Stringer, Katie; (2022) Amyloid-β aggregation and maturation dynamics and microglial response in evolving amyloid plaque pathology. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Amyloid-beta (Aβ) plaque deposition is one of the major pathological features of Alzheimer’s disease; however, the mechanism by which this occurs remains unclear. Microglia, the immune cells of the brain, have been shown to interact with plaques, but their significance to Aβ deposition is unknown.  This project aims to assess Aβ deposition both in vivo and in cultures obtained from amyloid precursor protein (App) knock-in mice (AppNL-F and AppNL-G-F), and also assess the interaction with microglia. Using a novel chemical imaging paradigm termed ‘iSILK’, involving stable isotope labelling and in situ mass spectrometry methods, here we analysed specific aggregation dynamics of individual Aβ species on a nanometer level. Additionally, we employed amyloid-specific dyes with high binding specificity in conjunction with hyperspectral and confocal imaging to quantitatively delineate plaque conformation and microgliosis in these mice. In these mice, iSILK revealed that plaques first form an aggregated core of entirely Aβ1-42, followed by further Aβ1-42 deposition, aggregation and later secretion and deposition of Aβ1-38. In addition, cortical plaques form prior to hippocampal plaques, which was further confirmed by hyperspectral imaging of the same plaques. Comparison between genotypes showed that AppNL-G-F mice have the most structurally mature plaques and increased plaque-associated microgliosis compared to age-matched AppNL-G-F mice. Furthermore, perturbation of microglia in AppNL-F/Trem2R47H mice resulted in a significant reduction of plaque coredness, alongside alterations in plaque-associated microgliosis. Organotypic hippocampal slice cultures experiments demonstrated that even with external manipulation, cultures from App knock-in mice do not develop amyloid plaques. Overall, the results of this study highlight important differences in amyloid plaque composition and microglial response depending on App genetic mutation, and also implicate the role of triggering receptor expressed on myeloid receptors 2 in facilitating plaque maturation. This work provides a basis for further development of therapeutic targets for individuals with these variants.

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