Сhanges in cognitive processes and transcriptional activity of the S100A6 and ASCL1 genes at different times after chronic administration of amyloidogenic alpha-synuclein oligomers
Abstract
The formation of neurotoxic amyloidogenic forms of the protein alpha-synuclein (α-syn) is a key molecular link in the pathogenesis of a number of neurodegenerative diseases, including Parkinson's disease (PD). There is reason to believe that the development of cognitive impairment at a subclinical level precedes the manifestation of motor symptoms of PD, and there is significant evidence that these disorders are associated with disorganization of the mechanisms regulating neurogenesis in the mature brain. However, information about the long-term influence of amyloidogenic forms of α-syn on the dynamics of cognitive activity and molecular processes in translational models of synucleinopathies are practically absent.
The aim of the work is to study the dynamics of the effects of intranasal administration of α-syn oligomers to young sexually mature animals in relation to exploratory activity and episodic memory, as well as the expression of the S100A6 and ASCL1 genes, which regulate various stages of neurogenesis, in the hippocampus, prefrontal cortex and cerebellum with simultaneous assessment of the structural functional connections between behavioral and molecular indicators.
Materials and methods. Male C57BL/6J mice, 2.5 months old, were intranasally injected with a solution of recombinant α-syn oligomers or saline for 14 days, followed by behavioral testing in a novel object recognition model at the ages of 3, 6, and 12 months. At each age point, the expression of the S100A6 and ASCL1 genes in the hippocampus, frontal cortex and cerebellum was determined using the polymerase chain reaction method.
Results. At the age of 3 months, mice treated with α-syn oligomers showed a decrease in movement speed relative to control under conditions of increasing context novelty while maintaining other behavioral indicators, as well as an increase in the expression of S100A6 and ASCL1 genes in the cortex and a decrease in ASCL1 activity in the cerebellum. At the age of 6 months, animals in the experimental group showed a decrease in exploratory activity and episodic memory, with no differences from the control in terms of transcriptional activity of the studied genes. At 12th months in the experimental group, disturbances in the initiation of exploratory behavior were revealed while maintaining its total duration and episodic memory; there was also a decrease in gene ASCL1 expression in the prefrontal cortex and cerebellum. Correlations of molecular and behavioral parameters identified at different time points indicate a possible compensatory/protective role of changes in gene ASCL1 expression after administration of α-syn in 3-month-old animals.
Conclusion. The results of the studies show that the dynamics of the development of cognitive deficit after administration of α-syn is determined not only by the toxic effects of amyloidogenic forms of the protein, but also by compensatory processes, including changes in the transcriptional activity of genes that regulate the processes of neurogenesis in the mature brain. The data obtained also suggest the existence of age-specific compensatory mechanisms associated with the regulation of the cellular proliferation/differentiation stages of neurogenesis. Further research aimed at identifying such mechanisms seems necessary for the development of personalized strategies for the prevention and treatment of neurodegenerative disorders.
