Wood, Jack Isaac; (2025) Investigating the impact of amyloid plaques on surrounding tissue with particular focus on microglia. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The deposition of Aβ plaques is widely considered the initiating event in the pathogenesis of Alzheimer’s disease (AD). This is followed by a substantial temporal delay before the onset of neurofibrillary tangle formation and cognitive decline. The reasons for this delay and the mechanisms by which Aβ plaques lead to tangle formation remain poorly understood. It is, therefore, critical to better understand the impact of Aβ plaques on surrounding brain tissue. This thesis addresses this by investigating both the immune response to plaques, characterised by the clustering and activation of microglial cells and the local toxicity induced by plaques, including synapse loss and the formation of dystrophic neurites. Using microglia-enriched spatial transcriptomics, I show that microglial contact with plaques is a modulator of microglial gene expression in both the NLF mouse model of AD and human AD brain tissue. Furthermore, I show that introducing the microglial-specific, AD-associated Trem2R47H risk mutation into NLF mice disrupts a gene module normally upregulated in response to plaque contact, involved in phagosomal, lysosomal, and lipid-processing pathways. This loss of microglial function associated with Trem2R47H also results in an increase of very small plaques. I demonstrate that plaque toxicity is influenced by both the age of a plaque and its structural morphology. To assess plaque age, I used a 15N-enriched heavy isotope diet to label newly deposited plaques, followed by spatial transcriptomics to assess surrounding gene expression. These early-deposited plaques were associated with a greater loss of synapse- related genes and an upregulation of genes involved in metabolism. Structural plaque types were classified using a combined staining approach, revealing an increase in diffuse plaques relative to more compact plaques as a mouse ages. Notably, the most aggregated plaque type showed substantial toxicity and synapse loss, whereas diffuse plaques exhibited no evidence of local synapse loss.

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