Characterisation of D409V/WT mice as a novel dementia model

Abstract

AbstractBackgroundAlzheimer’s disease (AD) and dementia with Lewy bodies (DLB) share various pathological and symptomatic traits. Such overlap complicates diagnosis, ultimately impacting the level of care and treatment options available to patients. The development of novel models to further understand DLB is therefore imperative. Recent research indicates mice with heterozygous mutations (D409V/WT) in the GBA gene to be a viable option, presenting DLB‐associated characteristics such as age‐related cognitive decline, an increase in monomeric α‐synuclein deposition and cholinergic dysfunction (Clarke et al., 2019).MethodsTo further characterise D409V/WT mice, we looked at measures of brain atrophy, patterns of neuronal firing, and transcriptomic changes. Global brain atrophy was assessed using six different measures surrounding cortical thickness and ventricle size from cresyl violet stained coronal sections. Neuronal activity in the medial septum was recorded through a series of multi‐electrode array (MEA) studies, and RNA was extracted from the same region in order to investigate transcriptional changes. All studies used WT littermates as controls.ResultsAt 12 months of age, D409V/WT mice exhibited both ventricle enlargement and cortical thinning when compared with WT controls. All six measures used were significant at the p < 0.05 level. Neuronal firing appeared to be disrupted among D409V/WT mice compared to WT controls, but this was not found to be significant. Further analysis is currently being undertaken to determine the effects of both cell and slice variation upon these results. We anticipate all further MEA analysis, and transcriptomic analysis to be complete by 31st May 2022.ConclusionsThese findings support D409V/WT mice to be a candidate model for DLB. Following further characterisation, we suggest this model may be useful in better understanding DLB and developing novel diagnostic tools.