the host brain. Dr. Qu’s behavioral research is now investigating the effects of hNSC transplantation on the cognitive function of brain-lesioned animals using several different types of mazes. It is hoped that this research will provide valuable data to assess the effectiveness of human neural stem cell transplantation as a means to replace degenerative cholinergic neurons in the central nervous system.
Agueda Rostagno, Ph.D.
Timothy J. Seabrook, Ph. D. One of the hallmarks of Alzheimer’s disease (AD) is the accumulation of a protein called beta-amyloid (Aß) in the brain. This protein is formed throughout life, but as some individuals age, the protein begins to accumulate in aggregates called plaques. Surrounding the Aß plaques in the brain is an area of inflammation that involves the immune cells of the brain, called the microglia. Microglia produce both noxious substances that can increase the damage to the brain caused by Aß and helpful substances that help brain cells maintain normal function. Dr. Seabrook is studying the effects of suppressing microglia on the formation of plaques in mice that have been engineered to produce an abnormal human form of Aß in their brain. These experiments will help elucidate the basic role of microglia in the formation of Aß. The role of microglia during vaccination will also be examined, which could lead to a better understanding of their role in this promising therapeutic area.
Sangram Sisodia, Ph.D. The neuropathological hallmark of Alzheimer’s disease (AD) is the presence of senile plaques throughout the cortex and hippocampus of affected individuals. Senile plaques are composed of extracellular deposits of a small peptide, termed beta-amyloid, or Aß. Aß is derived through the processing of a protein referred to as amyloid precursor protein (APP). There is evidence to suggest that the gene Presenilin 1 (PS1) is present as a complex with several additional membrane proteins, termed NCT, APH-1, and PEN-2. It is believed that these proteins are components of a complex required for “γ-secretase” activity, which leads to the release of the peptide from APP. However, the structural components that govern the interactions of this complex are not well understood. Dr. Sisodia has developed a model system in the yeast, Pichia pastoris, to provide a description of the structural determinants that promote the assembly of PS1, nicastrin (NCT), APH-1 and PEN-2, and to understand the order of the association of the components. This model will allow Dr. Sisodia to examine the interaction of these components and to define the minimal structural components required for the assembly of the complex. The information gained from this project could lay the groundwork for the development of new treatments that target γ-secretase and inhibit Aß production in the brain.
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.
John D. Sweatt, Ph.D. One of the major advances in neurobiology in the last century was the formation of the general theory that changes in synaptic connections between neurons underlie information storage in the central nervous system (CNS). By studying the mechanisms of long-lasting synaptic plasticity in model systems, researchers can generate insights into the mechanisms of learning and memory. Dr. Sweatt’s past research indicates that four protein kinases play particularly prominent roles in synaptic plasticity and memory. These kinases are designated as PKA, PKC, CaMKII, and ERK MAPK. This project involves the role of the alpha7 nicotinic acetylcholine receptor in regulating these protein kinases. Alpha7 nicotinic acetylcholine receptors are abundant in the hippocampus and in cholinergic neurons from the basal forebrain, and these structures are particularly vulnerable to the ravages of Alzheimer’s disease. Dr. Sweatt is now testing the hypothesis that beta-amyloid peptide directly activates the alpha7 nicotinic acetylcholine receptor and leads to the disruption of memory-related biochemical processes.
Gopal Thinakaran, Ph.D. Recent research efforts have uncovered a common thread that connects the effects of mutations in the proteins termed Presenilin 1, Presenilin 2 and the amyloid precursor protein (APP). All three mutant proteins increase the production of toxic beta-amyloid peptide (Aß), which accumulates in the brains of individuals with Alzheimer’s disease (AD). Dr. Thinakaran’s research seeks to gain new information regarding the molecules that play an essential role in the production of Aß peptides. Presenilins and a few other proteins act together to generate Aß by the enzymatic cleavage of amyloid precursor protein. Recently, specialized microdomains in the cell surface, called lipid raft, were found to be involved in the production of Aß. A better understanding of the relationship between Presenilin and associated proteins and lipid rafts will shed more light on the mechanisms involved in Aß production, and perhaps, lead to new therapeutic interventions for Alzheimer’s disease (AD).
Christopher H. van Dyck, M.D. Recent research efforts have uncovered a common thread that connects the effects of mutations in the proteins termed Presenilin 1, Presenilin 2 and the amyloid precursor protein (APP). All three mutant proteins increase the production of toxic beta-amyloid peptide (Aß), which accumulates in the brains of individuals with Alzheimer’s disease (AD). Dr. Thinakaran’s research seeks to gain new information regarding the molecules that play an essential role in the production of Aß peptides. Presenilins and a few other proteins act together to generate Aß by the enzymatic cleavage of amyloid precursor protein. Recently, specialized microdomains in the cell surface, called lipid raft, were found to be involved in the production of Aß. A better understanding of the relationship between Presenilin and associated proteins and lipid rafts will shed more light on the mechanisms involved in Aß production, and perhaps, lead to new therapeutic interventions for Alzheimer’s disease (AD). |