The hSNCA*E46K HET mouse as a potential model for PD dementia

Dementia occurs in about 60% of Parkinson’s disease (PD) patients. Nevertheless, it is mechanistically understudied due to the lack of adequate animal models. Synaptophysin is a synaptic vesicle glycoprotein, virtually present in all neurons that participate in synaptic transmission. Synaptophysin immunoreactivity has been shown to inversely correlate with dementia in neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease (Zhan et al., 1993; Heinonen et al., 1995; Heffernan et al., 1998).
Here we propose the transgenic mouse overexpressing the human, E46K mutated alpha synuclein (hSNCA*E46K) as a potential model for the study of PD related dementia in vivo. hSNCA*E46K heterozygous (HET) mice show an age-dependent decline of TH-positive axons and DAT positive synaptic terminals in the dorsal striatum (Hendrickx et al, 2021). Furthermore, it has been previously demonstrated that hSNCA*E46K HET mice show a decrease in cortical and hippocampal synaptophysin staining when compared to wild-type littermates at 13 months (Elan Pharmaceuticals – unpublished data).
We will investigate the impact of alpha-synuclein overexpression and synaptophysin decline at the cognitive level, using behavioral tests for short and long-term memory such as the Y maze and the Novel Object Recognition tests. Furthermore, we will profile the gene expression in the hippocampus of the mice by RNA-sequencing and Real Time-qPCR, starting with mice as young as 3 months old and following their longitudinal progression.
We expect our studies to shed light into the “genetics of dementia”, and to provide a valid system for the modeling and investigation of dementia in neurodegenerative diseases.

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