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Elucidating the role of DEPTOR in Alzheimer's disease.

Davies J, Zachariades E, Rogers-Broadway KR, Karteris E - Int. J. Mol. Med. (2014)

Bottom Line: This resulted in a significant increase in mTOR and a significant decrease in DEPTOR expression compared to the unstimulated controls.Moreover, to the best of our knowledge, we demonstrate for the first time a reduction in the protein level of DEPTOR in the precentral gyrus, postcentral gyrus and occipital lobe of a brain with AD compared to a normal control, as well as a significant reduction in DEPTOR expression in samples from late-onset AD (LOAD) compared to early-onset familial AD (EOFAD).This results in the accumulation of amyloid plaque, shifting the balance from neuroprotection to neurodegeneration.

View Article: PubMed Central - PubMed

Affiliation: Department of Biosciences, School of Health Sciences and Social Care, Brunel University, Uxbridge, UB8 3PH, UK.

ABSTRACT
The mammalian or mechanistic target of rapamycin (mTOR) is a Ser/Thr protein kinase that, in response to nutrient stimulation, regulates cellular growth, proliferation, survival, protein synthesis and gene transcription. It has also been implicated in Alzheimer's disease (AD) with neuronal cells and hippocampal slices of AD transgenic mice experiencing dysregulated mTOR and synaptic plasticity in response to treatment with the toxic amyloid β (Aβ(1-42)) peptide, which has been implicated in AD. DEP domain-containing mTOR-interacting protein (DEPTOR) is a protein which can bind to mTOR and cause its inhibition, and functions as a regulatory protein of mTOR to control its activity. The inhibition of mTOR has been shown to have a neuroprotective effect; in an animal model, it was shown to protect against Aβ-induced neurotoxicity. In the present study, to investigate to role of DEPTOR in a model of AD, we neuronally differentiated the SH-SY5Y cell line and examined the effects of treatment with an Aβ(42) peptide, thus mimicking plaque formation. This resulted in a significant increase in mTOR and a significant decrease in DEPTOR expression compared to the unstimulated controls. Moreover, to the best of our knowledge, we demonstrate for the first time a reduction in the protein level of DEPTOR in the precentral gyrus, postcentral gyrus and occipital lobe of a brain with AD compared to a normal control, as well as a significant reduction in DEPTOR expression in samples from late-onset AD (LOAD) compared to early-onset familial AD (EOFAD). The reduction in DEPTOR expression in cases of AD compared to healthy controls can lead to an augmentation of mTOR signalling, leading to Aβ accumulation, which in turn leads to a further reduction in DEPTOR expression. This results in the accumulation of amyloid plaque, shifting the balance from neuroprotection to neurodegeneration.

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Related in: MedlinePlus

(A) Immunohistochemical staining with a DEPTOR antibody revealed a reduction in its expression in the precentral gyrus, postcentral gyrus and occipital lobe of a brain with Alzheimer’s disease (AD) compared to a healthy control brain. (B) DEPTOR expression levels in human late onset AD (LOAD) samples were significantly reduced compared to early onset familial AD (EOFAD) samples. Data are the means ± standard error of the mean (SEM). *P<0.05, stastistically significant difference between LOAD and EOFAD (n=5).
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f3-ijmm-34-05-1195: (A) Immunohistochemical staining with a DEPTOR antibody revealed a reduction in its expression in the precentral gyrus, postcentral gyrus and occipital lobe of a brain with Alzheimer’s disease (AD) compared to a healthy control brain. (B) DEPTOR expression levels in human late onset AD (LOAD) samples were significantly reduced compared to early onset familial AD (EOFAD) samples. Data are the means ± standard error of the mean (SEM). *P<0.05, stastistically significant difference between LOAD and EOFAD (n=5).

Mentions: We then assessed the protein expression of DEPTOR from 3 brain regions from a single brain with AD and a normal (healthy) brain. The ages of the patients were of 75 and 54 years, respectively, and they were both male. In all 3 different regions, i.e., precentral gyrus, postcentral gyrus and occipital lobe, the expression of DEPTOR was markedly decreased in the patient with AD compared to the same region of the healthy control (Fig. 3A).


Elucidating the role of DEPTOR in Alzheimer's disease.

Davies J, Zachariades E, Rogers-Broadway KR, Karteris E - Int. J. Mol. Med. (2014)

(A) Immunohistochemical staining with a DEPTOR antibody revealed a reduction in its expression in the precentral gyrus, postcentral gyrus and occipital lobe of a brain with Alzheimer’s disease (AD) compared to a healthy control brain. (B) DEPTOR expression levels in human late onset AD (LOAD) samples were significantly reduced compared to early onset familial AD (EOFAD) samples. Data are the means ± standard error of the mean (SEM). *P<0.05, stastistically significant difference between LOAD and EOFAD (n=5).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4199409&req=5

f3-ijmm-34-05-1195: (A) Immunohistochemical staining with a DEPTOR antibody revealed a reduction in its expression in the precentral gyrus, postcentral gyrus and occipital lobe of a brain with Alzheimer’s disease (AD) compared to a healthy control brain. (B) DEPTOR expression levels in human late onset AD (LOAD) samples were significantly reduced compared to early onset familial AD (EOFAD) samples. Data are the means ± standard error of the mean (SEM). *P<0.05, stastistically significant difference between LOAD and EOFAD (n=5).
Mentions: We then assessed the protein expression of DEPTOR from 3 brain regions from a single brain with AD and a normal (healthy) brain. The ages of the patients were of 75 and 54 years, respectively, and they were both male. In all 3 different regions, i.e., precentral gyrus, postcentral gyrus and occipital lobe, the expression of DEPTOR was markedly decreased in the patient with AD compared to the same region of the healthy control (Fig. 3A).

Bottom Line: This resulted in a significant increase in mTOR and a significant decrease in DEPTOR expression compared to the unstimulated controls.Moreover, to the best of our knowledge, we demonstrate for the first time a reduction in the protein level of DEPTOR in the precentral gyrus, postcentral gyrus and occipital lobe of a brain with AD compared to a normal control, as well as a significant reduction in DEPTOR expression in samples from late-onset AD (LOAD) compared to early-onset familial AD (EOFAD).This results in the accumulation of amyloid plaque, shifting the balance from neuroprotection to neurodegeneration.

View Article: PubMed Central - PubMed

Affiliation: Department of Biosciences, School of Health Sciences and Social Care, Brunel University, Uxbridge, UB8 3PH, UK.

ABSTRACT
The mammalian or mechanistic target of rapamycin (mTOR) is a Ser/Thr protein kinase that, in response to nutrient stimulation, regulates cellular growth, proliferation, survival, protein synthesis and gene transcription. It has also been implicated in Alzheimer's disease (AD) with neuronal cells and hippocampal slices of AD transgenic mice experiencing dysregulated mTOR and synaptic plasticity in response to treatment with the toxic amyloid β (Aβ(1-42)) peptide, which has been implicated in AD. DEP domain-containing mTOR-interacting protein (DEPTOR) is a protein which can bind to mTOR and cause its inhibition, and functions as a regulatory protein of mTOR to control its activity. The inhibition of mTOR has been shown to have a neuroprotective effect; in an animal model, it was shown to protect against Aβ-induced neurotoxicity. In the present study, to investigate to role of DEPTOR in a model of AD, we neuronally differentiated the SH-SY5Y cell line and examined the effects of treatment with an Aβ(42) peptide, thus mimicking plaque formation. This resulted in a significant increase in mTOR and a significant decrease in DEPTOR expression compared to the unstimulated controls. Moreover, to the best of our knowledge, we demonstrate for the first time a reduction in the protein level of DEPTOR in the precentral gyrus, postcentral gyrus and occipital lobe of a brain with AD compared to a normal control, as well as a significant reduction in DEPTOR expression in samples from late-onset AD (LOAD) compared to early-onset familial AD (EOFAD). The reduction in DEPTOR expression in cases of AD compared to healthy controls can lead to an augmentation of mTOR signalling, leading to Aβ accumulation, which in turn leads to a further reduction in DEPTOR expression. This results in the accumulation of amyloid plaque, shifting the balance from neuroprotection to neurodegeneration.

Show MeSH
Related in: MedlinePlus