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Molecular interplay between hyperactive mammalian target of rapamycin signaling and Alzheimer's disease neuropathology in the NS-Pten knockout mouse model.

ABSTRACT: Dysregulation of the PI3K/Akt/mTOR signaling cascade has been associated with the pathology of neurodegenerative disorders, specifically Alzheimer's disease (AD). Both in-vivo models and post-mortem brain samples of individuals with AD have commonly shown hyperactivation of the pathway. In the present study, we examine how neuron subset-specific deletion of Pten (NS-Pten) in mice, which presents with hyperactive mammalian target of rapamycin (mTOR) activity, affects the hippocampal protein levels of key neuropathological hallmarks of AD. We found NS-Pten knockout (KO) mice to have elevated levels of amyloid-?, ?-synuclein, neurofilament-L, and pGSK3? in the hippocampal synaptosome compared with NS-Pten wild type mice. In contrast, there was a decreased expression of amyloid precursor protein, tau, GSK3?, and GSK3? in NS-Pten KO hippocampi. Overall, there were significant alterations in levels of proteins associated with AD pathology in NS-Pten KO mice. This study provides novel insight into how altered mTOR signaling is linked to AD pathology, without the use of an in-vivo AD model that already displays neuropathological hallmarks of the disease.

SUBMITTER: Hodges SL

PROVIDER: S-EPMC6533623 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Molecular interplay between hyperactive mammalian target of rapamycin signaling and Alzheimer's disease neuropathology in the NS-Pten knockout mouse model.

Hodges Samantha L SL Reynolds Conner D CD Smith Gregory D GD Jefferson Taylor S TS Nolan Suzanne O SO Lugo Joaquin N JN

Neuroreport 20180901 13

Dysregulation of the PI3K/Akt/mTOR signaling cascade has been associated with the pathology of neurodegenerative disorders, specifically Alzheimer's disease (AD). Both in-vivo models and post-mortem brain samples of individuals with AD have commonly shown hyperactivation of the pathway. In the present study, we examine how neuron subset-specific deletion of Pten (NS-Pten) in mice, which presents with hyperactive mammalian target of rapamycin (mTOR) activity, affects the hippocampal protein level ...[more]

PMID: 29965873

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Project description:Objective:The goal of this study was to identify changes in quantitative and qualitative aspects of neonatal ultrasonic vocalizations USVs in neuron-subset specific (NS-Pten) knockout males and females when compared with wild-type male and female mice. Background:One signaling cascade that plays a crucial role in the development of an autistic-like phenotype is the PI3K/Akt/mTOR pathway. Mouse models that illustrate this connection include Fmr1, Tsc1, and NS-Pten-deficient mice. While numerous studies have investigated ultrasonic vocalizations in Fmr1 knockout and Tsc1 heterogenous mice, none have investigated USVs in NS-Pten knockout mice using a full spectrum recording system. Methods:We recorded ultrasonic vocalizations from NS-Pten wild-type and knockout male and female mice on postnatal days 8 and 11. On these days, we measured the number and quality of calls emitted from pups when they were removed from their mothers. Results:We found that knockout pups emitted fewer vocalizations for both sexes (p < .05). Knockout males had calls of a shorter duration and lower peak amplitude on day 8, while showing a shorter duration, lower peak amplitude, and higher peak and fundamental frequency on day 11 (p < .001). Knockout females vocalized at a lower peak amplitude and fundamental frequency, and a higher peak frequency on day 8, while showing a shorter duration and a higher peak and fundamental frequency on day 11 (p < .001). Spectrographic analyses also revealed significant differences in call type for both genotypes and sexes (p < .05). Conclusions:These findings demonstrate that deletion of NS-Pten results in significant decreases in vocalizations across both sexes. Additionally, our findings indicate that the aberrant vocalizations and increased call duration seen in other mTOR models are also present in NS-Pten knockout mice. Our study provides evidence of a connection between hyperactive mTOR signaling and neonatal ultrasonic vocalizations.

Project description:UNLABELLED:Phosphatase and tensin homolog (PTEN) is a major negative regulator of the Akt/mammalian target of rapamycin (MTOR) pathway. Mutations in PTEN have been found in a subset of individuals with autism and macrocephaly. Further, focal cortical dysplasia (FCD) has been observed in patients with PTEN mutations prompting us to examine the role of Pten in neuronal migration. The dentate gyrus of Pten(Flox/Flox) mice was injected with Cre- and non-Cre-expressing retroviral particles, which integrate into the dividing genome to birthdate cells. Control and Pten knockout (KO) cell position in the granule cell layer was quantified over time to reveal that Pten KO neurons exhibit an aberrant migratory phenotype beginning at 7.5days-post retroviral injection (DPI). We then assessed whether rapamycin, a mTor inhibitor, could prevent or reverse aberrant migration of granule cells. The preventative group received daily intraperitoneal (IP) injections of rapamycin from 3 to 14 DPI, before discrepancies in cell position have been established, while the reversal group received rapamycin afterward, from 14 to 24 DPI. We found that rapamycin prevented and reversed somal hypertrophy. However, rapamycin prevented, but did not reverse aberrant migration in Pten KO cells. We also find that altered migration occurs through mTorC1 and not mTorC2 activity. Together, these findings suggest a temporal window by which rapamycin can treat aberrant migration, and may have implications for the use of rapamycin to treat PTEN-mutation associated disorders. SIGNIFICANCE STATEMENT:Mutations in phosphatase and tensin homolog (PTEN) have been linked to a subset of individuals with autism and macrocephaly, as well as Cowden Syndrome and focal cortical dysplasia. Pten loss leads to neuronal hypertrophy, but the role of Pten in neuronal migration is unclear. Here we have shown that loss of Pten leads to aberrant migration, which can be prevented but not reversed by treatment with rapamycin, a mTor inhibitor. These results are important to consider as clinical trials are developed to examine rapamycin as a therapeutic for autism with PTEN mutations. Our findings show that some abnormalities cannot be reversed, and suggest the potential need for genetic screening and preventative treatment.

Dataset Information

Molecular interplay between hyperactive mammalian target of rapamycin signaling and Alzheimer's disease neuropathology in the NS-Pten knockout mouse model.

Publications

Molecular interplay between hyperactive mammalian target of rapamycin signaling and Alzheimer's disease neuropathology in the NS-Pten knockout mouse model.

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