Neuronal plasticity and neurodegenerative diseases

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Neuron plasticity and Neurodegeneration

In the adult brain, neurons are continuously being remodelled, both morphological and synaptic, through which novel connections can be established that contribute to new circuits which may be used to store information. These processes constitute the cellular and molecular bases of neuronal plasticity, which in turn underlies the capacity of individuals to adapt to their exterior milieu. Any failing in these cellular and molecular processes may lead to the onset of neurodegenerative processes which are responsible for neurological disorders like Alzheimer’s disease.

Present Research

Some years ago we initiated a research program based on the role of neurotrophins in neuronal plasticity and survival. As a result, we found that NGF had a specific effect on cultured mouse hippocampal neurons, whereby it induced dendrite elongation and promoted GABAergic connectivity, both important factors in promoting neuronal survival. Further research revealed that these NGF-induced effects were mediated by the Homolog of Enhancer-of-split 1 (Hes1) Gene. Thus, NGF increased the expression of Hes1, whereas the expression of Hes6 (a natural inhibitor of Hes1) abrogated the effects of NGF on neurons in terms of dendrite growth and connectivity. A series of biochemical and cell biology experiments revealed some important steps in the signalling induced by NGF that promotes Hes1 expression, as outlined below (blue arrows):

 According to this scheme, NGF binds to p75NTR, the common neurotrophin receptor that inactivates the RhoA GTPase when it itself is activated. Both active RhoA and reactive oxygen species (ROS) inactivate protein tyrosine phosphatase 1B (PTP1B), whereas the inactivation of RhoA by NGF maintains the constitutive activity of this phosphatase. PTP1B acts as an activator of src family tyrosine kinases, which in turn phosphorylate I-kB, provoking its degradation and the ensuing activation of NF-kB that promotes Hes1 expression.

Amyloid beta (Aß) is a very important agent for the onset and progression of Alzheimer’s disease. Indeed, in parallel studies, we found that before killing cultured hippocampal neurons, Aß produces specific changes in neurons that included the shortening of dendrites and a specific loss in GABAergic connectivity. Most importantly, Aß induces a significant decrease in Hes1 expression, which in conjunction suggests that Aß behaves as a NGF antagonist. Further work revealed some of the steps in NGF signalling that are blocked by Aß and that finally result in the decreased Hes1 expression (red arrows in the Scheme). Thus, the addition of Aß to cultured hippocampal neurons activates RhoA and prevents NGF from augmenting PTP1B activity. Subsequently, Aß decreases the phosphorylation of I-kB and it impairs the NF-kB activation that is responsible for the decrease in Hes1 expression.

From this data, we set up a research programme that aims to inhibit the action of Aß by stimulating different steps in the NGF signalling cascade. For example, pharmacological inhibition of RhoA, overexpression of PTP1B, pharmacological activation of NF-kB or overexpression of Hes1 in cultured cells could each protect neurons against Aß toxicity.

In summary, we believe that it is possible to fight Aß induced damage by favouring and fostering the activity of NGF.
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Future trends

i) Binding studies of NGF, pro-NGF and Aß will be carried out in an attempt to determine how the p75NTR receptor is differentially activated, thereby leading to either the activation or deactivation of RhoA GTPase. The manipulation of p75NTR may help to avoid RhoA activation, consequently protecting neurons against Aß toxicity.

ii) We will continue to perform in vitro studies on cultured hippocampal neurons in order to explore whether mild activation of NF-kB by pharmacological means can protect neurons against the noxious effects of Aß. Indeed, our data will demonstrate whether the addition of TGFß1 will rescue a significant number of hippocampal neurons from death by activating NF-kB and stimulating Hes1 expression. In addition, TGFß1 prevents Aß from decreasing the expression of Hes1. The search for drugs that act as TGFß1 agonists is intensifying in the light of the known neuroprotective effects of this cytokine.

iii) We have already constructed a lentiviral vector expressing Hes1 and we propose to stereotaxically inject this vector into the dorsal hippocampus of mice models of Alzheimer’s disease (double mutants of presenilin1 and APP). The possible retardation of AD progression will be evaluated in both memory tests and by histological analysis of the animal’s brains.

 

Selected Publications:

Simon-Areces, J., Dopazo, A., Dettenhofer, M., Rodriguez-Tebar, A., Garcia-Segura, L.M. and Arevalo, M.A. (2011). Formin1 mediates the induction of dendritogenesis and synaptogenesis by neurogenin3 in mouse hippocampal neurons. PLoS One 6: e21825.

Pedro J. Chacon, Rosa Garcia-Mejias and Alfredo Rodriguez-Tebar. (2011). Inhibition of RhoA GTPase and the subsequent activation of PTP1B protects cultured hippocampal neurons against amyloid ? toxicity. Mol. Neurodegeneration 6: 14-24.

Chacón, P.J., Arévalo, M.A. and Rodriguez-Tébar, A.R. (2010). NGF-activated protein tyrosine phosphatase 1B mediates the phosphorylation and degradation of I-kappa-Balpha coupled to NF-kappa-B activation, thereby controlling dendrite morphology. Mol. Cell. Neurosci. 43: 384-393.

Arevalo, M.A., Roldan, P.M., Chacón, P.J. and Rodríguez-Tebar, A. (2009). Amyloid beta serves as an NGF-like neurotrophic factor or acts as a NGF antagonist depending on its concentration. J. Neurochem. 111: 1425-1433.

Singh, B., Henneberger, C., Betances, D., Arevalo, M.A., Rodríguez-Tébar, A., Meier, J.C. and Grantyn, R. (2006). Altered balance of glutamatergic/GABAergic synaptic input and associated changes in dendrite morphology after BDNF expression in BDNF-deficient hippocampal neurons. J. Neurosci. 26: 7189-200.

Arevalo, M.A. and Rodríguez-Tébar, A. (2006). Activation of casein kinase II and inhibition of phosphatase and tensin homologue deleted on chromosome 10 phosphatase by nerve growth factor/p75NTR inhibit glycogen synthase kinase-3beta and stimulate axonal growth. Mol. Biol. Cell. 17: 3369-3377.

Salama-Cohen, P., Arévalo, M.A., Grantyn, R. and Rodríguez-Tébar, A. (2006). Notch and NGF/p75NTR control dendrite morphology and the balance of excitatory/inhibitory synaptic input to hippocampal neurones through Neurogenin 3. J. Neurochem. 97: 1269-1278.

Salama-Cohen, P., Arévalo, M.A., Meier, J., Grantyn, R. and Rodríguez-Tébar A. (2005). NGF controls dendrite development in hippocampal neurons by binding to p75NTR and modulating the cellular targets of Notch. Mol. Biol. Cell. 16: 339-347.