TY - JOUR
T1 - Deficiency of GDNF receptor GFRα1 in Alzheimer's neurons results in neuronal death
AU - Konishi, Yoshihiro
AU - Yang, Libang
AU - He, Ping
AU - Lindholm, Kristina
AU - Lu, Bai
AU - Li, Rena
AU - Shen, Yong
N1 - Publisher Copyright:
© 2014 the authors.
PY - 2014/9/24
Y1 - 2014/9/24
N2 - We have recently developed aged cortical neuron cultures from autopsied human brains with Alzheimer's disease (AD). During the culturing process, we found that glutamatergic cortical neurons from the AD brain lacked a response to glial cell line-derived neurotrophic factor (GDNF), including no axonal regrowth, and were starting to undergo apoptosis. Here we showed that, in cortical neurons from age- and gender-matched cognitively normal control (NC) subjects (NC neurons), GDNF enhanced the expression of GDNF family receptor subtype α1 (GFRα1), but not the other three subtypes (GFRα2, GFRα3, and GFRα4), whereas GDNF failed to induce GFRα1 expression in cortical neurons from the AD brain (AD neurons). The exogenous introduction of GFRα1, but not of its binding partner α1-neural cell adhesion molecule, or RET into AD neurons restored the effect of GDNF on neuronal survival. Moreover, between NC and AD neurons, the AMPA receptor blocker CNQX and the NMDA receptor blocker AP-5 had opposite effects on the GFRα1 expression induced by GDNF. In NC neurons, the presence of glutamate receptors was necessary for GDNF-linked GFRα1 expression, while in AD neurons the absence of glutamate receptors was required for GFRα1 expression by GDNF stimulation. These results suggest that, in AD neurons, specific impairments of GFRα1, which may be linked to glutamatergic neurotransmission, shed light on developing potential therapeutic strategies for AD by upregulation of GFRα1 expression.
AB - We have recently developed aged cortical neuron cultures from autopsied human brains with Alzheimer's disease (AD). During the culturing process, we found that glutamatergic cortical neurons from the AD brain lacked a response to glial cell line-derived neurotrophic factor (GDNF), including no axonal regrowth, and were starting to undergo apoptosis. Here we showed that, in cortical neurons from age- and gender-matched cognitively normal control (NC) subjects (NC neurons), GDNF enhanced the expression of GDNF family receptor subtype α1 (GFRα1), but not the other three subtypes (GFRα2, GFRα3, and GFRα4), whereas GDNF failed to induce GFRα1 expression in cortical neurons from the AD brain (AD neurons). The exogenous introduction of GFRα1, but not of its binding partner α1-neural cell adhesion molecule, or RET into AD neurons restored the effect of GDNF on neuronal survival. Moreover, between NC and AD neurons, the AMPA receptor blocker CNQX and the NMDA receptor blocker AP-5 had opposite effects on the GFRα1 expression induced by GDNF. In NC neurons, the presence of glutamate receptors was necessary for GDNF-linked GFRα1 expression, while in AD neurons the absence of glutamate receptors was required for GFRα1 expression by GDNF stimulation. These results suggest that, in AD neurons, specific impairments of GFRα1, which may be linked to glutamatergic neurotransmission, shed light on developing potential therapeutic strategies for AD by upregulation of GFRα1 expression.
KW - Neurodegeneration
KW - Neuron
UR - http://www.scopus.com/inward/record.url?scp=84907284563&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84907284563&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.2582-13.2014
DO - 10.1523/JNEUROSCI.2582-13.2014
M3 - Article
C2 - 25253858
AN - SCOPUS:84907284563
SN - 0270-6474
VL - 34
SP - 13127
EP - 13138
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 39
ER -