title: Elucidating the role of DEPTOR in Alzheimer's disease.
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.
authors.affiliation: Department of Biosciences, School of Health Sciences and Social Care, Brunel University, Uxbridge, UB8 3PH, UK.
authors.forename: Julie
authors.initials: J
authors.lastname: Davies
authors.affiliation: Department of Biosciences, School of Health Sciences and Social Care, Brunel University, Uxbridge, UB8 3PH, UK.
authors.forename: Elena
authors.initials: E
authors.lastname: Zachariades
authors.affiliation: Department of Biosciences, School of Health Sciences and Social Care, Brunel University, Uxbridge, UB8 3PH, UK.
authors.forename: Karly-Rai
authors.initials: KR
authors.lastname: Rogers-Broadway
authors.affiliation: Department of Biosciences, School of Health Sciences and Social Care, Brunel University, Uxbridge, UB8 3PH, UK.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Karteris
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000633:toxicity; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009473:Neuronal Plasticity / Q000502:physiology; D010446:Peptide Fragments / Q000633:toxicity; D012333:RNA, Messenger; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D012333:RNA, Messenger; C075222:amyloid beta-protein (1-42); C556139:DEPTOR protein, human; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases