Abstract
Alzheimer’s disease (AD) is a devastating neurodegenerative disease with limited treatment options and no cure. Beta-amyloid (Aβ) is a hallmark of AD that has potent neurotoxicity in neural stem cells (NSCs). Dual specificity phosphatase 6 (DUSP6) is a member of the mitogen-activated protein kinases (MAPKs), which is involved in regulating various physiological and pathological processes. Whether DUSP6 has a protective effect on Aβ-induced NSC injury remains to be explored. C17.2 neural stem cells were transfected with DUSP6-overexpressed plasmid. NSCs with or without DUSP6 overexpression were administrated with Aβ25–35 at various concentrations (i.e., 0, 2.5, 5 μM). DUSP6 expression after Aβ treatment was detected by Real-Time Polymerase Chain Reaction (RT-PCR) and Western blot and cell vitality was examined by the CCK8 assay. The oxidative stress (intracellular reactive oxygen species (ROS) and malondialdehyde (MDA)), endoplasmic reticulum stress (ER calcium level) and mitochondrial dysfunction (cytochrome c homeostasis) were tested. The expression of p-ERK1/2 and ERK1/2 were assayed by Western blot. Our results showed that Aβ decreased the expression of DUSP6 in a dose-dependent manner. The overexpression of DUSP6 increased the cell vitality of NSCs after Aβ treatment. Oxidative stress, ER stress, and mitochondrial dysfunction induced by Aβ could be restored by DUSP6 overexpression. Additionally, the Aβ-induced ERK1/2 activation was reversed. In summary, DUSP6 might have a neuroprotective effect on Aβ-induced cytotoxicity, probably via ERK1/2 activation.
Highlights
Alzheimer’s disease (AD) is the most prevalent cause of dementia and affects 1 in 10 people over 65 years of age [1]
neural stem cells (NSCs) were either pre-transfected with Dual specificity phosphatase 6 (DUSP6) overexpression plasmid or transfected. Both groups were treated with 5 μM Aβ25–35 for 24 h. (A) Endoplasmic reticulum (ER)
Both groups were treated with 5 μM Aβ25–35 for 24 h. (A) Endoplasmic reticulum in NSCs was calcium was detected by fluorescent probe Fura-2/AM; (B) Cytosolic Ca2+ content (ER) calcium was detected by fluorescent probe Fura-2/AM; (B) Cytosolic Ca2+ content in NSCs was measured with Indo-1/AM. (C) An enzyme-linked immunosorbent assay (ELISA) kit was adopted for measured with Indo-1/AM. (C) An enzyme-linked immunosorbent assay (ELISA) kit was adopted the assay of cytochrome c in NSCs’ mitochondria
Summary
Alzheimer’s disease (AD) is the most prevalent cause of dementia and affects 1 in 10 people over 65 years of age [1]. Neural stem cell (NSC) therapy brings new hope to AD treatment. NSCs potent neurotoxicity on the central nervous system [5]. The protein level of DUSP6 was found to be decreased in AD brain lysates and cytotoxicity. The protein level of DUSP6 was found to be decreased in AD brainDUSP6 lysates knockdown increased the level of phospho-ERK to promote high levels of tau phosphorylation [9,10]. DUSP6 knockdown increased the level of phospho-ERK to promote high levels of tau. Is associated with endoplasmic reticulum stress, which system [13]. AD is associated with endoplasmic reticulum stress, which is is thought thought to to trigger trigger cell cell death death under under Aβ. Aβ-induced cytotoxicity in NSCs and the underlying molecular mechanisms involving oxidative stress, Aβ-induced cytotoxicity in NSCs and the underlying molecular mechanisms involving oxidative mitochondrial dysfunction, and reticulum stress. stress
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