Abstract
Amyloid-β (Aβ) deposition, a hallmark of Alzheimer’s disease, is known to induce free radical production and oxidative stress, leading to neuronal damage. During oxidative stress, several cell types (including astrocytes) can activate the nuclear factor erythroid 2-related factor 2 (Nrf2), a regulator of several phase II detoxifying and antioxidant genes, such as the System Xc− subunit xCT. Here, we studied (i) the effect of the Aβ fragment 25-35 (Aβ25-35) on Nrf2-dependent System Xc− expression in U373 human astroglial cells and (ii) the effect of Aβ25-35-induced astrocytic response on neuronal cell viability using an in vitro co-culture system. We found that Aβ25-35 was able to activate an antioxidant response in astrocytes, by inducing both Nrf2 activation and System Xc− up-regulation. However, this astrocytic response caused an enhanced cell mortality of co-cultured SH-SY5Y cells, taken as a neuronal model. Consistently, the specific System Xc− inhibitor sulfasalazine prevented the increase of both neuronal mortality and extracellular glutamate levels, thus indicating that the neurotoxic effect was due to an augmented release of glutamate through the transporter. The involvement of NMDA receptor activation in this pathway was also demonstrated using the specific inhibitor MK801 that completely restored neuronal viability at the control levels. The present study sheds light on the Nrf2/system Xc− pathway in the toxicity induced by Aβ25-35 and may help to better understand the involvement of astrocytes in neuronal death during Alzheimer’s disease.
Highlights
Alzheimer’s disease (AD) is recognized by World Health Organization as a global public health priority, being the leading cause of dementia, responsible for 50–75% of all world cases and results in the deterioration of selective cognitive performance, including memory and mental processing [1,2].AD is characterized by deposition of amyloid-β peptide (Aβ) in senile plaques, intracellular neurofibrillary tangles consisting of hyper-phosphorylated tau, synaptic dysfunction and neuronal death
We investigated whether Aβ fragment 25-35 (Aβ25-35) could activate nuclear factor erythroid 2-related factor 2 (Nrf2) in astroglial cells
U373 cells were treated with Aβ25-35 (50 μM) for 2, 4 and 24 h and Nrf2 levels were measured in nuclear extracts by Western blot analysis
Summary
Alzheimer’s disease (AD) is recognized by World Health Organization as a global public health priority, being the leading cause of dementia, responsible for 50–75% of all world cases and results in the deterioration of selective cognitive performance, including memory and mental processing [1,2]. AD is characterized by deposition of amyloid-β peptide (Aβ) in senile plaques, intracellular neurofibrillary tangles consisting of hyper-phosphorylated tau, synaptic dysfunction and neuronal death. The predominant forms of Aβ in the human brain as well as in human cerebrospinal fluid (CSF) are the full length Aβ1-40 and Aβ1-42 peptides and shorter carboxyterminal Aβ peptides, as well as amino-terminal truncated species [7]. The predominant N-terminal truncated Aβ peptides are Aβ3-40/42 , Aβ11-40/42 , and Aβ17-40/42 [7]. Note that many Aβ fragments (e.g., Aβ1-16 , Aβ1-33 , Aβ1-39 ) in CSF can discriminate AD patients from non-demented controls [8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
