Anne B. Young, MD PhD - US grants

We have recently observed 35-75% decreases in cortical and hippocampal glutamate receptors in brains of people dying with senile dementia of the Alzheimer's type (SDAT). Other receptors (muscarinic cholinergic, GABA, benzodiazepine, dopamine and opiate) show little or no change in cortex of SDAT. However, the activity of the enzyme choline acetyltransferase (CAT) and levels of somatostatin are also reduced in SDAT. We propose to study three aspects of these deficiencies. First, we will study the relationship between glutamate receptors, the clinical degree of dementia and the pathological indices of disease (senile plaques and neurofibrillary tangles) in a series of patients dying of SDAT. Second, we will study the effects of cholinergic inputs to cortex on cortical glutamatergic function in rats. Third, we will study the effects of somatostatin depletion on cortical glutamate function in rats. The techniques we will use include quantitative autoradiography of receptors in human and rat brain, stereotaxic lesions using ibotenic acid, somatostatin depletion using cysteamine, glutamate release, levels and uptake, choline acetyltransferase activity and choline uptake. The investigators have experience in using all the proposed methodologies. The significance of the research is that the studies should yield important information about how the various neurochemical abnormalities demonstrated in SDAT relate to the pathogenesis of the disease.

The overall goal of the Michigan ADRC is to promote research and education on Alzheimer's disease and related dementias and to assure the dissemination amongst scientists, physicians and caregivers in Michigan of state-of-the art methods of evaluation and care by its educational activities. The ADRC will provide core resources for both clinical and fundamental scientific research. It will serve as a focus for interactions between investigators examining various aspects of cognitive dysfunction in aging. It will promote new research on dementia by funding pilot projects by young investigators or established investigators with new interests in cognitive disorders. Finally, it will educate health professionals and caregivers throughout the state in the optimal techniques for making a correct diagnosis and for managing and treating persons with dementia. The Michigan ADRC will maintain four core facilities. The resources of each of the cores will be accessible to scientists, health professionals, caregivers and patients throughout the state. The Clinical Core will consist of a clinical evaluation unit, a neuropsychology unit, and a data management/biostatistics unit that will maintain, among other things, a patient registry. The Neuropathology Core will serve to acquire postmortem material, give a detailed neuropathologic assessment of each case and provide documented postmortem material for investigators. The Administrative Core will coordinate the functions of all the ADRc research projects, the core facilities and the pilot projects. The Research Training and Information Transfer Core will attempt to unify methods of patient assessment and evaluation throughout the State of Michigan in the secondary care centers. The initial scientific efforts of the ADRC will capitalize on the scientific expertise already available at the University of Michigan in studies of Alzheimer's disease, Parkinson's disease with dementia, Huntington's disease and olivopontocerebellar atrophy using PET scanning, detailed clinical evaluations and postmortem autoradiographic and immunocytochemical studies. Four projects will focus on studies of the relationship of dysfunction in the cholinergic, glutamaterigic and dopaminergic systems to the cognitive and motor manifestations of the primary dementias. Two clinical projects will related directly to two basic science projects. The projects will also relate to research on cognitive disorders funded through other sources. Although the research projects have clear thematic relationship, research in more diverse areas will be promoted by inclusion of five pilot projects form investigators with various backgrounds and interests.

This is a resubmission of a new program project application directed by the Chief of Neurology at Massachusetts General Hospital, Dr. Anne B. Young, who was Director of the Michigan Alzheimer's Disease Research Center before moving to MGH in August, 1991. Prior to Dr. Young's arrival, the investigators were each examining independent aspects of neurodegeneration and Alzheimer's disease (AD) and in this new effort, they will combine forces to explore the excitotoxic and metabolic cascade that predisposes the brain to aging and AD. Five projects and two cores are proposed. Project 1 will examine the hypothesis that cells that are vulnerable in AD contain a high density of NMDA and metabotropic receptors, protein kinases and amyloid precursor protein (APP) or amyloid precursor-like protein (APLP) and a low density of GLuR2. receptors. Project 2 will examine the hypotheses that neurons in "at-risk" regions develop abnormal tau proteins early in the disease, that vulnerable neurons contain high densities of MAP kinases, and that APP and APLP are differentially expressed near sine plaques. Project will investigate the hypotheses that progressive impairment of mitochondrial energy metabolism develops in normal aging, that defective energy metabolism occurs in AD brain and peripheral tissues and that these events predispose to increased cortical and hippocampal damage. Project 4 will examine the regulatory characteristics of the APP gene family (APP, APLP1 and APLP2, etc), their promoters, their processing (i.e., splicing, synthesis, degradation) and the hypothesis that APP and APP-like messages are altered in specific brain regions in aging and AD. Project 5 will utilize a model of aging neurons in cell culture to study the effects of excitatory, thermal-, metabolic and age-induced stress on amyloid precursor protein processing. All projects will utilize the administrative and reagent cores and the latter will perform molecular assays common to all projects. The revised program is thus a multidisciplinary effort that includes state-of-the-art molecular, cell culture, neurochemical, electrophysiologic, anatomic and neuropathologic techniques to study the cellular vulnerability in aging and AD.

Toxic actions of the neurotransmitter, glutamic acid, have been implicated in a number of diseases that effect the brain including stroke, epilepsy, Huntington~s disease, Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. These toxic actions of glutamate are mediated through the same neurotransmitter receptors on nerve cells that ordinarily serve to convey glutamate's excitatory signal to nerve cells. Recent experimental evidence suggests that some subtypes of metabotropic glutamate receptors may attenuate glutamate excitotoxicity while other subtypes of metabotropic glutamate receptors aggravate excitotoxicity. In addition, drugs that specifically bind to the different subtypes of metabotropic receptors have been invented recently. This project will use molecular pharmacologic techniques to better define the role of metabotropic glutamate receptors in excitotoxic and metabolic death of nerve cells. A combination of stereotaxic lesions, pharmacological manipulations, quantitative morphometry and in situ hybridization histochemistry will be used to test the hypothesis that metabotropic receptors linked to the phosphatidyl inositol second messenger system aggravate while metabotropic receptors linked to the adenylate cyclase second messenger system attenuate excitotoxicity. Injections of antisense messenger RNA to specifically block synthesis of the different metabotropic receptors will be used to further define the roles of the different metabotropic receptors.

Submitted in response to RFA NS-98-001 this center will study how aberrant trafficking of alpha-synuclein, which may involve the two novel proteins (parkin and torsinA), leads to the death of dopamine neurons in Parkinson's disease. We will also study the nature of the basal ganglia dysfunction caused by parkinsonism and we will use the techniques so developed to validate our models of molecular mechanisms. Four projects and two cores will be involved. The first project, under Dr. Bradley Hyman, will determine the role of alpha-synuclein in Lewy body formation using transgenic animals and confocal microscopy. The second, under Dr. Xandra Breakefield, will use molecular biological techniques to determine the degree to which different alleles of the genes for alpha-synuclein, parkin, torsinA, which is mutated in early onset torsion dystonia, and that for Rapid Onset Dystonia Parkinsonism contribute to the susceptibility to Parkinson's disease. The third project, under Dr. John Penney, will determine if the most vulnerable dopamine neurons are the ones that bear the highest burden of these potentially pathogenic molecules using double-label in situ hybridization and antisense RNA techniques. The fourth project, under Dr. Ann Graybiel, will focus on determining the neural systems consequences of parkinsonism and the alpha- synuclein and dystonia mutations in experimental animals using tetrode recordings. The projects are highly integrated, each interacting extensively with all the others to contribute to the overall program. The center will be supported by an administrative core and a vital, training and clinical core that will provide a superb training ground for the next generation of parkinson's disease researchers. Finally, the two institutions involved ensure that the center will exist in a highly supportive environment.

Submitted in response to RFA NS-98-001 this center will study how aberrant trafficking of alpha-synuclein, which may involve the two novel proteins (parkin and torsinA), leads to the death of dopamine neurons in Parkinson's disease. We will also study the nature of the basal ganglia dysfunction caused by parkinsonism and we will use the techniques so developed to validate our models of molecular mechanisms. Four projects and two cores will be involved. The first project, under Dr. Bradley Hyman, will determine the role of alpha-synuclein in Lewy body formation using transgenic animals and confocal microscopy. The second, under Dr. Xandra Breakefield, will use molecular biological techniques to determine the degree to which different alleles of the genes for alpha-synuclein, parkin, torsinA, which is mutated in early onset torsion dystonia, and that for Rapid Onset Dystonia Parkinsonism contribute to the susceptibility to Parkinson's disease. The third project, under Dr. John Penney, will determine if the most vulnerable dopamine neurons are the ones that bear the highest burden of these potentially pathogenic molecules using double-label in situ hybridization and antisense RNA techniques. The fourth project, under Dr. Ann Graybiel, will focus on determining the neural systems consequences of parkinsonism and the alpha- synuclein and dystonia mutations in experimental animals using tetrode recordings. The projects are highly integrated, each interacting extensively with all the others to contribute to the overall program. The center will be supported by an administrative core and a vital, training and clinical core that will provide a superb training ground for the next generation of parkinson's disease researchers. Finally, the two institutions involved ensure that the center will exist in a highly supportive environment.

DESCRIPTION (provided by applicant): The MGH/MIT Morris Udall Center of Excellence in PD Research is taking a broad, collaborative and interactive approach to the study of Parkinson's disease. The Projects address critical questions concerning the selective vulnerability of dopamine neurons, the mechanism and consequences of Lewy body formation and alpha-synuclein aggregation, the neural systems consequences of parkinsonism and synuclein pathology, and molecular approaches for modifying this pathology. These issues will be explored using a range of systems, from yeast genetics, to mammalian cell culture, to rodent models to human postmortem material. The Center incorporates state-of-the-art technologies including high throughput yeast genetic screens to identify modifiers of synuclein aggregation and toxicity, viral vector gene transfer to study factors in mammalian cell culture and rodent models, multi-unit tetrode recordings to study striatal plasticity, fluorescence lifetime imaging to study protein-protein interactions, and laser capture microdissection and gene arrays to study transcriptional dysregulation. The Center has a Clinical and Training Core that provides care to patients with Parkinson's disease, gathers data on clinical features of the disease and response to therapy, solicits brain donations for neuropathological study, and trains outstanding clinician scientists to be future leaders in the field. The Center also has a Bioinformatics Core that serves to integrate and analyze data across the projects, and facilitate sharing of the information. The Administrative Core is charged with management of the Center and facilitating the sharing of information, ideas, and reagents among the investigators and with other components of the Udall Centers consortium. The investigators of the MGH/MIT Center are dedicated to a program of collaborative and interactive studies which will lead to better treatments for people with Parkinson's disease.

DESCRIPTION (provided by applicant): Project Description: This proposal describes the Research Training Program for Neurology and Neurosurgery Residents at Massachusetts General Hospital (MGH) and Brigham and Women's Hospital (BWH) of Harvard Medical School (HMS). The program combines the exciting variety of collaborative research opportunities available at these campuses with a dedicated core group of neuroscience mentors. Mentors have been carefully selected by the PIs on the basis of research activity, experience guiding clinicians in the early stages of successful research careers, and commitment to this program to develop neurology and neurosurgery residents into effective physician-scientists. A steering committee has been meeting regularly during the creation of this application and will closely oversee all aspects of the resident research training experience. Public Health Relevance: There is a widely recognized need for translational and clinical research in neurological diseases. Neurology and neurosurgery resident trainees are young physicians who are completing their clinical training and have first-hand knowledge of the limits of current technologies. Many of the residents at Massachusetts General Hospital and Brigham and Women's Hospitals of Harvard Medical School have extensive research backgrounds, and have expressed interest in neurological research. This application will link the tremendous depth and breadth of research resources available in the Harvard system to a small group of dedicated senior neuroscientists. These scientists are active researchers who have abundant experience training young physician researchers and who care deeply about the future of neurological research. These senior scientists will serve as mentors to guide the initial research experience of the neurology residents. A steering committee will help match residents and mentors and will monitor all aspects of the program's efficacy.