sirolimus and Cognition-Disorders

The discovery that rapamycin increases lifespan in mice and restores/delays many aging phenotypes has led to the speculation that rapamycin has 'anti-aging' properties. The major question discussed in this review is whether a manipulation that has anti-aging properties can alter the onset and/or progression of Alzheimer's disease, a disease in which age is the major risk factor. Rapamycin has been shown to prevent (and possibly restore in some cases) the deficit in memory observed in the mouse model of Alzheimer's disease (AD-Tg) as well as reduce Aβ and tau aggregation, restore cerebral blood flow and vascularization, and reduce microglia activation. All of these parameters are widely recognized as symptoms central to the development of AD. Furthermore, rapamycin has also been shown to improve memory and reduce anxiety and depression in several other mouse models that show cognitive deficits as well as in 'normal' mice. The current research shows the feasibility of using pharmacological agents that increase lifespan, such as those identified by the National Institute on Aging Intervention Testing Program, to treat Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Autophagy; Behavior, Animal; Cerebrovascular Circulation; Cognition Disorders; Disease Models, Animal; Longevity; Memory Disorders; Mice; Neurofibrillary Tangles; Plaque, Amyloid; Sirolimus; TOR Serine-Threonine Kinases; Vasodilator Agents

An increasing amount of evidence suggests that the dysregulation of the Akt-mTOR (Akt-mammalian Target Of Rapamycin) signaling network is associated with intellectual disabilities, such as fragile X, tuberous sclerosis and Rett's syndrome. The Akt-mTOR pathway is involved in dendrite morphogenesis and synaptic plasticity, and it has been shown to modulate both glutamatergic and GABAergic synaptic transmission. We have recently shown that the AktmTOR pathway is hyperactive in the hippocampus of Ts1Cje mice, a model of Down's syndrome, leading to increased local dendritic translation that could interfere with synaptic plasticity. Rapamycin and rapalogs are specific inhibitors of mTOR, and some of these inhibitors are Food and Drug Administration-approved drugs. In this review, we discuss the molecular basis and consequences of Akt-mTOR hyperactivation in Down's syndrome, paying close attention to alterations in the molecular mechanisms underlying synaptic plasticity. We also analyze the pros and cons of using rapamycin/rapalogs for the treatment of the cognitive impairments associated with this condition.

Topics: Animals; Cognition Disorders; Disease Models, Animal; Down Syndrome; Humans; Immunosuppressive Agents; Mice; Oncogene Protein v-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Autophagy plays a critical role in multiple pathological lesions of Alzheimer's disease (AD), such as the formation of amyloid plaques from amyloid-β (Aβ) production and accumulation via dysregulating amyloid precursor protein turnover and enhancing the activity of β- and/or γ-secretases, intraneuronal neurofibrillary tangles (NFT) because of tau hyperphosphorylation, and neuronal apoptosis. Dysfunction of the autophagy-lysosome system also contributes to Aβ accumulation and the formation of tau oligomers and insoluble aggregates, because induction of autophagy enhances the clearance of both soluble and aggregated forms of Aβ and tau proteins. The mammalian target of rapamycin (mTOR) pathway plays a central role in controlling protein homeostasis and negatively regulates autophagy. Inhibition of mTOR by rapamycin improves cognitive deficits and rescues Aβ pathology and NFTs by increasing autophagy. Several mTOR signaling components may be potential biomarkers of cognitive impairment in the clinical diagnosis of AD. Thus, mTOR-related agents through the control of autophagy-lysosome protein degradation are emerging as an important therapeutic target for AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Autophagy; Cognition Disorders; Humans; Immunosuppressive Agents; Neurofibrillary Tangles; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Our previous investigation demonstrated that autophagy significantly reduced melamine-induced cell death in PC12 cells via inhibiting the excessive generation of ROS. In the present study, we further examine if rapamycin, used as an autophagy activator, can play a significant role in protecting neurons and alleviating the impairment of spatial cognition and hippocampal synaptic plasticity in melamine-treated rats. Male Wistar rats were divided into three groups: control, melamine-treated, and melamine-treated + rapamycin. The animal model was established by administering melamine at a dose of 300 mg/kg/day for 4 weeks. Rapamycin was intraperitoneally given at a dose of 1 mg/kg/day for 28 consecutive days. The Morris water maze test showed that spatial learning and reversal learning in melamine-treated rats were considerably damaged, whereas rapamycin significantly impeded the cognitive function impairment. Rapamycin efficiently alleviated the melamine-induced impairments of both long-term potentiation (LTP) and depotentiation, which were damaged in melamine rats. Rapamycin further increased the expression level of autophagy markers, which were significantly enhanced in melamine rats. Moreover, rapamycin noticeably decreased the reactive oxygen species level, while the superoxide dismutase activity was remarkably increased by rapamycin in melamine rats. Malondialdehyde assay exhibited that rapamycin prominently reduced the malondialdehyde (MDA) level of hippocampal neurons in melamine-treated rats. In addition, rapamycin significantly decreased the caspase-3 activity, which was elevated by melamine. Consequently, our results suggest that regulating autophagy may become a new targeted therapy to relieve the damage induced by melamine.

Topics: Animals; Cognition Disorders; Male; Maze Learning; Neuronal Plasticity; Rats; Rats, Wistar; Reactive Oxygen Species; Sirolimus; Treatment Outcome; Triazines

The mammalian target of rapamycin complex 1 (mTORC1) signaling pathway mediates many aspects of cell growth and regeneration and is upregulated after moderate to severe traumatic brain injury (TBI). The significance of this increased signaling event for recovery of brain function is presently unclear. We analyzed the time course and cell specificity of mTORC1 signal activation in the mouse hippocampus after moderate controlled cortical impact (CCI) and identified an early neuronal peak of activity that occurs within a few hours after injury. We suppressed this peak activity by a single injection of the mTORC1 inhibitor rapamycin 1 h after CCI and showed that this acute treatment significantly diminishes the extent of neuronal death, astrogliosis, and cognitive impairment 1-3 days after injury. Our findings suggest that the early neuronal peak of mTORC1 activity after TBI is deleterious to brain function, and that acute, early intervention with mTORC1 inhibitors after injury may represent an effective form of treatment to improve recovery in human patients.

Topics: Animals; Behavior, Animal; Brain Injuries; Cell Death; Cognition Disorders; Disease Models, Animal; Gliosis; Hippocampus; Maze Learning; Mechanistic Target of Rapamycin Complex 1; Mice; Mice, Inbred C57BL; Multiprotein Complexes; Protein Kinase Inhibitors; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Autophagy is associated with regulation of both the survival and death of neurons, and has been linked to many neurodegenerative diseases. Postoperative cognitive dysfunction is commonly observed in elderly patients following anesthesia, but the pathophysiological mechanisms are largely unexplored. Similar effects have been found in aged rats under sevoflurane anesthesia; however, the role of autophagy in sevoflurane anesthesia-induced hippocampal neuron apoptosis of older rats remains elusive. The present study was designed to investigate the effects of autophagy on the sevoflurane-induced cognitive dysfunction in aged rats, and to identify the role of autophagy in sevoflurane-induced neuron apoptosis. We used 20-month-old rats under sevoflurane anesthesia to study memory performance, neuron apoptosis, and autophagy. The results demonstrated that sevoflurane anesthesia significantly impaired memory performance and induced hippocampal neuron apoptosis. Interestingly, treatment of rapamycin, an autophagy inducer, improved the cognitive deficit observed in the aged rats under sevoflurane anesthesia by improving autophagic flux. Rapamycin treatment led to the rapid accumulation of autophagic bodies and autophagy lysosomes, decreased p62 protein levels, and increased the ratio of microtubule-associated protein light chain 3 II (LC3-II) to LC3-I in hippocampal neurons through the mTOR signaling pathway. However, administration of an autophagy inhibitor (chloroquine) attenuated the autophagic flux and increased the severity of sevoflurane anesthesia-induced neuronal apoptosis and memory impairment. These findings suggest that impaired autophagy in the hippocampal neurons of aged rats after sevoflurane anesthesia may contribute to cognitive impairment. Therefore, our findings represent a potential novel target for pro-autophagy treatments in patients with sevoflurane anesthesia-induced neurodegeneration.

Topics: Anesthetics, Inhalation; Animals; Autophagy; Cognition Disorders; Male; Methyl Ethers; Rats; Rats, Sprague-Dawley; Sevoflurane; Sirolimus

Defect of autophagy is common to many neurodegenerative disorders because it serves as a major degradation pathway for the clearance of various aggregate-prone proteins. Mammalian target of rapamycin (mTOR) signaling, which is recognized as the most important negative regulator of autophagy, is also involved in neurodegenerative diseases. However, the role of mTOR and its dependent autophagy in normal brain during aging remains unknown. Furthermore, caloric restriction (CR) is frequently used as a tool to study mechanisms behind aging and age-associated diseases because CR can prevent age-related diseases and prolong lifespan in several model organisms. Inhibiting mTOR and promoting autophagy activity play roles in aging delayed by CR. However, whether CR can ameliorate age-related cognition deficits by inhibiting mTOR and activate autophagy in hippocampus needs to be further investigated. Here we showed a decline of autophagic degradation in mice hippocampus in correlation with age-dependent cognitive dysfunction, whereas the activity of mTOR and its upstream brain-derived neurotrophic factor (BDNF)/phosphatidylinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling was decreased with aging. In addition, facilitating the mTOR pathway successfully declines and sustains autophagic degradation with aging in hippocampus by CR treatment and is involved in CR by ameliorating age-related cognitive deficits.

Topics: Age Factors; Aging; Animals; Autophagy; Brain; Brain-Derived Neurotrophic Factor; Caloric Restriction; Cognition Disorders; Disease Models, Animal; Food Deprivation; Gene Expression Regulation; Male; Maze Learning; Mice; Mice, Inbred C57BL; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; Time Factors

Abnormal levels of mammalian target of rapamycin (mTOR) signaling have been recently implicated in the pathophysiology of neurodegenerative diseases, such as Alzheimer's disease (AD). However, the implication of mTOR in diabetes mellitus (DM)-related cognitive dysfunction still remains unknown. In the present study, we found that phosphorylated mTOR at Ser2448, phosphorylated p70S6K at Thr421/Ser424 and phosphorylated tau at Ser396 were significantly increased in the hippocampus of streptozotocin (STZ)-induced diabetic mice when compared with control mice. A low dose of rapamycin was used to elucidate the role of mTOR signaling in DM-related cognitive deficit. Rapamycin restored abnormal mTOR/p70S6K signaling and attenuated the phosphorylation of tau protein in the hippocampus of diabetic mice. Furthermore, the spatial learning and memory function of diabetic mice significantly impaired compared with control mice, was also reversed by rapamycin. These findings indicate that mTOR/p70S6K signaling pathway is hyperactive in the hippocampus of STZ-induced diabetic mice and inhibiting mTOR signaling with rapamycin prevents the DM-related cognitive deficits partly through attenuating the hyperphosphorylation of tau protein.

Topics: Animals; Cognition Disorders; Diabetes Mellitus, Experimental; Disease Models, Animal; Hippocampus; Maze Learning; Mice; Phosphorylation; Signal Transduction; Sirolimus; tau Proteins; TOR Serine-Threonine Kinases

Several lines of evidence have indicated that rapamycin acts as an inhibitor of mammalian target of rapamycin (mTOR) and this produces therapeutic benefits as a treatment for Alzheimer's disease (AD) by activating an autophagic pathway. Similarly, postoperative cognitive dysfunction (POCD) is a decline in cognitive function for weeks or months after surgery. POCD and AD are both characterized by cognitive dysfunction, and more importantly, are both related to aging. We therefore hypothesized that rapamycin may have a therapeutic effect to relieve POCD. Inhibition of mTOR induces autophagic effect, thereby leading to a slower aging process, so this would be a novel target for the prevention and treatment of POCD.

Topics: Aging; Cognition Disorders; Humans; Models, Biological; Postoperative Complications; Sirolimus; TOR Serine-Threonine Kinases

Topics: Cognition Disorders; Humans; Immunosuppressive Agents; Receptors, Serotonin; Schizophrenia; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Aging is, by far, the greatest risk factor for most neurodegenerative diseases. In non-diseased conditions, normal aging can also be associated with declines in cognitive function that significantly affect quality of life in the elderly. It was recently shown that inhibition of Mammalian TOR (mTOR) activity in mice by chronic rapamycin treatment extends lifespan, possibly by delaying aging {Harrison, 2009 #4}{Miller, 2011 #168}. To explore the effect of chronic rapamycin treatment on normal brain aging we determined cognitive and non-cognitive components of behavior throughout lifespan in male and female C57BL/6 mice that were fed control- or rapamycin-supplemented chow. Our studies show that rapamycin enhances cognitive function in young adult mice and blocks age-associated cognitive decline in older animals. In addition, mice fed with rapamycin-supplemented chow showed decreased anxiety and depressive-like behavior at all ages tested. Levels of three major monoamines (norepinephrine, dopamine and 5-hydroxytryptamine) and their metabolites (3,4-dihydroxyphenylacetic acid, homovanillic acid, and 5-hydroxyindolacetic acid) were significantly augmented in midbrain of rapamycin-treated mice compared to controls. Our results suggest that chronic, partial inhibition of mTOR by oral rapamycin enhances learning and memory in young adults, maintains memory in old C57BL/6J mice, and has concomitant anxiolytic and antidepressant-like effects, possibly by stimulating major monoamine pathways in brain.

Topics: Aging; Analysis of Variance; Animals; Avoidance Learning; Behavior, Animal; Biogenic Monoamines; Brain; Cognition Disorders; Disease Models, Animal; Female; Gene Expression Regulation; Hindlimb Suspension; Immunosuppressive Agents; Male; Maze Learning; Memory; Mice; Mice, Inbred C57BL; Sex Factors; Sirolimus; Time Factors; TOR Serine-Threonine Kinases

Infantile spasms are seizures manifesting within a spectrum of epileptic encephalopathies of infancy that often lead to cognitive impairment. Their current therapies, including adrenocorticotropic hormone (ACTH), high dose steroids, or vigabatrin, are not always effective and may be associated with serious side effects. Overactivation of the TORC1 complex of the mTOR pathway is implicated in the pathogenesis of certain genetic and acquired disorders that are linked with infantile spasms, like tuberous sclerosis. Here, we tested the therapeutic potential of rapamycin, a TORC1 inhibitor, as a potential treatment for infantile spasms in the multiple-hit rat model of ACTH-refractory symptomatic infantile spasms, which is not linked to tuberous sclerosis. Rapamycin or vehicle was given after spasms appeared. Their effects on spasms, other seizures, performance in Barnes maze, and expression of the phosphorylated S6 ribosomal protein (pS6: a TORC1 target) in the cortex, using immunofluorescence, were compared. Rapamycin suppressed spasms dose-dependently and improved visuospatial learning, although it did not reduce the frequency of other emerging seizures. High-dose pulse rapamycin effected acute and sustained suppression of spasms and improved cognitive outcome, without significant side effects. Therapeutically effective rapamycin doses normalized the pS6 expression, which was increased in perilesional cortical regions of pups with spasms. These findings support that pathological overactivation of TORC1 may be implicated in the pathogenesis of infantile spasms, including those that are not linked to tuberous sclerosis. Furthermore, a high-dose, pulse rapamycin treatment is a promising, well tolerated and disease-modifying new therapy for infantile spasms, including those refractory to ACTH.

Topics: Animals; Animals, Newborn; Cognition Disorders; Disease Models, Animal; Drug Administration Schedule; Humans; Infant, Newborn; Male; Rats; Rats, Sprague-Dawley; Sirolimus; Spasms, Infantile; Transcription Factors

Previous studies have shown that inducing autophagy ameliorates early cognitive deficits associated with the build-up of soluble amyloid-β (Aβ). However, the effects of inducing autophagy on plaques and tangles are yet to be determined. While soluble Aβ and tau represent toxic species in Alzheimer's disease (AD) pathogenesis, there is well documented evidence that plaques and tangles also are detrimental to normal brain function. Thus, it is critical to assess the effects of inducing autophagy in an animal model with established plaques and tangles. Here we show that rapamycin, when given prophylactically to 2-month-old 3xTg-AD mice throughout their life, induces autophagy and significantly reduces plaques, tangles and cognitive deficits. In contrast, inducing autophagy in 15-month-old 3xTg-AD mice, which have established plaques and tangles, has no effects on AD-like pathology and cognitive deficits. In conclusion, we show that autophagy induction via rapamycin may represent a valid therapeutic strategy in AD when administered early in the disease progression.

Topics: Alzheimer Disease; Animals; Autophagy; Cognition Disorders; Memory Disorders; Mice; Microglia; Neurofibrillary Tangles; Plaque, Amyloid; Risk Factors; Sirolimus; Time Factors

Fragile X syndrome, the most common form of inherited mental retardation and leading genetic cause of autism, is caused by transcriptional silencing of the Fmr1 gene. The fragile X mental retardation protein (FMRP), the gene product of Fmr1, is an RNA binding protein that negatively regulates translation in neurons. The Fmr1 knock-out mouse, a model of fragile X syndrome, exhibits cognitive deficits and exaggerated metabotropic glutamate receptor (mGluR)-dependent long-term depression at CA1 synapses. However, the molecular mechanisms that link loss of function of FMRP to aberrant synaptic plasticity remain unclear. The mammalian target of rapamycin (mTOR) signaling cascade controls initiation of cap-dependent translation and is under control of mGluRs. Here we show that mTOR phosphorylation and activity are elevated in hippocampus of juvenile Fmr1 knock-out mice by four functional readouts: (1) association of mTOR with regulatory associated protein of mTOR; (2) mTOR kinase activity; (3) phosphorylation of mTOR downstream targets S6 kinase and 4E-binding protein; and (4) formation of eukaryotic initiation factor complex 4F, a critical first step in cap-dependent translation. Consistent with this, mGluR long-term depression at CA1 synapses of FMRP-deficient mice is exaggerated and rapamycin insensitive. We further show that the p110 subunit of the upstream kinase phosphatidylinositol 3-kinase (PI3K) and its upstream activator PI3K enhancer PIKE, predicted targets of FMRP, are upregulated in knock-out mice. Elevated mTOR signaling may provide a functional link between overactivation of group I mGluRs and aberrant synaptic plasticity in the fragile X mouse, mechanisms relevant to impaired cognition in fragile X syndrome.

Topics: Adaptor Proteins, Signal Transducing; Animals; CA1 Region, Hippocampal; Carrier Proteins; Cell Cycle Proteins; Cognition Disorders; Disease Models, Animal; Eukaryotic Initiation Factor-4A; Eukaryotic Initiation Factors; Excitatory Postsynaptic Potentials; Fragile X Mental Retardation Protein; Fragile X Syndrome; Gene Expression Regulation; Immunoprecipitation; In Vitro Techniques; Long-Term Synaptic Depression; Methoxyhydroxyphenylglycol; Mice; Mice, Knockout; Oncogene Protein v-akt; Phosphatidylinositol 3-Kinases; Phosphoproteins; Phosphorylation; Receptors, Metabotropic Glutamate; Serine; Signal Transduction; Sirolimus

Reduced TOR signaling has been shown to significantly increase lifespan in a variety of organisms [1], [2], [3], [4]. It was recently demonstrated that long-term treatment with rapamycin, an inhibitor of the mTOR pathway[5], or ablation of the mTOR target p70S6K[6] extends lifespan in mice, possibly by delaying aging. Whether inhibition of the mTOR pathway would delay or prevent age-associated disease such as AD remained to be determined.. We used rapamycin administration and behavioral tools in a mouse model of AD as well as standard biochemical and immunohistochemical measures in brain tissue to provide answers for this question. Here we show that long-term inhibition of mTOR by rapamycin prevented AD-like cognitive deficits and lowered levels of Abeta(42), a major toxic species in AD[7], in the PDAPP transgenic mouse model. These data indicate that inhibition of the mTOR pathway can reduce Abeta(42) levels in vivo and block or delay AD in mice. As expected from the inhibition of mTOR, autophagy was increased in neurons of rapamycin-treated transgenic, but not in non-transgenic, PDAPP mice, suggesting that the reduction in Abeta and the improvement in cognitive function are due in part to increased autophagy, possibly as a response to high levels of Abeta.. Our data suggest that inhibition of mTOR by rapamycin, an intervention that extends lifespan in mice, can slow or block AD progression in a transgenic mouse model of the disease. Rapamycin, already used in clinical settings, may be a potentially effective therapeutic agent for the treatment of AD.

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Autophagy; Cognition Disorders; Disease Models, Animal; Immunosuppressive Agents; Mice; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Topics: Animals; Brain; Cognition Disorders; Epilepsy; Humans; Mental Disorders; Neurons; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

Tuberous sclerosis is a single-gene disorder caused by heterozygous mutations in the TSC1 (9q34) or TSC2 (16p13.3) gene and is frequently associated with mental retardation, autism and epilepsy. Even individuals with tuberous sclerosis and a normal intelligence quotient (approximately 50%) are commonly affected with specific neuropsychological problems, including long-term and working memory deficits. Here we report that mice with a heterozygous, inactivating mutation in the Tsc2 gene (Tsc2(+/-) mice) show deficits in learning and memory. Cognitive deficits in Tsc2(+/-) mice emerged in the absence of neuropathology and seizures, demonstrating that other disease mechanisms are involved. We show that hyperactive hippocampal mammalian target of rapamycin (mTOR) signaling led to abnormal long-term potentiation in the CA1 region of the hippocampus and consequently to deficits in hippocampal-dependent learning. These deficits included impairments in two spatial learning tasks and in contextual discrimination. Notably, we show that a brief treatment with the mTOR inhibitor rapamycin in adult mice rescues not only the synaptic plasticity, but also the behavioral deficits in this animal model of tuberous sclerosis. The results presented here reveal a biological basis for some of the cognitive deficits associated with tuberous sclerosis, and they show that treatment with mTOR antagonists ameliorates cognitive dysfunction in a mouse model of this disorder.

Topics: Animals; Behavior, Animal; Cognition Disorders; Female; Heterozygote; Hippocampus; Learning; Male; Mice; Mice, Inbred C57BL; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins