Everolimus (EVR), as a rapamycin analog, is a selective inhibitor of the mammalian target of rapamycin (mTOR) kinase and its associated signaling pathway. mTOR is a serine/threonine protein kinase and its hyperactivity is involved in the pathophysiology of Alzheimer's disease (AD) and associated cognitive deficits.
Twenty individuals reported previously with rare missense or nonsense mutations or other coding disturbances of the FMR1 gene ranged in age from infancy to 50 years; most were verbal with limited speech, had autism and hyperactivity, and all had intellectual disability.
A novel biomimetic 3D hydrogel platform that enables quantitative analysis of cell invasion and viability at the individual cell level is developed using automated data acquisition methods with an invasive lung disease (lymphangioleiomyomatosis, LAM) characterized by hyperactivemammalian target of rapamycin complex 1 (mTORC1) signaling as a model.
The authors have recently shown that Fmr1KO mice with a yeast artificial chromosome containing the human FMR1 gene have corrected or overcorrected abnormal behaviors including hyperactivity and altered social interactions.
Rapamycin and its chemical derivatives are the only drugs that inhibit the hyperactivity of mTOR, but numerous side effects have been described due to its therapeutic use.
Abnormal synaptic transmission through metabotropic glutamate receptor 5 may underlie in a part of ASD associated with hyperactivemTOR-mediated signaling.
These data demonstrate that neuronal mTORhyperactivity levels influence the severity of epilepsy and associated neuropathology in experimental TSC and FCD.
Loss of regulated Cav2.3 expression could underlie the neuronal hyperactivity and aberrant calcium spiking in FMRP KO mice and contribute to FXS, potentially serving as a novel target for future therapeutic strategies.<b>SIGNIFICANCE STATEMENT</b> Patients with fragile X syndrome (FXS) exhibit signs of neuronal and circuit hyperexcitability, including anxiety and hyperactive behavior, attention deficit disorder, and seizures.
In an earlier study, Fmr1 knockout mice carrying a yeast-artificial chromosome (YAC) transgene that over-expresses normal human FMRP (KOYAC) showed a correction or overcorrection of some behavioral responses, such as hyperactivity and anxiety-related responses.
Moreover, we demonstrated that PRAS40 down-regulates mTORhyperactivity under stress conditions and alleviates neurotoxic prion peptide-induced apoptosis.
In the present study, we examine how neuron subset-specific deletion of Pten (NS-Pten) in mice, which presents with hyperactivemammalian target of rapamycin (mTOR) activity, affects the hippocampal protein levels of key neuropathological hallmarks of AD.
Although we currently know that the neoplasm may result from the hyperactivity of protein kinase B (PKB or Akt) or extracellular-regulated kinase (Erk), which upregulates mammalian target of rapamycin kinase (mTOR) and leads to translation of proteins responsible for cell cycle regulation, there are still many questions to be answered.
These results suggest abnormal neuronal activity in the Fmr1-KO mouse during SWRs, and hyperactivity during other wake and sleep states, with likely adverse consequences for memory processes.