sirolimus and Memory-Disorders

To understand the underlying brain mechanisms involved in the aging process and mental deterioration could be key to the development of behavioral patterns that guarantee reaching advanced ages with the highest possible quality of life and reduce the cognitive loss associated with senescence.. To describe and analyze different animal and human studies that demonstrate that a caloric restriction diet may rescue cerebral aging and the cognitive decline associated to aging.. For more than 100 years it has been known that caloric restriction extends life span in many laboratory animal. This effect seems to derive from the reduction of age-related symptoms, such as obesity, the onset of cancerous tumors and some metabolic diseases. However, while the consequences of caloric restriction on health are well-established, their ability to reverse age-dependent memory deficits remains a controversial issue. The analyses of the effects of caloric restriction on different animals provides progress for the understanding of its beneficial effects on the neurobiology of cognitive processes during aging.. Caloric restriction attenuates the normal or pathological aging of the brain and reduces age-related memory problems. Dietary intervention could become a very effective method to promote a better quality of life and prevent the age-related cognitive deficits.. Envejecimiento y memoria: efectos de la restriccion calorica.. Introduccion. El conocimiento de los mecanismos cerebrales involucrados en el proceso de envejecimiento y el deterioro mental podria ser clave para el desarrollo de pautas de conducta que garanticen alcanzar edades avanzadas con la maxima calidad de vida posible y reducir la perdida cognitiva asociada a la senectud. Objetivo. Describir y analizar diferentes investigaciones con animales y humanos que demuestran que una dieta con restriccion calorica aminora el envejecimiento cerebral y el declive cognitivo asociados a la edad. Desarrollo. Desde hace mas de 100 años se conoce que la restriccion calorica incrementa la longevidad de los animales de laboratorio. Este efecto parece derivar de la disminucion de algunos sintomas que acompañan al envejecimiento, como la obesidad, la aparicion de tumores cancerigenos y algunas enfermedades metabolicas. Sin embargo, mientras las consecuencias de la restriccion calorica sobre la salud estan bien determinadas, su capacidad para frenar el declive cognitivo que acompaña al envejecimiento sigue siendo un tema controvertido. La investigacion de los efectos de la restriccion calorica en animales de laboratorio proporciona los primeros avances para la comprension de sus efectos beneficiosos en la neurobiologia de los procesos cognitivos durante el envejecimiento. Conclusiones. La restriccion calorica atenua el envejecimiento normal o patologico del cerebro y reduce los problemas de memoria asociados a la vejez. La intervencion dietetica podria convertirse en un metodo muy eficaz para fomentar una mejor calidad de vida y prevenir el deficit cognitivo que acompaña a la ancianidad.

Topics: Aged; Aged, 80 and over; Aging; Animals; Brain Chemistry; Caloric Restriction; Diet, Mediterranean; Female; Humans; Longevity; Male; Maze Learning; Memory; Memory Disorders; Mice; Mice, Inbred C57BL; Middle Aged; Models, Animal; Multicenter Studies as Topic; Rats; Rats, Inbred Strains; Resveratrol; Sirolimus

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

Topics: Alzheimer Disease; Cognitive Dysfunction; Humans; Memory Disorders; Seizures; Sirolimus

Alzheimer's disease (AD), the most common neurodegenerative disorder, is characterized by progressive cognitive impairment and memory loss. The mammalian target of rapamycin (mTOR) signaling pathway could regulate learning and memory. The effect of rapamycin (Rapa) on mTOR activity could slow or prevent the progression of AD by affecting various essential cellular processes. Previously, we prepared transferrin (Tf) decorated-nanostructured lipid carriers (NLCs) for rapamycin (150 ± 9 nm) to protect the drug from chemical and enzymatic degradation and for brain targeted delivery of rapamycin. Herein, the effect of Tf-NLCs compared to untargeted anionic-NLCs and free rapamycin, were studied in amyloid beta (Aβ) induced rat model of AD. Behavioral test revealed that the Rapa Tf-NLCs were able to significantly improve the impaired spatial memory induced by Aβ. Histopathological studies of hippocampus also showed neural survival in Rapa Tf-NLCs treated group. The immunosuppressive, and delayed wound healing adverse effects in the rapamycin solution treated group were abolished by incorporating the drug into NLCs. The Aβ induced oxidative stress was also reduced by Rapa Tf-NLCs. Molecular studies on the level of Aβ, autophagy (LC3) and apoptotic (caspase-3) markers, and mTOR activity revealed that the Rapa Tf-NLCs decreased the Aβ level and suppressed the toxic effects of Aβ plaques by modulating the mTOR activity and autophagy, and decreasing the apoptosis level. As a conclusion, the designed Tf-NLCs could be an appropriate and a safe brain delivery system for rapamycin and make this drug more efficient in AD for improving memory and neuroprotection.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Lipids; Mammals; Memory Disorders; Rats; Sirolimus; TOR Serine-Threonine Kinases; Transferrin

After long times of ongoing research, still there is no appropriate cure for Alzheimer's disease (AD). Recently, epigenetic alterations, particularly miRNA, have gotten attention in AD research. Among various miRNA, miR-34c has been addressed to be elevated in the brain of AD patients, however, its exact role and downstream mechanisms have not been elucidated yet. This study aimed to investigate the therapeutic potential of miR-34c antagomir on cognitive dysfunction induced by streptozocin (STZ), considering postsynaptic density protein 95 (PSD-95) and mammalian target of rapamycin expression (mTOR). Forty rats were cannulated intraventricularly under deep anesthesia using stereotaxic apparatus and divided into five groups: saline + saline, STZ + saline, STZ + miR-34c antagomir, STZ + lipofectamine, and STZ + scrambled, and received the related treatments for two weeks. At the end of the treatments, spatial memory and locomotor activity were assessed by Morris water maze (MWM), and open fields, respectively. Finally, PSD-95 and mTOR levels were measured by quantitative real-time PCR (qPCR) and western blotting on hippocampal samples. Results showed that miR-34c antagomir markedly ameliorated spatial learning and memory deficits induced by STZ, and significantly enhanced PSD-95 and mTOR levels in the hippocampus. In conclusion, miR-34c antagomir may be considered as a promising novel therapeutic target for AD patients.

Topics: Alzheimer Disease; Animals; Antagomirs; Disease Models, Animal; Disks Large Homolog 4 Protein; Hippocampus; Mammals; Maze Learning; Memory Disorders; MicroRNAs; Rats; Sirolimus; Streptozocin; TOR Serine-Threonine Kinases

Recently, it was reported that mechanistic/mammalian target of rapamycin complex 1 (mTORC1) activity during memory retrieval is required for normal expression of aversive and non-aversive long-term memories. Here we used inhibitory-avoidance task to evaluate the potential mechanisms by which mTORC1 signaling pathway participates in memory retrieval. First, we studied the role of GluA-subunit trafficking during memory recall and its relationship with mTORC1 pathway. We found that pretest intrahippocampal infusion of GluR23ɣ, a peptide that selectively blocks GluA2-containing AMPA receptor (AMPAR) endocytosis, prevented the amnesia induced by the inhibition of mTORC1 during retrieval. Additionally, we found that GluA1 levels decreased and GluA2 levels increased at the hippocampal postsynaptic density subcellular fraction of rapamycin-infused animals during memory retrieval. GluA2 levels remained intact while GluA1 decreased at the synaptic plasma membrane fraction. Then, we evaluated the requirement of AMPAR subunit expression during memory retrieval. Intrahippocampal infusion of GluA1 or GluA2 antisense oligonucleotides (ASO) 3 h before testing impaired memory retention. The memory impairment induced by GluA2 ASO before retrieval was reverted by GluA23ɣ infusion 1 h before testing. However, AMPAR endocytosis blockade was not sufficient to compensate GluA1 synthesis inhibition. Our work indicates that de novo GluA1 and GluA2 AMPAR subunit expression is required for memory retrieval with potential different roles for each subunit and suggests that mTORC1 might regulate AMPAR trafficking during retrieval. Our present results highlight the role of mTORC1 as a key determinant of memory retrieval that impacts the recruitment of different AMPAR subunits.

Topics: Animals; Avoidance Learning; Endocytosis; Male; Mechanistic Target of Rapamycin Complex 1; Memory Disorders; Memory, Long-Term; Mental Recall; Models, Biological; Rats, Wistar; Receptors, AMPA; Signal Transduction; Sirolimus

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Cerebrovascular Disorders; Cognitive Dysfunction; Fear; Female; Humans; Male; Memory Disorders; Mice; Mice, Transgenic; Microvessels; Neurovascular Coupling; Nitric Oxide Synthase Type III; Sirolimus; TOR Serine-Threonine Kinases

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

Numerous studies have reported that epilepsy causes memory deficits. The present study was aimed at studying the effect of rapamycin against the memory deficiency of the pentylenetetrazole (PTZ)-kindled animal model of epilepsy. In the present experiment, we randomly chose thirty male rats from the species of Wistar and categorized them in groups of control and experiment (6 for each group). The groups of experiment received the injection of rapamycin (0.5, 1 and 2 mg/kg) intraperitoneally (i.p.) and the group of control received normal saline (0.9%) treatment. Through the PTZ's sub-threshold dose (35 mg kg

Topics: Animals; Brain; Disease Models, Animal; Kindling, Neurologic; Male; Memory; Memory Disorders; Neurons; Pentylenetetrazole; Rats; Rats, Wistar; Seizures; Sirolimus

Over the years, iron accumulation in specific brain regions has been observed in normal aging and related to the pathogenesis of neurodegenerative disorders. Many neurodegenerative diseases may involve cognitive dysfunction, and we have previously shown that neonatal iron overload induces permanent cognitive deficits in adult rats and exacerbates age-associated memory decline. Autophagy is a catabolic pathway involved in the removal of toxic protein aggregates, which are a hallmark of neurodegenerative events. In the present study, we investigated whether iron accumulation would interfere with autophagy and also sought to determine the effects of rapamycin-induced stimulation of autophagy in attenuating iron-related cognitive deficits. Male Wistar rats received a single daily oral dose of vehicle or iron carbonyl (30 mg/kg) at postnatal days 12-14. In adulthood, they received daily intraperitoneal injections of vehicle or rapamycin (0.25 mg/kg) for 14 days. Results showed that iron given in the neonatal period impaired inhibitory avoidance memory and induced a decrease in proteins critically involved in the autophagy pathway, Beclin-1 and LC3, in the hippocampus. Rapamycin in the adulthood reversed iron-induced memory deficits, decreased the ratio phospho-mTOR/total mTOR, and recovered LC3 II levels in iron-treated rats. Our results suggest that iron accumulation, as observed in neurodegenerative disorders, hinders autophagy, which might play a role in iron-induced neurotoxicity. Rapamycin, by inducing authophagy, was able to ameliorate iron-induced cognitive impairments. These findings support the use of rapamycin as a potential neuroprotective treatment against the cognitive decline associated to neurodegenerative disorders.

Topics: Animals; Autophagy; Cognitive Dysfunction; Disease Models, Animal; Female; Hippocampus; Iron; Iron Overload; Memory Disorders; Neurodegenerative Diseases; Rats, Wistar; Sirolimus

The aim of the present study is to investigate the effect of acute excessive administration of ethanol on the expression of proteins related to the PI3K/Akt/mTOR signalling pathway in the mouse hippocampus and to reveal the possible molecular mechanism of learning and memory deficits induced by ethanol. A total of 120 8-week-old Kunming mice (half male and half female) were randomly assigned into low-dose, moderate-dose, and high-dose male and female groups with intragastric administration of 12.5, 25 and 50% ethanol, respectively, at the dosage of 0.1 ml/10 g·day for 14 days. The male and female control groups received an equal volume of distilled water. Then, the spatial learning and memory of the mice were evaluated by the Morris water maze task. The expression of p-mTOR, p-Akt, mTOR and Akt proteins was tested by western blotting and immunohistochemical staining methods in the hippocampal formation in each group, and haematoxylin-eosin stain was used to identify morphological changes in the hippocampal region. Our results indicated that 25 and 50% ethanol administration led to cognitive dysfunction and hippocampal pyramidal cell impairment in the female and male mice, with the male mice showing more severe impairment. In the 50% ethanol group, the male mice exhibited low expression levels of p-Akt and p-mTOR, but the female mice had no significant differences compared with the respective control group. Interestingly, the male expression levels of p-Akt and p-mTOR were significantly lower than those of females. Overall, these findings suggested that the cognitive deficits induced by ethanol are more serious in male mice than in female mice, and the PI3K/Akt/mTOR signalling pathway in the hippocampus might be involved in the impairment process.

Topics: Animals; Cognitive Dysfunction; Ethanol; Female; Hippocampus; Male; Memory; Memory Disorders; Phosphatidylinositol 3-Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Topics: Aging; Alzheimer Disease; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Cognitive Dysfunction; Memory Disorders; Mice, Mutant Strains; Mice, Transgenic; Molecular Targeted Therapy; Monomeric GTP-Binding Proteins; Neuropeptides; Prosencephalon; Ras Homolog Enriched in Brain Protein; Sirolimus; Spatial Memory

In neurodegenerative diseases like AD, tau forms neurofibrillary tangles, composed of tau protein. In the AD brain, activated caspases cleave tau at the 421th Asp, generating a caspase-cleaved form of tau, TauC3. Although TauC3 is known to assemble rapidly into filaments in vitro, a role of TauC3 in vivo remains unclear. Here, we generated a transgenic mouse expressing human TauC3 using a neuron-specific promoter. In this mouse, we found that human TauC3 was expressed in the hippocampus and cortex. Interestingly, TauC3 mice showed drastic learning and spatial memory deficits and reduced synaptic density at a young age (2-3months). Notably, tau oligomers as well as tau aggregates were found in TauC3 mice showing memory deficits. Further, i.p. or i.c.v. injection with methylene blue or Congo red, inhibitors of tau aggregation in vitro, and i.p. injection with rapamycin significantly reduced the amounts of tau oligomers in the hippocampus, rescued spine density, and attenuated memory impairment in TauC3 mice. Together, these results suggest that TauC3 facilitates early memory impairment in transgenic mice accompanied with tau oligomer formation, providing insight into the role of TauC3 in the AD pathogenesis associated with tau oligomers and a useful AD model to test drug candidates.

Topics: Animals; Avoidance Learning; Brain; Caspases; Cell Line, Tumor; Dendritic Spines; Disease Models, Animal; Female; Humans; Male; Maze Learning; Memory Disorders; Mice, Transgenic; Neurons; Nootropic Agents; Protein Multimerization; Recognition, Psychology; Sirolimus; Spatial Memory; tau Proteins

Targeting group II metabotropic glutamate receptors (mGluR2/3) has been proposed to correct the dysfunctional glutamatergic system, particularly NMDA receptor (NMDAR) hypofunction, for treatment of schizophrenia. However, how activation of mGluR2/3 affects NMDAR function in adult animals remains elusive. Here we show the effects of LY395756 (LY39), a compound acting as both an mGluR2 agonist and mGluR3 antagonist, on the NMDAR expression and function of normal adult rat prefrontal cortex (PFC) as well as working memory function in the MK801 model of schizophrenia. We found that in vivo administration of LY39 significantly increased the total protein levels of NMDAR subunits and NR2B phosphorylationin the PFC, along with the amplitude of NMDAR-mediated miniature excitatory postsynaptic currents (mEPSC) in the prefrontal cortical neurons. Moreover, LY39 also significantly increased mTOR and pmTOR expression, but not ERK1/2, Akt, and GSK3β, suggesting an activation of mTOR signaling. Indeed, the mTOR inhibitor rapamycin, and actinomycin-D, a transcription inhibitor, blocked the enhanced effects of LY39 on NMDAR-mEPSCs. These results indicate that LY39 regulates NMDAR expression and function through unidentified mTOR-mediated protein synthesis in the normal adult rat PFC. However, this change is insufficient to affect working memory function in normal animals, nor to reverse the MK801-induced working memory deficit. Our data provide the first evidence of an in vivo effect of a novel compound that acts as both an mGluR2 agonist and mGluR3 antagonist on synaptic NMDAR expression and function in the adult rat PFC, although its effect -on PFC-dependent cognitive function remains to be explored.

Topics: Amino Acids, Dicarboxylic; Animals; Attention; Bridged Bicyclo Compounds; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Agents; Gene Expression Regulation; Immunosuppressive Agents; In Vitro Techniques; Male; MAP Kinase Signaling System; Memory Disorders; Memory, Short-Term; Patch-Clamp Techniques; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Sirolimus; Synaptic Membranes; Synaptic Potentials

Down's syndrome (DS) is the most prevalent genetic intellectual disability. Memory deficits significantly contribute to the cognitive dysfunction in DS. Previously, we discovered that mTOR-dependent local translation, a pivotal process for some forms of synaptic plasticity, is deregulated in a DS mouse model. Here, we report that these mice exhibit deficits in both synaptic plasticity (i.e., BDNF-long term potentiation) and the persistence of spatial long-term memory. Interestingly, these deficits were fully reversible using rapamycin, a Food and Drug Administration-approved specific mTOR inhibitor; therefore, rapamycin may be a novel pharmacotherapy to improve cognition in DS.

Topics: Animals; Brain-Derived Neurotrophic Factor; CA1 Region, Hippocampal; Disease Models, Animal; Down Syndrome; Long-Term Potentiation; Male; Maze Learning; Memory Disorders; Memory, Long-Term; Mice, Inbred C3H; Mice, Inbred C57BL; Mice, Transgenic; Nootropic Agents; Sirolimus; Spatial Memory; Synaptic Transmission; Tissue Culture Techniques; TOR Serine-Threonine Kinases

In a variety of neurodegenerative tauopathies including Alzheimer's disease, frontotemporal dementia and some types of Parkinson's disease, tau protein is abnormally hyperphosphorylated by several kinases and eventually aggregates to form neurofibrillary tangles, a neurotoxic pathological characteristic that closely correlates with cognitive impairments. Hence, targeting hyperphosphorylated tau protein has now been considered as a valid therapeutic approach for these neurodegenerative tauopathies. As a newly developed analog of rapamycin, temsirolimus was approved by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of renal cell carcinoma. Recent findings suggested that temsirolimus also provided beneficial effects in animal models of Huntington's disease and spinocerebellar ataxia type 3, two neurodegenerative diseases caused by accumulation of aberrant proteins within brain. To date, the therapeutic potentials of temsirolimus in neurodegenerative tauopathies have not been determined. Herein, we demonstrated for the first time that temsirolimus treatment effectively enhanced autophagic clearance of hyperphosphorylated tau in okadaic acid-incubated SH-SY5Y cells and in brain of P301S transgenic mice. Meanwhile, we showed that inactivation of glycogen synthase kinase-3β, the most important tau kinase, might contribute to the temsirolimus-induced reduction of tau hyperphosphorylation in these two tauopathy models. More importantly, temsirolimus administration rescued spatial learning and memory impairments in P301S transgenic mice. These findings highlight temsirolimus administration as a potential therapeutic strategy for neurodegenerative tauopathies.

Topics: Animals; Autophagy; Brain; Cell Line, Tumor; Disease Models, Animal; Enzyme Inhibitors; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Male; Memory Disorders; Mice, Inbred C57BL; Mice, Transgenic; Neuroprotective Agents; Okadaic Acid; Phosphorylation; Sirolimus; Spatial Learning; Spatial Memory; tau Proteins; Tauopathies

The acute activation of the dopamine D1-like receptors (D1R) is involved in a plethora of functions ranging from increased locomotor activity to the facilitation of consolidation, storage, and retrieval of memories. Although much less characterized, epileptiform activities, usually triggered by disruption of the glutamate and GABA balance, have also been reported to involve the dopaminergic transmission. Using a combination of biochemical, immunohistochemical, electrophysiological, and behavioral approaches we have investigated the consequences of repeated stimulation of D1R using the selective D1R-like agonist SKF81297. Here, we report that repeated systemic administration of SKF81297 induces kindled seizures in mice. These seizure episodes parallel the hyperactivation of the mTOR signaling in the hippocampus, leading to disrupted long-term potentiation (LTP) in the dentate gyrus (DG) and altered recognition memories. The mTOR inhibitor rapamycin delays the development of SKF81297-induced kindled seizures, and rescues LTP in the DG and object recognition. Our results show that repeated stimulation of D1R is sufficient to induce generalized seizures leading to the overactivation of mTOR signaling, disrupted hippocampal plasticity, and impaired long-term recognition memories. This work highlights the interest of mTOR inhibitors as therapeutic strategies to reverse plasticity and cognitive deficits.

Topics: Animals; Benzazepines; Cerebral Cortex; Dentate Gyrus; Dopamine Agonists; Excitatory Postsynaptic Potentials; Extracellular Signal-Regulated MAP Kinases; Long-Term Potentiation; Male; Memory Disorders; Mice, Inbred C57BL; Motor Activity; Neuroprotective Agents; Receptors, Dopamine D1; Recognition, Psychology; Seizures; Signal Transduction; Sirolimus; Tissue Culture Techniques; TOR Serine-Threonine Kinases

Cognitive impairments are prominent sequelae of prolonged continuous seizures (status epilepticus; SE) in humans and animal models. While often associated with dendritic injury, the underlying mechanisms remain elusive. The mammalian target of rapamycin complex 1 (mTORC1) pathway is hyperactivated following SE. This pathway modulates learning and memory and is associated with regulation of neuronal, dendritic, and glial properties. Thus, in the present study we tested the hypothesis that SE-induced mTORC1 hyperactivation is a candidate mechanism underlying cognitive deficits and dendritic pathology seen following SE. We examined the effects of rapamycin, an mTORC1 inhibitor, on the early hippocampal-dependent spatial learning and memory deficits associated with an episode of pilocarpine-induced SE. Rapamycin-treated SE rats performed significantly better than the vehicle-treated rats in two spatial memory tasks, the Morris water maze and the novel object recognition test. At the molecular level, we found that the SE-induced increase in mTORC1 signaling was localized in neurons and microglia. Rapamycin decreased the SE-induced mTOR activation and attenuated microgliosis which was mostly localized within the CA1 area. These findings paralleled a reversal of the SE-induced decreases in dendritic Map2 and ion channels levels as well as improved dendritic branching and spine density in area CA1 following rapamycin treatment. Taken together, these findings suggest that mTORC1 hyperactivity contributes to early hippocampal-dependent spatial learning and memory deficits and dendritic dysregulation associated with SE.

Topics: Animals; Dendrites; Dendritic Spines; Disease Models, Animal; Electroencephalography; Gliosis; Hippocampus; Ion Channels; Male; Maze Learning; Mechanistic Target of Rapamycin Complex 1; Memory Disorders; Microglia; Multiprotein Complexes; Neurons; Phosphorylation; Pilocarpine; Rats; Ribosomal Protein S6 Kinases; Sirolimus; Status Epilepticus; TOR Serine-Threonine Kinases

Hippocampal demyelination, a common feature of postmortem multiple sclerosis (MS) brains, reduces neuronal gene expression and is a likely contributor to the memory impairment that is found in >40% of individuals with MS. How demyelination alters neuronal gene expression is unknown.. To explore whether loss of hippocampal myelin alters expression of neuronal microRNAs (miRNAs), we compared miRNA profiles from myelinated and demyelinated hippocampi from postmortem MS brains and performed validation studies.. A network-based interaction analysis depicts a correlation between increased neuronal miRNAs and decreased neuronal genes identified in our previous study. The neuronal miRNA miR-124 was increased in demyelinated MS hippocampi and targets mRNAs encoding 26 neuronal proteins that were decreased in demyelinated hippocampus, including the ionotrophic glutamate receptors AMPA2 and AMPA3. Hippocampal demyelination in mice also increased miR-124, reduced expression of AMPA receptors, and decreased memory performance in water maze tests. Remyelination of the mouse hippocampus reversed these changes.. We establish here that myelin alters neuronal gene expression and function by modulating the levels of the neuronal miRNA miR-124. Inhibition of miR-124 in hippocampal neurons may provide a therapeutic approach to improve memory performance in MS patients.

Topics: Animals; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Gene Expression Regulation; Hippocampus; Humans; Immunosuppressive Agents; Memory Disorders; Mice; MicroRNAs; Monoamine Oxidase Inhibitors; Multiple Sclerosis; Neurons; Postmortem Changes; Receptors, AMPA; RNA, Messenger; Sirolimus

Understanding the factors that contribute to age-related cognitive decline is imperative, particularly as age is the major risk factor for several neurodegenerative disorders. Levels of several cytokines increase in the brain during aging, including IL-1β, whose levels positively correlate with cognitive deficits. Previous reports show that reducing the activity of the mammalian target of rapamycin (mTOR) extends lifespan in yeast, nematodes, Drosophila, and mice. It remains to be established, however, whether extending lifespan with rapamycin is accompanied by an improvement in cognitive function. In this study, we show that 18-month-old mice treated with rapamycin starting at 2 months of age perform significantly better on a task measuring spatial learning and memory compared to age-matched mice on the control diet. In contrast, rapamycin does not improve cognition when given to 15-month-old mice with pre-existing, age-dependent learning and memory deficits. We further show that the rapamycin-mediated improvement in learning and memory is associated with a decrease in IL-1β levels and an increase in NMDA signaling. This is the first evidence to show that a small molecule known to increase lifespan also ameliorates age-dependent learning and memory deficits.

Topics: Aging; Animals; Drosophila melanogaster; Interleukin-1beta; Learning; Memory Disorders; Mice; N-Methylaspartate; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

TDP-43 is a multifunctional DNA/RNA-binding protein that has been identified as the major component of the cytoplasmic ubiquitin (+) inclusions (UBIs) in diseased cells of frontotemporal lobar dementia (FTLD-U) and amyotrophic lateral sclerosis (ALS). Unfortunately, effective drugs for these neurodegenerative diseases are yet to be developed. We have tested the therapeutic potential of rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) and three other autophagy activators (spermidine, carbamazepine, and tamoxifen) in a FTLD-U mouse model with TDP-43 proteinopathies. Rapamycin treatment has been reported to be beneficial in some animal models of neurodegenerative diseases but not others. Furthermore, the effects of rapamycin treatment in FTLD-U have not been investigated. We show that rapamycin treatment effectively rescues the learning/memory impairment of these mice at 3 mo of age, and it significantly slows down the age-dependent loss of their motor function. These behavioral improvements upon rapamycin treatment are accompanied by a decreased level of caspase-3 and a reduction of neuron loss in the forebrain of FTLD-U mice. Furthermore, the number of cells with cytosolic TDP-43 (+) inclusions and the amounts of full-length TDP-43 as well as its cleavage products (35 kDa and 25 kDa) in the urea-soluble fraction of the cellular extract are significantly decreased upon rapamycin treatment. These changes in TDP-43 metabolism are accompanied by rapamycin-induced decreases in mTOR-regulated phospho-p70 S6 kinase (P-p70) and the p62 protein, as well as increases in the autophagic marker LC3. Finally, rapamycin as well as spermidine, carbamazepine, and tamoxifen could also rescue the motor dysfunction of 7-mo-old FTLD-U mice. These data suggest that autophagy activation is a potentially useful route for the therapy of neurodegenerative diseases with TDP-43 proteinopathies.

Topics: Analysis of Variance; Animals; Autophagy; Blotting, Western; Carbamazepine; Caspase 3; Fluorometry; Frontotemporal Dementia; In Situ Nick-End Labeling; Maze Learning; Memory Disorders; Mice; Psychomotor Performance; Rotarod Performance Test; Sirolimus; Spermidine; Tamoxifen; TDP-43 Proteinopathies; TOR Serine-Threonine Kinases

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

Soluble oligomeric aggregates of the amyloid-beta (A beta) peptide are believed to be the most neurotoxic A beta species affecting the brain in Alzheimer disease (AD), a terminal neurodegenerative disorder involving severe cognitive decline underscored by initial synaptic dysfunction and later extensive neuronal death in the CNS. Recent evidence indicates that A beta oligomers are recruited at the synapse, oppose expression of long-term potentiation (LTP), perturb intracellular calcium balance, disrupt dendritic spines, and induce memory deficits. However, the molecular mechanisms behind these outcomes are only partially understood; achieving such insight is necessary for the comprehension of A beta-mediated neuronal dysfunction. We have investigated the role of the phosphatase calcineurin (CaN) in these pathological processes of AD. CaN is especially abundant in the CNS, where it is involved in synaptic activity, LTP, and memory function. Here, we describe how oligomeric A beta treatment causes memory deficits and depresses LTP expression in a CaN-dependent fashion. Mice given a single intracerebroventricular injection of A beta oligomers exhibited increased CaN activity and decreased pCREB, a transcription factor involved in proper synaptic function, accompanied by decreased memory in a fear conditioning task. These effects were reversed by treatment with the CaN inhibitor FK506. We further found that expression of hippocampal LTP in acutely cultured rodent brain slices was opposed by A beta oligomers and that this effect was also reversed by FK506. Collectively, these results indicate that CaN activation may play a central role in mediating synaptic and memory disruption induced by acute oligomeric A beta treatment in mice.

Topics: Amyloidogenic Proteins; Animals; Behavior, Animal; Calcineurin; Conditioning, Psychological; CREB-Binding Protein; Disease Models, Animal; Drug Interactions; Fear; Female; Immunosuppressive Agents; In Vitro Techniques; Injections, Intra-Articular; Long-Term Potentiation; Male; Membrane Potentials; Memory Disorders; Mice; Mice, Inbred C57BL; Patch-Clamp Techniques; Phosphoric Monoester Hydrolases; Rats; Rats, Sprague-Dawley; Sirolimus; Tacrolimus

Cognitive impairment is one of the most important negative consequences associated with cannabis consumption. We found that CB1 cannabinoid receptor (CB1R) activation transiently modulated the mammalian target of rapamycin (mTOR)/p70S6K pathway and the protein synthesis machinery in the mouse hippocampus, which correlated with the amnesic properties of delta9-tetrahydrocannabinol (THC). In addition, non-amnesic doses of either the mTOR blocker rapamycin or the protein synthesis inhibitor anisomycin abrogated the amnesic-like effects of THC, pointing to a mechanism involving new protein synthesis. Moreover, using pharmacological and genetic tools, we found that THC long-term memory deficits were mediated by CB1Rs expressed on GABAergic interneurons through a glutamatergic mechanism, as both the amnesic-like effects and p70S6K phosphorylation were reduced in GABA-CB1R knockout mice and by NMDA blockade.

Topics: Animals; Anisomycin; Central Nervous System Agents; Cognition; Dronabinol; gamma-Aminobutyric Acid; Glutamic Acid; Hippocampus; Male; Memory; Memory Disorders; Mice; Mice, Knockout; Neurons; Protein Kinases; Protein Synthesis Inhibitors; Receptor, Cannabinoid, CB1; Receptors, N-Methyl-D-Aspartate; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases