Premature cognitive decline in a mouse model of tuberous sclerosis.
J KrummeichL NardiC CaliendoD AschauerV EngelhardtA ArltJ MaierF BickerM D KwiatkowskiK RolskiK VinczeR SchneiderS RumpelS GerberM J SchmeisserSusann SchweigerPublished in: Aging cell (2024)
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.
Keyphrases
- mouse model
- cognitive decline
- cognitive impairment
- cell proliferation
- poor prognosis
- binding protein
- end stage renal disease
- temporal lobe epilepsy
- mild cognitive impairment
- chronic kidney disease
- ejection fraction
- newly diagnosed
- copy number
- cerebral ischemia
- genome wide
- pi k akt
- peritoneal dialysis
- long non coding rna
- genome wide identification
- electronic health record
- patient reported outcomes
- gene expression
- big data
- signaling pathway
- ultrasound guided
- growth hormone
- brain injury
- insulin resistance
- artificial intelligence