Age-dependent neurodegeneration and neuroinflammation in a genetic A30P/A53T double-mutated α-synuclein mouse model of Parkinson's disease

Abstract

The pathogenesis of Parkinson's disease (PD) is closely interwoven with the process of aging. Moreover, increasing evidence from human postmortem studies and from animal models for PD point towards inflammation as an additional factor in disease development. We here assessed the impact of aging and inflammation on dopaminergic neurodegeneration in the hm²α-SYN-39 mouse model of PD that carries the human, A30P/A53T double-mutated α-synuclein gene. At 2-3 months of age, no significant differences were observed comparing dopaminergic neuron numbers of the substantia nigra (SN) pars compacta of hm²α-SYN-39 mice with wildtype controls. At an age of 16-17 months, however, hm²α-SYN-39 mice revealed a significant loss of dopaminergic SN neurons, of dopaminergic terminals in the striatum as well as a reduction of striatal dopamine levels compared to young, 2-3 months transgenic mice and compared to 16-17 months old wildtype littermates. A significant age-related correlation of infiltrating CD4⁺ and CD8⁺ T cell numbers with dopaminergic terminal loss of the striatum was found in hm²α-SYN-39 mice, but not in wildtype controls. In the striatum of 16-17 months old wildtype mice a slightly elevated CD8⁺ T cell count and CD11b⁺ microglia cell count was observed compared to younger aged mice. Additional analyses of neuroinflammation in the nigrostriatal tract of wildtype mice did not yield any significant age-dependent changes of CD4⁺, CD8⁺ T cell and B220⁺ B cell numbers, respectively. In contrast, a significant age-dependent increase of CD8⁺ T cells, GFAP⁺ astrocytes as well as a pronounced increase of CD11b⁺ microglia numbers were observed in the SN of hm²α-SYN-39 mice pointing towards a neuroinflammatory processes in this genetic mouse model for PD. The findings in the hm²α-SYN-39 mouse model strengthen the evidence that T cell and glial cell responses are involved in the age-related neurodegeneration in PD. The slow and age-dependent progression of neurodegeneration and neuroinflammation in the hm²α-SYN-39 PD rodent model underlines its translational value and makes it suitable for studying anti-inflammatory therapies.

Keywords: Alpha-synuclein; Dopamine; Genetic mouse model; Neurodegeneration; Neuroinflammation; Parkinson's disease; hm(2)α-SYN-39.