Characterising the D409V/WT mouse as a novel model of Lewy body dementia

Background

The overlap in both pathological and symptomatic traits observed among Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) patients make accurate diagnosis difficult. Novel models to further study DLB are therefore imperative, and previous research suggests mice with heterozygous mutations in the GBA gene (D409V/WT) to be a viable option. These mice display age‐related cognitive decline and α‐synuclein deposition in the brain (Clarke et al., 2019), and our prior work found there to be significant atrophy in the brain by 12 months of age.

Method

We aimed to further characterise disease‐associated pathology exhibited by these mice. Cortical thickness and vesicle size was measured among mice of 3, 6, 9, 12, and 18 months of age in order to assess atrophy progression with age. Neuronal firing in the medial septum was measured at both baseline and following application of NMDA – a drug used to elicit neuronal activity. Firing rate and latency to reach peak NMDA response were used to assess neuronal dysfunction. Finally, differential expression and weighted gene co‐expression network analysis (WGCNA) was conducted to assess transcriptomic changes in the medial septum. All studies used wild‐type littermates as controls.

Result

Age‐associated cortical thinning and ventricle enlargement were observed, with all six measures reaching statistical significance by 12 months of age. Although latency to reach peak neuronal firing showed no difference between groups, firing rate was significantly reduced in D409V/WT mice across all conditions. Differential expression analysis found significant downregulated genes in the medial septum of the D409V/WT mice compared to the WT controls, and WGCNA analysis found various clusters of genes to be associated with both genotype and sex.

Conclusion

These results present examples of DLB‐associated pathology exhibited by the D409V/WT mice, supporting their potential as a novel model of disease. However, further characterisation is needed in order for these mice to be considered a reliable model, and to be employed in wide‐scale research.

References: Clarke, E. et al. (2019) ‘Age‐related neurochemical and behavioural changes in D409V/WT GBA1 mouse: Relevance to lewy body dementia’, Neurochemistry International, 129. https://doi.org/10.1016/j.neuint.2019.104502.