sirolimus and Learning-Disabilities

Tuberous sclerosis complex is an autosomal dominant disease, with variable expressivity and multisystemic involvement, which is characterised by the growth of benign tumours called hamartomas. The organs that are most commonly affected are the brain, skin, kidneys, eyes, heart and lungs. Of all the children with this disease, 85% present neurological manifestations that, due to their severity, are the main cause of morbidity and mortality. The most significant neurological manifestations are epilepsy, autism spectrum disorders and mental retardation. It has been shown that in tuberous sclerosis complex the genes TSC1 and TSC2 alter the mTOR enzyme cascade, which sets off inhibition of this pathway. The possibility of resorting to treatments applied at the origin, thus inhibiting this pathway, is currently being evaluated.

Topics: Anticonvulsants; Astrocytoma; Autistic Disorder; Brain Diseases; Brain Neoplasms; Drug Design; Epilepsy; Everolimus; Glioma, Subependymal; Hamartoma; Humans; Intellectual Disability; Learning Disabilities; Molecular Targeted Therapy; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

mTOR signaling, involving mTORC1 and mTORC2 complexes, critically regulates neural development and is implicated in various brain disorders. However, we do not fully understand all of the upstream signaling components that can regulate mTOR signaling, especially in neurons. Here, we show a direct, regulated inhibition of mTOR by Tanc2, an adaptor/scaffolding protein with strong neurodevelopmental and psychiatric implications. While Tanc2-null mice show embryonic lethality, Tanc2-haploinsufficient mice survive but display mTORC1/2 hyperactivity accompanying synaptic and behavioral deficits reversed by mTOR-inhibiting rapamycin. Tanc2 interacts with and inhibits mTOR, which is suppressed by mTOR-activating serum or ketamine, a fast-acting antidepressant. Tanc2 and Deptor, also known to inhibit mTORC1/2 minimally affecting neurodevelopment, distinctly inhibit mTOR in early- and late-stage neurons. Lastly, Tanc2 inhibits mTORC1/2 in human neural progenitor cells and neurons. In summary, our findings show that Tanc2 is a mTORC1/2 inhibitor affecting neurodevelopment.

Topics: Animals; Brain; Cells, Cultured; HEK293 Cells; Humans; Immunosuppressive Agents; Learning Disabilities; Maze Learning; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Memory Disorders; Mice, Inbred C57BL; Mice, Knockout; Neuronal Plasticity; Neurons; Proteins; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Fetal alcohol spectrum disorders (FASDs) are one of the most common consequences of ethanol exposure during pregnancy. In adulthood, these disorders can be manifested by learning and memory deficits and depressive-like behavior. Ethanol-induced oxidative stress may be one of the factors that induces FASD development. The mammalian target of the Rapamycin (mTOR) signaling pathway that acts via two distinct multiprotein complexes, mTORC1 and mTORC2, can affect oxidative stress. We investigated whether mTOR-dependent or mTOR-independent mechanisms are engaged in this phenomenon. Thus, Rapamycin-a selective inhibitor of mTORC1, Torin-2-a non-selective mTORC1/mTORC2 inhibitor, and FK-506-a drug that impacts oxidative stress in an mTOR-independent manner were used. Behavioral tests were performed in adult (PND60-65) rats using a passive avoidance (PA) task (aversive learning and memory) and forced swimming test (FST) (depressive-like behaviors). In addition, the biochemical parameters of oxidative stress, such as lipid peroxidation (LPO), as well as apurinic/apyrimidinic (AP)-sites were determined in the hippocampus and prefrontal cortex in adult (PND65) rats. The rat FASD model was induced by intragastric ethanol (5 g/kg/day) administration at postnatal day (PND)4-9 (an equivalent to the third trimester of human pregnancy). All substances (3 mg/kg) were given 30 min before ethanol. Our results show that neonatal ethanol exposure leads to deficits in context-dependent fear learning and depressive-like behavior in adult rats that were associated with increased oxidative stress parameters in the hippocampus and prefrontal cortex. Because these effects were completely reversed by Rapamycin, an mTORC1 inhibitor, this outcome suggests its usefulness as a preventive therapy in disorders connected with prenatal ethanol exposure.

Topics: Animals; Behavior, Animal; Depression; Fetal Alcohol Spectrum Disorders; Learning Disabilities; Oxidative Stress; Rats; Rats, Wistar; Sirolimus

Apolipoprotein E ɛ4 allele is a common susceptibility gene for late-onset Alzheimer's disease. Brain vascular and metabolic deficits can occur in cognitively normal apolipoprotein E ɛ4 carriers decades before the onset of Alzheimer's disease. The goal of this study was to determine whether early intervention using rapamycin could restore neurovascular and neurometabolic functions, and thus impede pathological progression of Alzheimer's disease-like symptoms in pre-symptomatic Apolipoprotein E ɛ4 transgenic mice. Using in vivo, multimodal neuroimaging, we found that apolipoprotein E ɛ4 mice treated with rapamycin had restored cerebral blood flow, blood-brain barrier integrity and glucose metabolism, compared to age- and gender-matched wild-type controls. The preserved vasculature and metabolism were associated with amelioration of incipient learning deficits. We also found that rapamycin restored the levels of the proinflammatory cyclophilin A in vasculature, which may contribute to the preservation of cerebrovascular function in the apolipoprotein E ɛ4 transgenics. Our results show that rapamycin improves functional outcomes in this mouse model and may have potential as an effective intervention to block progression of vascular, metabolic and early cognitive deficits in human Apolipoprotein E ɛ4 carriers. As rapamycin is FDA-approved and neuroimaging is readily used in humans, the results of the present study may provide the basis for future Alzheimer's disease intervention studies in human subjects.

Topics: Alzheimer Disease; Animals; Apolipoprotein E4; Blood-Brain Barrier; Cerebrovascular Circulation; Glucose Metabolism Disorders; Learning Disabilities; Metabolic Diseases; Mice; Mice, Transgenic; Neuroimaging; Secondary Prevention; Sirolimus; Vascular Diseases