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Title: Studies on the preparation and properties of neurofibrillary tangles from brains of patients with Alzheimer-type dementia
Author: Hussey, Susan
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1988
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Alzheimer's disease and senile dementia of the Alzheimer type (Alzheimer-type dementia, ATD) are progressive dementing illnesses characterised histopathologically by the presence of neurofibrillary tangles and plaques. Ultrastructurally tangles are composed of paired helical filaments (PHF) (Kidd, 1963) of unknown origin. The purpose of this study was to investigate the biochemical and biophysical properties of tangles, and their constituent PHF. Investigation of tangle solubility by quantitative light microscopy of brain homogenates showed that a proportion of tangles, which varied between brains (ATD and Down's Syndrome with ATD pathology) were soluble in sodium dodecylsulphate (SDS) and NaOH. Tangle solubility in 1&37 SDS was inversely related to duration of dementia suggesting that patients with a long standing illness have more fragile tangles. Ultrastructural studies were carried out on tangle enriched fractions prepared by ultracentrifugation of supernatants from SDS treated brain homogenates and by sucrose density gradient centrifugation of brain homogenates not treated with SDS. PHF in the former preparation were found to be longer with lengthened pitches compared to PHF in the latter preparation. PHF from another SDS treated preparation which was repeatedly freeze thawed (up to 25oC) were observed to lose their their helical configuration. These electronmicroscopic observations suggest that the helical substructure of PHF can be subject to conformational change, whilst filament structure is retained. Preparation of tangle enriched fractions from ATD brains was investigated using Percoll, sucrose gradient centrifugation and fluorescence activated cell sorting (FACS). Percoll proved unsatisfactory; and sucrose gradient centrifugation was used to prepare fractions enriched in tangles from ATD brains, and control fractions prepared in the same way, from control brains. Tangle preparation using FACS was a new technique, whereby tangles labelled with the fluorescent dye, congo red, could be sorted from ATD brain homogenate. Partially purified tangle preparations were investigated using spectroscopy. The resulting spectra showed features consistent with an increase in β sheet in the tangle enriched versus the control fraction.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available