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Claudine L. Bitel
Integrative Neuroscience Program
B.S. 1998, Trinity College (Hartford, CT)
Thesis Advisor: Peter Frederikse, Ph.D.
Department of Pharmacology and Physiology
Wednesday, April 7, 2010
10:00 a.m., MSB H-609b
Alzheimer’s disease (AD) is the major age-related degenerative disease of the brain and is primarily caused by two mechanisms: 1) â-amyloid peptides (Aâ) production and 2) cargo vesicle transport defects involving the Alzheimer Aâ precursor protein. However, it is known that Alzheimer biology and thus Alzheimer pathology are also central to major degenerative diseases elsewhere in the body. The Alzheimer Precursor Protein (APP) can be cleaved to produce Aâ. Normally APP is a transmembrane protein in vesicles that interacts with kinesins to link vesicles and their contents to microtubules for transport. Alzheimer pathology and Aâ deposition has been described in lens, muscle and pancreas. Thus, we reasoned Monitoring Aâ peptide biomarkers that also increase in tissues throughout the body might provide important diagnostic information about corresponding Alzheimer pathology in brain. Recently, diabetes, which produces system-wide hyperglycemia and oxidative stress has been shown to have strong epidemiological and mechanistically links with Alzheimer disease processes. These factors strongly identify diabetes and the production of hyperglycemia as a useful model to examine Alzheimer pathology in brain and examine its relationship with the production and progression of AD pathology in other organs, and to consider the potential for coordinate onset and production of AD pathology elsewhere in the body to provide a diagnostic tool for detecting and monitoring AD pathology in brain. Findings from our laboratory and others showed that Alzheimer pathology also occurs in age-related disease in the lens. Striking similarities that have been described between elongated lens fiber cells of the lens and neurons suggested these two cell types might more extensively share molecular and cellular process surrounding APP and Aâ biology, fundamental disease processes and susceptibility to systemic stress of aging or metabolic disease. Our studies showed that a broad array of neuronal proteins that work with APP in synaptic vesicle transport are also utilized in post-mitotic lens fiber cells that make up the interior of the lens. These APP-associated vesicle transport proteins are expressed along the length of fiber cells, where microtubules are observed. My studies have gone on to show that fundamental regulatory mechanisms which have a basic role in neuronal development and process formation, and determine the expression and alternative splicing of many neuronal proteins, also occur in elongating lens fiber cells. These include the role of the REST/NRSF master neuronal transcription factor, and PTB/nPTB, HuR/HuB/C/D, and Fox-1, Fox-2 RNA binding proteins (RBPs). These RBPs comprehensively reprogram gene expression by regulation of alternative splicing, and translation of transcripts in neurons. Together, REST, RBPs, and “brain-specific” miRNAs we also show are also uniquely expressed in the lens, form a genetic switch that governs neurogenesis, and these studies show the factors are “one-for one” used in a similar manner in the lens. These findings strongly reinforce the notion that lens cells and neurons share not only much of the biology surrounding APP transport, but also share extensive this fundamental interlocking regulatory mechanism that has been previously characterized as determining neuronal cell identity. These findings demonstrate an even more remarkable degree of shared basic molecular and cellular biology in lens cells and neurons, and suggest that additional diseases of the nervous system may have corresponding phenotypes in the lens. Regarding disease and specifically diabetes, it has been established that AD (a.k.a. Type III diabetes) and lens degenerative disease (collectively referred to as cataract) are each closely linked with diabetes. To then test our ideas that corresponding Alzheimer pathology is produced in
lens and brain, we chose to use a diabetes model in rabbits. Unlike mice or rats, rabbits produce Aâ peptides that have the same amino acid sequence as human Aâ. This is key, because human Aâ peptides have a different amino acid composition that has a much greater capacity to bind metals, and particularly copper. Aâ-Cu binding strongly potentiates and increases the pathological effects of Aâ. As a result, increased cleavage of APP produces deleterious Aâ, and can disrupt the central process of cargo vesicle transport in these elongated cells. Four months after we produced diabetes in a group of rabbits, we examined lens, brain and also muscle (Aâ pathology is also a hallmark of age-related muscle degenerative disease), and observed clear pathological changes in each tissue. In each tissue, we observed many regions with Aâ peptide accumulation and deposits. In brain, hippocampus and cortex exhibited extensive Aâ deposits and plaques, which were detected with anti-Aâ antibodies, or with antibodies raised against ADDL small stable oligomers, considered to by a highly pathological form of Aâ. ADDLs strongly link AD and diabetes, by binding at neuronal (post-synaptic) membrane surfaces and coordinately inducing receptor endocytosis of Insulin receptors and AMPA receptors and their co-localization with ADDLs, and the present data demonstrate for the first time ADDL and IR and AMPAR co-localization in diabetic brain. Moreover, this mechanism can apply to other cell types further linking AD mechanisms and diabetes in other tissues and organs. To quantify these findings, ELISAs measured ~3.5-fold increases in lens, ~7-fold increase in Aâ levels in quadriceps muscle samples, and ~3.5-fold increase in Aâ levels in cortex and in hippocampus assayed separately. Together these studies laid down the fundamental basis for designing and testing methods to assess Aâ biomarkers in the lens, and to determine the relationship between Aâ increases in lens and brain, which we
characterized in this “end-point” study of Alzheimer pathophysiology in diabetic hyperglycemic rabbits. In summary, my research identified and characterized a striking degree of shared molecular and cellular biology in lens cells and neurons, that question the evolutionary origins of neuronal cell identity and synaptic vesicle transport, and demonstrate shared APP and Aâ disease mechanisms that produce coordinate production of Aâ pathology in brain and other tissues in the body confronted with systemic pathophysiology and stress in diabetes.