Mice: FBV or mixed FBV-C57BL6
Expression of the full-length human mutant (G2019S) LRRK2 protein using the bacterial artificial chromosome (BAC).
Endogenous LRRK2: yes
Corresponding human genotype: The G2019S substitution in the LRRK2 gene is believed to be the most common mutation associated with Parkinson’s disease. It is located in the kinase domain of the protein.
Targeted gene: LRRK2
Overall transgene expression is about 2.5 fold higher than the endogenous LRRK2 in the brain of the transgenic animals; expression in 14 fold higher in the hippocampus. Anatomical expression patterns are similar to the endogenous mouse gene.
5 months: No neurodegeneration is observed. Interestingly, a significant decrease in proliferating cells can be observed in the dentate gyrus and the subventricular zone of transgenic animals when compared to control littermates.
22-24 months: No differences in the number of TH-positive cells in the SN.
18 months: In vivo striatal level of DA is significantly lower in transgenic mice compared to control littermates at baseline but not after amphetamine injection (striatal microdialysis). However, no differences in the level of DA or its metabolites (DOPAC, HVA) are observed in the striatum of transgenic mice post-mortem (HPLC). A modest but non-significant increase in the number of striatal dopamine D1 and D2 receptors density is also observed.
6-12 months: No abnormalities is observed in alpha-synuclein, phosphorylated alpha-synuclein or phosphorylated tau in various brain sections (immunostaining).
18-24 months: No abnormalities are detected with alpha-synuclein or phosphorylated α-synuclein staining. However, accumulation of phosphorylated tau proteins is observed in various structures of the brain of transgenic animals, including: the midbrain, striatum, cortex, hippocampus and thalamus.
9 months: No significant changes are observed during most motor assessments (open field, rotarod and pole tests; animals with mixed FBV-C57BL6 background)
22-24 months: No significant changes are observed during most motor assessments (beam crossing test, inked footprint analysis, negative geotaxis test). In the open field test, the transgenic mice move faster and over longer exploratory path than wild type animals. Despite showing comparable overall activity levels to the control animals, they also spend less time exploring the central zone of the opened field and perform less turns.
Response to dopaminergic treatment
18 months: No difference can be observed in the changes in the striatal ratio of DA metabolites and stored DA induced by treatment with the D2 receptor antagonist raclopride.
8-10 months: Working memory seems intact in transgenic animals. However, very subtle impairments can be observed in spatial learning, spatial memory and cognitive flexibility (Y-maze and radial arm water maze; animals with mixed FBV-C57BL6 background).
18-24 months: An increase of activated microglia (Iba-1 immuno staining) is visible only in the hippocampus of transgenic mice; levels in other brain regions are not altered.