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High glucose forces a positive feedback loop connecting ErbB4 expression and mTOR/S6K pathway to aggravate the formation of tau hyperphosphorylation in differentiated SH-SY5Y cells
- Source :
- Neurobiology of Aging. 67:171-180
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- High glucose (HG)-induced mammalian target of rapamycin (mTOR) overactivation acts as a signaling hub for the formation of tau hyperphosphorylation, which contributes to the development of diabetes-associated cognitive deficit. How HG induces the sustained activation of mTOR in neurons is not clearly understood. ErbB4, a member of the receptor tyrosine kinase family, plays critical roles in development and function of neural circuitry, relevant to behavioral deficits. Here, we showed HG-induced ErbB4 overexpression in differentiated SH-SY5Y cells and primary hippocampal neurons and hippocampal pyramidal neurons of streptozotocin-induced diabetic rats. Inhibition of ErbB4 signaling prevented the HG-induced activation of mTOR/S6K signaling to suppress tau hyperphosphorylation. In contrast, ErbB4 overexpression increased the activation of mTOR/S6K signaling, resulting in tau hyperphosphorylation similar to HG treatment. We also demonstrated that HG upregulated the expression of ErbB4 at a mTOR-dependent posttranscriptional level. Together, our results provide the first evidence for the presence of a positive feedback loop for the sustained activation of mTOR involving overexpressed ErbB4, leading to the formation of tau hyperphosphorylation under HG condition. Therefore, ErbB4 is a potential therapeutic target for diabetes-associated neurodegeneration.
- Subjects :
- Male
0301 basic medicine
Aging
Receptor, ErbB-4
SH-SY5Y
Gene Expression
tau Proteins
P70-S6 Kinase 1
Hippocampal formation
Receptor tyrosine kinase
Rats, Sprague-Dawley
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
Diabetes Mellitus
medicine
Animals
Cognitive Dysfunction
Phosphorylation
Cells, Cultured
PI3K/AKT/mTOR pathway
ERBB4
Feedback, Physiological
Neurons
biology
Chemistry
TOR Serine-Threonine Kinases
General Neuroscience
Neurodegeneration
medicine.disease
Cell biology
Glucose
030104 developmental biology
Hyperglycemia
biology.protein
Neurology (clinical)
Geriatrics and Gerontology
030217 neurology & neurosurgery
Signal Transduction
Developmental Biology
Subjects
Details
- ISSN :
- 01974580
- Volume :
- 67
- Database :
- OpenAIRE
- Journal :
- Neurobiology of Aging
- Accession number :
- edsair.doi.dedup.....b1aa8fcc76cf1ceef73b1d0a9d74a491