Lary C. Walker, PhD - US grants

The principal goal of the Training & Information Transfer Core of our Alzheimer's Disease Research Center (ADRC) is to communicate information concerning issues related to aging and age-associated disorders, particularly Alzheimer's disease (AD). We have a major commitment to educating the public, training promising young professionals, providing opportunities for these individuals to do clinical and basic research, and disseminating basic and clinical research findings to the lay, medical, and scientific community. Using a variety of information transfer vehicles, our program is directed at three groups: the lay public, including members of families of affected individuals; minorities; young professionals (medical/graduate students, clinical investigators, and basic scientists); and members of the AD clinical and research community (clinicians, scientists, and professional caregivers). Our outreach programs are designed to communicate with local and regional associations of health professionals outside of academic communities. Our ADRC supports care-giving management programs at nursing homes and community hospitals. Moreover, our staff is very active in interactions with support groups and the education of students at all levels concerning basic neurobiology, aging, and AD. To enhance our outreach efforts, we are initiating a newsletter for families and caregivers. Furthermore, we are making a concerted effort to educate minorities in our region concerning AD and related disorders and to recruit African- Americans for our research programs. To train young clinicians and scientists, we coordinate a series of lectures and seminars that deal with clinical and basic science issues, clinical-pathological conferences, and a Visiting Professor lectureship. At the national and international levels, our ADRC professional clinicians and scientists participate in a broad range of meetings ranging from clinical issues to cellular and molecular biological approaches to AD. By facilitating the flow of ideas and information at a number of levels, these activities help to relieve the burden imposed by AD on caregivers and on society and to speed the development of diagnostic, therapeutic, and preventive measures.

neuropathology; disease /disorder model; Alzheimer's disease; Primates; animal colony;

ATGN; Age; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's Disease; Alzheimers Dementia; Alzheimers disease; Amyloidosis; Antibody Formation; Antibody Production; Antibody Response; Antigens; B blood cells; B-Cells; B-Lymphocytes; Blood Plasma; Blood Vessels; Bursa-Dependent Lymphocytes; Bursa-Equivalent Lymphocyte; CRISP; Cerebral Amyloid Angiopathy; Collaborations; Computer Retrieval of Information on Scientific Projects Database; Congophilic Angiopathy; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Development; Funding; Grant; ITX; Immunization; Immunologic Stimulation; Immunological Stimulation; Immunologically Directed Therapy; Immunology; Immunology (Including BRMP); Immunology (NCI Program); Immunostimulation; Immunotherapy; Institution; Investigators; Mammals, Primates; Modeling; Monkeys; NIH; National Institutes of Health; National Institutes of Health (U.S.); Plasma; Primary Senile Degenerative Dementia; Primates; Proteins; Reporting; Research; Research Personnel; Research Resources; Researchers; Resources; Reticuloendothelial System, Serum, Plasma; Safety; Saimiri; Saimirus; Sensitization, Immunologic; Sensitization, Immunological; Serum, Plasma; Source; Squirrel Monkey; United States National Institutes of Health; aged; amyloid disease; antibody biosynthesis; dementia of the Alzheimer type; gene product; immune therapy; immunogen; immunoglobulin biosynthesis; primary degenerative dementia; senile dementia of the Alzheimer type; vascular

Addiction, Drug; Affect; Age; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's Disease; Alzheimer's disease risk; Alzheimers Dementia; Alzheimers disease; Amyloid Plaques; Biologic Marker; Biological Markers; Brain; Brain Pathology; CRISP; Cells; Change of Life, Female; Chemical Dependence; Chemicals; Computer Retrieval of Information on Scientific Projects Database; Deep; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Dependence, Drug; Depth; Development; Disease; Disorder; Drug Addiction; Drug Dependency; Encephalon; Encephalons; Engineering; Engineerings; Funding; Genital System, Female, Ovary; Grant; Hormonal; Hormonal Change; Human; Human, General; Institution; Investigators; Mammals, Mice; Man (Taxonomy); Man, Modern; Menopause; Mice; Molecular Marker; Murine; Mus; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nervous System, Brain; Neuritic Plaques; Numbers; Ovary; Phase; Primary Senile Degenerative Dementia; Proteins; Protocol; Protocols documentation; Research; Research Personnel; Research Resources; Researchers; Resources; Senile Plaques; Signature Molecule; Source; Structure; United States National Institutes of Health; Woman; Work; amyloid beta plaque; amyloid-b plaque; biomarker; cored plaque; dementia of the Alzheimer type; diffuse plaque; disease/disorder; gene product; in vivo; men; men's; menopausal; mouse model; primary degenerative dementia; senile dementia of the Alzheimer type

21+ years old; AD model; APF-1; ATP-Dependent Proteolysis Factor 1; Adult; Age-Months; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's Disease; Alzheimer's disease model; Alzheimers Dementia; Alzheimers disease; Amyloid A4 Protein Precursor; Amyloid Protein Precursor; Amyloid beta-Protein Precursor; Axon; Brain; CMV; CRISP; Cell Body; Common Rat Strains; Computer Retrieval of Information on Scientific Projects Database; Cytomegalovirus; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Dendrites; Disease; Disorder; Electrons; Encephalon; Encephalons; Evaluation; Fluorescence; Funding; GFP; Grant; Green Fluorescent Proteins; HCMV; HMG-20; High Mobility Protein 20; Human, Adult; Institution; Investigators; Lentivirinae; Lentivirus; Localized; MT-bound tau; Mammals, Primates; Mammals, Rats; Mammals, Rodents; Microscopic; NIH; National Institutes of Health; National Institutes of Health (U.S.); Negative Beta Particle; Negatrons; Nerve Cells; Nerve Unit; Nervous System, Brain; Neural Cell; Neurocyte; Neurons; PDGF; Pathogenesis; Pathology; Platelet-Derived Growth Factor; Polyubiquitin Gene Product; Primary Senile Degenerative Dementia; Primates; Promoter; Promoters (Genetics); Promotor; Promotor (Genetics); Publications; Rat; Rattus; Research; Research Personnel; Research Resources; Researchers; Resources; Rodent; Rodentia; Rodentias; Saimiri; Saimirus; Salivary Gland Viruses; Scientific Publication; Source; Squirrel Monkey; Subfamily lentivirinae; Transgenes; Transgenic Organisms; Ubiquitin; Ubiquitin C; United States National Institutes of Health; Virus-Lenti; adult animal; adult human (21+); amyloid precursor protein; cell body (neuron); cytomegalovirus group; dementia of the Alzheimer type; disease/disorder; human cytomegalovirus; mature animal; microtubule associated protein tau; microtubule bound tau; microtubule-associated protein tau; microtubule-bound tau; neural cell body; neuronal; neuronal cell body; non-human primate; nonhuman primate; primary degenerative dementia; senile dementia of the Alzheimer type; soma; tau; tau Proteins; tau expression; tau factor; transgene expression; transgenic

APP-PS1; APP/PS1; Alzheimer; Alzheimer disease; Alzheimer sclerosis; Alzheimer syndrome; Alzheimer's; Alzheimer's Disease; Alzheimers Dementia; Alzheimers disease; Ammon Horn; Animals; Antibodies; Brain; CRISP; Characteristics; Computer Retrieval of Information on Scientific Projects Database; Confocal Microscopy; Contralateral; Cornu Ammonis; Dementia, Alzheimer Type; Dementia, Primary Senile Degenerative; Dementia, Senile; Deposit; Deposition; ELISA; Encephalon; Encephalons; Enzyme-Linked Immunosorbent Assay; Funding; Grant; Hippocampus; Hippocampus (Brain); Human; Human, General; Immune Precipitation; Immunofluorescence; Immunofluorescence Immunologic; Immunologic, Immunofluorescence; Immunoprecipitation; Injection of therapeutic agent; Injections; Institution; Investigators; MALDI-TOF Mass Spectrometry; Mammals, Mice; Mammals, Primates; Man (Taxonomy); Man, Modern; Matrix-Assisted Laser Desorption Ionization Time-of-Flight MS; Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry; Mice; Mice, Transgenic; Microscopy, Confocal; Murine; Mus; NIH; National Institutes of Health; National Institutes of Health (U.S.); Nervous System, Brain; Pathology; Patients; Pattern; Peptides; Plant Embryos; Population; Primary Senile Degenerative Dementia; Primates; Research; Research Personnel; Research Resources; Researchers; Resistance; Resources; Saimiri; Saimirus; Seeds; Source; Squirrel Monkey; Testing; Transgenic Mice; United States National Institutes of Health; Zygotes, Plant; aged; dementia of the Alzheimer type; hippocampal; internal control; primary degenerative dementia; resistant; seed; senile dementia of the Alzheimer type

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. There is now strong evidence that Alzheimer's disease is caused by proteins that mistakenly bind to one another to form toxic aggregates in the brain. The protein that drives this process is known as A[unreadable]. Little is known about the strains of disease-causing proteins in the living brain. We have developed a new way of causing proteins to aggregate in the brain based on the simple principle that a particular protein molecule with a particular abnormal shape can cause normal versions of the same molecule to become abnormal by a process analagous to seeded crystallization. Recently we have found that molecules that have been developed to image A[unreadable] in Alzheimer's disease may actually distinguish between toxic and benign aggregates of A[unreadable]. A[unreadable]-binding agents thus have the potential to distinguish among stuctural variants of A[unreadable] that may be differentially toxic to the brain.

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common cause of dementia in aging humans, currently afflicting approximately 5 million Americans. Research recently has shown that an important feature of AD is the abnormal accumulation of specific proteins in the brain, and that the aggregation of the protein A¿ is a primary event. However, how this process of aggregation is initiated, and how the aggregates spread from one region to another, remains uncertain. The goal of our research is to understand the cellular and molecular processes that initiate the pathogenesis of AD. Our previous studies found that the deposition of A¿ can be induced, or seeded, in the brains of transgenic mouse models of AD by the infusion of dilute, A¿-rich brain extracts containing aggregated A¿. Very recently we found that A¿ aggregation can be seeded by injections of A¿-rich brain extracts into the abdominal cavity of mice. Preliminary data implicate mononuclear phagocytes (macrophages) as the vectors of the seeds, in that A¿-seed- laden macrophages enter the circulation following the intraperitoneal injection of seed. However, direct evidence for the cellular transport of the seeds into the brain is lacking. The objective of this project is to clarify the role of macrophages in disseminating the seeds for A¿ aggregation using a transgenic mouse model and in vitro models of the processing of seeds by macrophages. In the vast majority of AD cases, the factors that precipitate protein aggregation remain unknown. Understanding the cellular mechanisms underlying induced A¿ aggregation and spread could eventually point the way to new therapies for Alzheimer's disease and other debilitating brain disorders of the elderly.

DESCRIPTION (provided by applicant): Cerebrovascular disease is one of the most common causes of dementia in aging humans. With the growing elderly population in Western societies, vascular cognitive impairment (VCI) will become a significant healthcare burden in the 21st century. Recent advances in magnetic resonance imaging (MRI) are continually lowering the threshold for detection of vascular anomalies in the brain, leading to a growing awareness that small vessel disease and microinfarcts can cumulatively lead to VCI. However, the power of MRI currently is limited by the inability to link anomalous MR signals unambiguously to specific lesion types. Valid animal models would greatly accelerate diagnostic and therapeutic approaches to cerebrovascular disease. The explicit identification of MR anomalies has been a particular problem in investigating cerebral A[unreadable]-amyloid angiopathy (CAA), a disease of the elderly in which misfolded A[unreadable] peptide accumulates in the walls of brain blood vessels. Investigators have increasingly employed novel imaging protocols to analyze CAA non-invasively. However, there is a critical need for information that will enable the interpretation of neuroimaging data on CAA and other vascular disorders in patients. The aged squirrel monkey is a unique animal model of naturally occurring CAA that is highly similar to the disorder in humans. The overarching goal of our research program is to clarify the role of CAA in vascular dysfunction and cognitive decline in the elderly. The objective of this proposal is to employ this exceptional primate model to optimize the power of MRI to non-invasively identify and characterize CAA-related lesions in living patients. To achieve this goal, we first will investigate a unique sample of archived brains from aged squirrel monkeys with CAA, along with postmortem tissue samples from humans with CAA, in a powerful (7T) MRI scanner. In this way, we can detect a variety of vascular lesions under optimal conditions. Next, we will use the information gained from these ex vivo imaging studies to image a small cohort of aged squirrel monkeys in vivo. The brains then will be examined microscopically to identify and characterize the MRI anomalies unambiguously, and to determine the cellular and molecular features of the lesions. We predict that MRI signal anomalies will be linked to specific histopathological indicators of CAA and associated lesions. The findings from this novel primate model will establish a foundation for future non-invasive studies of the pathogenesis, diagnosis and treatment of CAA in aged humans. PUBLIC HEALTH RELEVANCE: In this investigation of cerebral amyloid angiopathy (CAA), the key question that we will address is whether anomalies detected by high field MRI can be unambiguously linked to specific lesions, including microinfarcts, focal inflammation, and white matter changes. We will approach this question by analyzing histochemically the signal anomalies detected in a 7T MRI scanner in aged squirrel monkeys (which develop profound, human-like CAA) and in tissue samples from aged humans with CAA. The impact of this research is that 1) it will enable clinicians to confidently link anomalous signals in living patients to specific lesion types, improving diagnostic precision and thus simplifying therapeutic decisions;2) it will provide information on the cellular and molecular features of microvascular lesions that will help to identify new therapeutic targets;and 3) it will validate the aged squirrel monkey as a biologically proximate animal model of microvascular disease in aging humans.

ABSTRACT/SUMMARY: PROJECT 3 An important mission of the NIH is to reduce the profound toll that chronic diseases take on individuals, families, and society. As life expectancy continues to rise, the spectre of Alzheimer's disease looms ever larger over the US and the rest of the world, yet there is no effective preventive or treatment for the disorder. To overcome this obstacle, it is essential to understand the fundamental biology of Alzheimer's disease, and important strides have been made in this regard in recent years. It is now evident, for example, that an early and obligatory event in the pathogenesis of Alzheimer's disease is the accumulation of an abnormally folded protein fragment called Aß. Surprisingly, however, recently developed methods for imaging these lesions in the living brain indicate that some people with large amounts of Aß pathology become demented, whereas others do not. In other words, not all aggregates of Aß appear to be equally toxic to brain cells. In this Project, we propose that the pathobiological characteristics of Aß result from variations in the multidimensional architecture of the misfolded protein. Specifically, we hypothesize that Aß can misfold and aggregate into different forms, or strains, and that these strains govern the toxicity of the molecules. To test this hypothesis, we propose to: 1) Investigate the molecular and structural features of aggregated Aß that define the strains; 2) Determine how these features affect the onset of Alzheimer's disease; 3) Identify other molecules within cells that influence the characteristics of Aß strains; and 4) Replicate Aß strains in transgenic mouse models of Aß pathology. By clarifying the nature and diversity of human Aß strains and their relationship to the disease phenotype, it is the objective of this project to identify new molecular therapeutic targets for Alzheimer's disease.

? DESCRIPTION (provided by applicant): Alzheimer's disease - the most common age-related neurodegenerative disorder - is a personal and societal tragedy of immense and growing proportions. Over 5 million Americans currently suffer from Alzheimer's disease (AD), and the number is expected to triple by 2050. Despite recent progress in characterizing AD, therapeutic interventions have been disappointing in large part because we lack a complete understanding of the mechanisms that contribute to this disease. Research suggests that peripheral inflammation is an important and modifiable risk factor for AD, and epidemiologic studies suggest that mid-life metabolic syndrome, obesity, and hypertension are inter-related health care conditions that increase the risk of age-related neurodegenerative disorders, particularly AD. The mechanistic links between these systemic disorders and neurodegeneration are poorly understood, but may be the key to developing effective anti-AD therapeutics. These risk factors are particularly prevalent in African Americans, who are also at increased risk for AD. The novel overarching hypothesis of this proposal is that chronic systemic disorders (i.e. metabolic syndrome and hypertension) are mechanistically linked to AD through a multistage process that involves dysregulation of the renin angiotensin system (RAS), systemic inflammation and a heightened peripheral immune response, followed by increased immune cell trafficking across the blood brain barrier (BBB) and leading to chronic neuroinflammation, CNS dysfunction, and cognitive decline. To test this hypothesis, we have assembled an interdisciplinary team of experts in inflammation, RAS dysfunction and neurodegeneration to address the following questions: 1) What is the relationship between chronic peripheral inflammation and Alzheimer-like pathology in a transgenic mouse model of Alzheimer-like pathology? 2) How is overactivation of the renin-angiotensin system related to brain inflammation, immune function and AD-like pathogenesis in this model? and 3) How is RAS dysfunction related to central inflammation and immune function in humans at risk for AD? In addressing the third question we will focus on African Americans, who are particularly vulnerable to metabolic syndrome and AD yet have received little attention in systematic investigations. Successful completion of the proposed studies will provide new and potentially paradigm- shifting mechanistic information on how diet- and hypertension-induced chronic peripheral inflammation and chronic brain inflammation contribute to the development of AD.