Alzheimer’s disease (AD) is the most common form of dementia, with more than 25 million people worldwide suffering this progressive intellectual failure. The disease was first described by the German psychiatrist, Alois Alzheimer in 1907, and is characterised by the appearance of proteinaceous depositions (first isolated in 1984), which are comprised of insoluble amyloid-ß (Aß)-aggregates. Aβ is derived from the β-amyloid precursor protein from which it is generated by the action of two proteases. Initially it was assumed that the insoluble amyloid fibrils, which were easily detectable, mediated the observed toxicity although it was recognised that amyloid plaque number did not correlate well with the severity of dementia. However, further studies with synthetic and human-derived Aß provided strong evidence that soluble prefibrillar aggregates of Aß mediated the synaptic failure and loss of cognitive performance. In 2008 genetic evidence showed that the presence of soluble Aß-oligomers is sufficient to cause an AD-like dementia, which centres the oligomeric Aβ as the probable effector of synapse loss. Although a variety of assemblies have been described their meta-stability and technical limitations caused a controversial debate about aggregate related pathogenesis. Thus, this study aimed to establish a structure-activity relationship comparing different synthetic Aß-aggregates using biophysical methods to follow aggregation and to assess morphology, absolute MW and meta-stability of monomeric, oligomeric, protofibrillar and fibrillar Aß. However, interference with the aggregate equilibrium, by changing the ionic environment, can cause structural conversion of Aß-aggregates. Therefore, different Aß-aggregates were only compared in short-termed physiological settings i.e. neuronal binding and hippocampal neurotransmission. Herein, only prefibrillar aggregates bound to neurons and differentially impaired hippocampal neurotransmission either by inhibition of basal neurotransmission or NMDA-dependent long-term potentiation. In addition, changing the ionic environment provoked a structural conversion, which also changed the pathogenic mode of action. This study provides experimental evidence that different soluble Aß-aggregates are highly potent synaptotoxins, impairing neurotransmission by different mechanisms. Furthermore, solution-based biophysical characterisation and acute biological paradigms are crucial for differential characterisation of Aß-aggregates revealing that virtually similar aggregates can have opponent pathogenic effects; thus, morphology only does not explain observed pathogenicity.
Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:632161 |
Date | January 2012 |
Creators | Moreth, Jens |
Contributors | Edwards, Gillian |
Publisher | University of Manchester |
Source Sets | Ethos UK |
Detected Language | English |
Type | Electronic Thesis or Dissertation |
Source | https://www.research.manchester.ac.uk/portal/en/theses/characterisation-of-different-amyloidss-aggregates-in-alzheimers-disease(88c7e7d8-dd08-4559-aa20-40f26950f0d5).html |
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