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Title: Functional genomic characterisation of animal models of AD : relevance to human dementia
Author: Castanho, I.
ISNI:       0000 0004 7962 9310
Awarding Body: University of Exeter
Current Institution: University of Exeter
Date of Award: 2019
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The onset and progression of Alzheimer's disease (AD) is characterised by increasing intracellular aggregation of hyperphosphorylated tau protein and the accumulation of amyloid beta (Aβ) in the neocortex. Despite recent success in identifying genetic risk factors for AD, the transcriptional and epigenomic mechanisms involved in disease progression are not fully understood. The main aim of this project was to evaluate transcriptional and epigenomic differences associated with the development of tau and amyloid pathology. To achieve this, I used transgenic mice harbouring human tau (rTg4510) and amyloid precursor protein (J20) mutations. I profiled transcriptional and epigenomic variation in brains from rTg4510 and J20 mice, collected at four time points carefully selected to span from early to late stages of neuropathology in each model. I identified robust gene expression and methylomic changes in both models, including genes associated with familial AD from genetic studies of human patients, and genes annotated to both common and rare variants identified in genome-wide association and exome-sequencing studies of late-onset sporadic AD. I quantified neuropathological burden across multiple brain regions in the same individual mice, identifying genomic changes paralleling the development of tau pathology in rTg4510 mice and amyloid pathology in J20 mice. Furthermore, I compared gene co-expression networks identified in my rTg4510 and J20 samples to those identified in AD human brains, finding considerable overlap with disease-associated co-expression modules (or clusters of genes) identified in the human cortex. In summary, this project represents the most systematic analysis of transcriptional and methylomic variation in mouse models of tau and amyloid pathology, providing further support for an immune-response component in the accumulation of AD-associated neuropathology, and highlighting novel molecular pathways involved in AD progression.
Supervisor: Mill, J. ; Lunnon, K. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Alzheimer ; Mouse ; Gene expression ; Epigenetics ; DNA methylation ; Tau ; Amyloid