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Investigating the biochemical signature and in vivo seeding activity of amyloid-β from distinct Alzheimer’s Disease subtypes

Thomas, David Mark Xavier; (2019) Investigating the biochemical signature and in vivo seeding activity of amyloid-β from distinct Alzheimer’s Disease subtypes. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Multimeric assemblies of amyloid-Aβ (Aβ) are thought to play a key role in the progression of Alzheimer’s Disease (AD), but these aggregates display substantial structural heterogeneity in the human brain and it is unknown which conformational variants contribute most significantly to disease, or via which causal pathways they do so. One mechanism through which these aggregates could contribute to cognitive impairment is via binding to specific receptors at the surface of neuronal and glial cells, thereby activating neurodegenerative signalling cascades. The first work reported here describes a comparative analysis of several putative receptors, which revealed that prion protein (PrP), leukocyte immunoglobulin-like receptor B2 (LilrB2), and fc-gamma receptor type IIb (FcγRIIb) all bound nanomolar concentrations of aggregated Aβ in cellular binding assays, and recombinantly expressed PrP and FcγRIIb also both bound low nanomolar concentrations of Aβ aggregates in plate-based and solution-based in vitro binding assays. However, comparative binding affinities differed substantially depending on experimental system. Recent evidence has also suggested that the presence of certain Aβ assemblies in the post-mortem AD brain may correlate with variations in AD clinical phenotype, suggesting a mechanism similar to that of prion disease wherein distinct prion strains are associated with different clinical and pathological characteristics. Here, brain extracts from typical slowly-progressive AD patients (Slow-AD) were biochemically compared with brain extracts from atypical ‘rapidly-progressive’ AD patients (Rapid-AD), as well as a subset of patients with substantial amyloid pathology but no cognitive impairment at the time of death (High-Amyloid controls). Extensive variability in Aβ biochemical signature was observed between patients, but this did not correlate with disease phenotype. To investigate the potential role of ‘strains’ of assemblies of Aβ, typical AD and Rapid-AD brain extracts were intracerebrally inoculated in NL-F mice, with separate groups of mice culled at 4, 8 and 12 months post inoculation (mpi). Inoculation with either Slow-AD or Rapid-AD brain extracts led to accelerated and spatiotemporally distinct deposition of Aβ in these mice, which preferentially targeted the cerebellum. However, inoculation with Rapid-AD brain extracts induced less aggressive amyloid deposition than equivalent Slow-AD inoculations, which may suggest that Aβ assemblies present in Rapid-AD brains possess distinct in vivo seeding activity which may have contributed to the atypical clinical presentation observed in these patients. These results warrant further study of the in vivo seeding activity of Aβ assemblies in Slow-AD and Rapid-AD brains, which may support the targeting of unique therapeutics for distinct subtypes of AD.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Investigating the biochemical signature and in vivo seeding activity of amyloid-β from distinct Alzheimer’s Disease subtypes
Event: UCL
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2019. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases > MRC Prion Unit at UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10080338
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