RT Journal Article
SR Electronic
T1 Ciliary Neurotrophic Factor Cell-Based Delivery Prevents Synaptic Impairment and Improves Memory in Mouse Models of Alzheimer's Disease
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 7516
OP 7527
DO 10.1523/JNEUROSCI.4182-09.2010
VO 30
IS 22
A1 Pierre Garcia
A1 Ihsen Youssef
A1 Jo K. Utvik
A1 Sabrina Florent-Béchard
A1 Vanassa Barthélémy
A1 Catherine Malaplate-Armand
A1 Badreddine Kriem
A1 Christophe Stenger
A1 Violette Koziel
A1 Jean-Luc Olivier
A1 Marie-Christine Escanye
A1 Marine Hanse
A1 Ahmad Allouche
A1 Cédric Desbène
A1 Frances T. Yen
A1 Rolf Bjerkvig
A1 Thierry Oster
A1 Simone P. Niclou
A1 Thierry Pillot
YR 2010
UL http://www.jneurosci.org/content/30/22/7516.abstract
AB The development of novel therapeutic strategies for Alzheimer's disease (AD) represents one of the biggest unmet medical needs today. Application of neurotrophic factors able to modulate neuronal survival and synaptic connectivity is a promising therapeutic approach for AD. We aimed to determine whether the loco-regional delivery of ciliary neurotrophic factor (CNTF) could prevent amyloid-β (Aβ) oligomer-induced synaptic damages and associated cognitive impairments that typify AD. To ensure long-term administration of CNTF in the brain, we used recombinant cells secreting CNTF encapsulated in alginate polymers. The implantation of these bioreactors in the brain of Aβ oligomer-infused mice led to a continuous secretion of recombinant CNTF and was associated with the robust improvement of cognitive performances. Most importantly, CNTF led to full recovery of cognitive functions associated with the stabilization of synaptic protein levels in the Tg2576 AD mouse model. In vitro as well as in vivo, CNTF activated a Janus kinase/signal transducer and activator of transcription-mediated survival pathway that prevented synaptic and neuronal degeneration. These preclinical studies suggest that CNTF and/or CNTF receptor-associated pathways may have AD-modifying activity through protection against progressive Aβ-related memory deficits. Our data also encourage additional exploration of ex vivo gene transfer for the prevention and/or treatment of AD.