A53T α-synuclein induces neurogenesis impairment and cognitive dysfunction in line M83 transgenic mice and reduces the proliferation of embryonic neural stem cells

Abstract

Dementia with Lewy body (DLB) is the second most common degenerative dementia after Alzheimer's disease. There is no therapeutic drug for DLB currently. It's urgent for us to understand the pathological mechanism of dementia mediated by α-synuclein, as the main component of Lewy body. Here, we found that the A53T α-synuclein transgenic mice showed decreased nesting behavior starting from the age of 1 month. The results in Morris water maze test suggested that the 6-month-old mice had learning memory deficits. Golgi staining indicated that the apical neuronal dendritic spines of hippocampal CA1 neurons were significantly reduced in 6-month-old homozygotes and heterozygotes, although MAP2 protein expression revealed no significant difference in the hippocampus among wild-type mice, homozygotes and heterozygotes. In vitro, we proved mutant A53T α-synuclein decreased the dendritic branches and dendrite spines on the embryonic mice hippocampal neurons. Furthermore, Ki67 immunofluorescence staining identified that the Ki67-positive cells of the hippocampal dentate gyrus and subventricular zone were significantly reduced in 6-month-old homozygotes and heterozygotes, compared with age-matched wild-type mice. Similarly, when 6-month-old mice were injected with BrdU for one day, the immunostaining results also confirmed that BrdU-positive cells were significantly reduced in homozygous and heterozygous mice. Lastly, we transfected primary embryonic hippocampal neural stem cells with lentivirus vector expressing A53T α-synuclein in vitro. Both BrdU staining and Western blotting showed that A53T α-synuclein significantly decreased the proliferation of embryonic neural stem cells. Taken together, these data suggest that A53T α-synuclein can induce adult neurogenesis impairment and cognitive dysfunction. The A53T α-synuclein transgenic mice may be used as an animal model for DLB. Promoting adult neurogenesis may be a promising approach to treat DLB pathogenesis.

Keywords: A53T α-synuclein; Dementia; Line M83; Neural stem cells; Neurogenesis.