Characterising models of Alzheimer’s disease and dementia with Lewy bodies: with focus on transcriptomics

Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) are two of the most common forms of dementia. AD is largely characterised by the accumulation of amyloid-beta (Aβ) and hyperphosphorylated tau (p-Tau) in the brain, and mouse models of disease have been developed surrounding said pathology. Transcriptional changes in the brains J20 mice – an amyloid model of AD – have been described, but the spatial distribution of such changes is yet to be investigated. The aggregation of alpha synuclein (α-synuclein) into Lewy bodies (LBs) and Lewy neurites (LNs) is the key pathological trait of DLB, but there are currently no established mouse models surrounding said pathology. The D409V/WT mice harbours a mutation in the Gba1 gene, a recently discovered genetic risk factor of human DLB. This mouse shows promise as a novel DLB model but are not very well characterised. The main aim of this project was to further characterise the J20 and D409V/WT mice, with a focus on transcriptomic changes in the brain. I used Spatial Transcriptomic technology to investigate region-specific changes in gene expression in the hippocampus of J20 mice compared with WT controls, identifying differentially expressed genes (DEGs) and modules of co-expressed genes, as well as associated functional pathways. Region-specific transcriptional differences were observed between J20 and WT mice, as were corresponding functional pathways. I also investigated transcriptomic changes in the medial septum (MS) of D409V/WT mice, using bulk RNA-seq to again identify DEGs, modules of co-expressed genes, associated functional pathways. Various transcriptional differences and associated functional pathways were observed between D409V/WT and WT mice, which reflect pathological outcomes expected during DLB. Furthermore, I used electrophysiology and cresyl violet staining to investigate dysfunctions in neuronal activity in the MS, as well as global atrophy in the brains of D409V/WT mice. A trend towards reduced neuronal activity, cortical thinning and ventricle enlargement were observed among D409V/WT mice compared with WT controls. In summary, this project provides the first spatially-defined analysis of transcriptomic changes in the brains of J20 mice, as well as further characterisation of the D409V/WT mice to support the utility of said mouse as a model for DLB.