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Published on: May 28, 2017
Premature cognitive decline in a mouse model of tuberous sclerosis
J Krummeich1, L Nardi2, C Caliendo1
1Institute of Human Genetics, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
Abstract:
Little is known about the influence of (impaired) neurodevelopment on cognitive aging. We here used a mouse model for tuberous sclerosis (TS) carrying a heterozygous deletion of the Tsc2 gene. Loss of Tsc2 function leads to mTOR hyperactivity in mice and patients. In a longitudinal behavioral analysis, we found premature decline of hippocampus-based cognitive functions together with a significant reduction of immediate early gene (IEG) expression. While we did not detect any morphological changes of hippocampal projections and synaptic contacts, molecular markers of neurodegeneration were increased and the mTOR signaling cascade was downregulated in hippocampal synaptosomes. Injection of IGF2, a molecule that induces mTOR signaling, could fully rescue cognitive impairment and IEG expression in aging Tsc2+/- animals. This data suggests that TS is an exhausting disease that causes erosion of the mTOR pathway over time and IGF2 is a promising avenue for treating age-related degeneration in mTORopathies.
Insights
Tuberous sclerosis (TS) impairs cognitive aging by reducing mTOR signaling. Insulin-like growth factor 2 (IGF2) treatment rescued cognitive decline and restored gene expression in aging mice with TS.
Area of Science:
- Neuroscience
- Genetics
- Aging Research
Background:
- Neurodevelopmental disorders like tuberous sclerosis (TS) have unknown effects on cognitive aging.
- Tuberous sclerosis is linked to Tsc2 gene mutations, causing mTOR hyperactivity.
Purpose of the Study:
- To investigate the impact of impaired neurodevelopment on cognitive aging using a mouse model of tuberous sclerosis.
- To explore the role of the mTOR pathway in age-related cognitive decline in TS.
Main Methods:
- Longitudinal behavioral analysis in Tsc2+/- mice.
- Assessment of immediate early gene (IEG) expression.
- Analysis of hippocampal morphology, synaptic contacts, and molecular markers of neurodegeneration.
- Investigation of mTOR signaling cascade in synaptosomes.
- Intervention with IGF2 to assess rescue effects.
Main Results:
- Tsc2+/- mice exhibited premature decline in hippocampus-dependent cognitive functions and reduced IEG expression.
- No morphological changes were observed, but neurodegeneration markers increased and mTOR signaling decreased in aging Tsc2+/- synaptosomes.
- IGF2 administration fully rescued cognitive impairment and normalized IEG expression.
Conclusions:
- Tuberous sclerosis accelerates cognitive aging through an 'exhausting' effect on the mTOR pathway over time.
- IGF2 shows potential as a therapeutic agent for age-related cognitive decline in mTORopathies.
