Proteoglycans in Alzheimer's Disease, Down's Syndrome, and Aging

Proteoglycans and glycosamaminoglycans are a specific class of carbohydrates that have been identified and localized to the protein deposits (ie. “amyloid”) in the brains of patients with Alzheimer ‘ s disease, and Down ‘s syndrome. We postulate that amyloid accumulates in these diseases due to their interaction with specific classes of proteoglycans which are elevated in the affected brain tissue. It is also postulated that the accumulation of proteoglycans in specific regions of the brain (ie. in specific subsets of neurons) contributes to the development of the characteristic lesions (ie. plaques and tangles) in aged, Alzheimer’s and Down ‘ s syndrome patients . The overall objective of the present proposal is to elucidate and structurally define the specific nature of the proteoglycans that interact with amyloid deposits in Alzheimer ‘ s disease, Familial Alzheimer’s disease and Down ‘ s syndrome and to define the mechanisms of this interaction. The specific aims of the present proposal are: 1. To Determine The Content and Composition of Proteoglycans Present in the Characteristic Lesions of Alzheimer ‘ s Disease and Familial Alzheimer ‘ s Disease A variety of methods will be used to identify and detemine the precise structures of the proteoglycans present in brain tissue derived from normal aged, Alzheimer’s disease, and Familial Alzheimer ‘ s disease patients to detemine whether a different proteoglycan accumulates in the diseased state in comparison to that found in normal aging brain. Additionally, we will isolate from Alzheimer’s brain tissue obtained at autopsy, the characteristic lesions (ie. neuritic plaque, neurofibrillary tangle and blood vessels containing amyloid deposits) in order to determine the identity and specific structure of the proteoglycans associated within each of these lesions. We will also quantitate the amounts of proteoglycans in brain tissue and in these isolated lesions in comparison to the amounts of the major known protein component present (ie. the beta-amyloid protein). 2. To Determine the Specific Brain Sites of Proteoglycan Accumulation and Synthesis in Normal Aged, Alzheimer ‘s Disease, Familial Alzheimer ‘ s Disease, and Down ‘s Syndrome. Different methods will be used to precisely identify the cells which synthesize the proteoglycans that accumulate in the characteristic lesions of Alzheimer’s disease, Familial Alzheimer’s disease and Down ‘ s syndrome. We will also deterrrUne whether different types and/or populations of proteoglycans are present in brain areas susceptible to the accumulation to “plaques and tangles” in comparison to non-susceptible areas. In addition, we will use brain tissue derived from different ages of Down ‘s syndrome patients as a model to study the accumulation of proteoglycans in relation to the development of “plaques and tangles” . Since almost all Down’s syndrome patients over the age of neuropathology similar to that observed in the brains of this latter study will help us determine whether  proteoglycans is an early or late event in the development the brains of Alzheimer’s patients. 3. To Determine the Mechanisms of Proteoglycan Accumulation and Its Association with Amyloid It is postulated that specific proteoglycans accumulate in association with the “amyloid” deposits in the brains of Alzheimer’s disease and Down’s syndrome due to their binding affinity with specific proteins (ie . beta-amyloid protein and/or its precursor) present in these 1esions. We will determine the precise mode of proteoglycan-amyloid interaction and the specific regions of proteoglycans, amyloid protein involved, using a variety of methods. In addition, we will determine whether the interaction of proteoglycans with the amyloid protein influences the ability of amyloid to be degraded. These latter studies will allow us to define the mechanisms by which proteoglycans interact with amyloid and whether this interaction influences the breakdown or clearance of amyloid. The long term-goals of this project are to use the knowledge acquired from these studies to thoroughly understand the role of proteoglycans in the normal aging brain, and in lesion development in Alzheimer ‘s disease and related disorders. Once understanding the mechanisms involved, we hope to be able to develop novel therapeutic strategies that may prove useful in altering or preventing lesion advancement in Alzheimer’s disease and related disorders.