Deficiency of GDNF receptor GFRα1 in Alzheimer's neurons results in neuronal death

Yoshihiro Konishi, Libang Yang, Ping He, Kristina Lindholm, Bai Lu, Rena Li, Yong Shen

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)13127-13138
Number of pages12
JournalJournal of Neuroscience
Issue number39
StatePublished - Sep 24 2014

Bibliographical note

Publisher Copyright:
© 2014 the authors.


  • Neurodegeneration
  • Neuron


Dive into the research topics of 'Deficiency of GDNF receptor GFRα1 in Alzheimer's neurons results in neuronal death'. Together they form a unique fingerprint.

Cite this