Turnbull, Catherine Mary; (2024) Characterising tau morphotypes within different subtypes of Alzheimer’s disease (AD) and their transmission in AD mouse models. Doctoral thesis (Ph.D), UCL (University College London).

Text Catherine Mary Turnbull - PhD Thesis.pdf - Accepted Version Access restricted to UCL open access staff until 1 October 2025. Download (15MB)

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, which causes cognitive impairment due to progressive neuronal loss. This incurable disease is principally associated with proteins named amyloid-β (Aβ) and tau, whereby Aβ forms Aβ plaques and vascular deposits, whilst tau forms neurofibrillary tangles (NFTs), respectively. There is a great deal of heterogeneity amongst AD cases concerning clinical presentation, age of onset and the rate of clinical decline. Recent evidence has indicated that different Aβ and tau strains are associated with AD and other tauopathies. These strains contain different underlying disease-related assemblies, which contribute to a different pathology in its host, maintained after serial passages. This can be considered analogous to prion diseases, which involve the self-replication of the infectious agent known as a prion. Consequently, Aβ and tau assemblies can be regarded as “prion-like” due to shared properties with the prion, whereby the Aβ and tau conformers can self-replicate through a process of template-seeded aggregation, by converting endogenous Aβ and tau proteins, respectively. Thus, this thesis aims to determine whether tau strains could, at least in part, explain the heterogeneity observed between AD subtypes. Here, we show that the AD mouse model, expressing both humanised Aβ and all 6 isoforms of human tau (AppNL-F/NL-F/hTauKI/KI), is superior for modelling tau transmissions in vivo for typical AD (tAD) cases compared to the APPNL-F/NL-F and TauKI/KI models expressing human Aβ or tau alone. Moreover, three distinct subtypes of AD were studied where there was evidence of prion-like properties regarding seeding, aggregation and transmission within the AppNL-F/NL-F/hTauKI/KI AD line. Our results demonstrated that there is heterogeneity between subtypes, and amongst AD cases, which displayed template-seeded aggregation after inoculation. Furthermore, we anticipate that these results will lead to future studies to elucidate and isolate distinct tau strains, after serial passages, within the AppNL-F/NL-F/hTauKI/KI line.

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