ABSTRACT
Title
Rescue of TGF-ß1 signaling pathway as a new strategy for neuroprotection in AD
Authors
F. Caraci
University of Catania, Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Catania, Italy
University of Catania, Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Catania, Italy
Abstract
Transforming growth factor-ß1 (TGF-ß1) is a neurotrophic factor that signals through transmembrane serine/threonine kinase receptors, namely the activin receptor-like kinase 5 (ALK-5) type I, and also through additional signaling pathways such as the phosphatidylinositol-3-OH kinase (PI-3-K)/Akt pathway. The deficiency of TGF-β1 signaling has been shown to increase both Aβaccumulation and Aβ-induced neurodegeneration in AD models.Recently, a specific impairment of TGF-β1 signaling pathway has been demonstrated inAD brain(1). TGF-ß1 is a well-known inhibitor of cell proliferation and may contribute to keep postmitotic neurons in a differentiated state. A reduced TGF-ß1 signaling seems to contribute both to microglial activation and ectopic cell cycle re-activation in neurons, two events that contribute to neurodegeneration in the AD brain.
We examined the neuroprotective activity of TGF-β1 in pure cultures of rat cortical neurons challenged with synthetic β-amyloid (Aβ). Aβ induced the apoptosis of about 30-40% of the total neuronal population. TGF-β1 was equally protective when added either in combination with, or 6 hours after Aβ. Co-added TGF-ß1 prevented Aβ-induced cell cycle reactivation, whereas lately added TGF-β1 rescued late β-catenin degradation and tau hyperphosphorylation. We also assessed the neuroprotective activity of endogenous TGF-β1 in vivo. Aβ injection into the rat dorsal hippocampus had a small neurotoxic effect that was amplified by i.c.v. injection of SB431542, a selective inhibitor of TGF-β1 receptor, thus suggesting that endogenous TGF-β1 acts as a factor limiting Aβ toxicity.
We then examined the neuroprotective activity of different drugs, such as lithium and agonists of group II metabotropic glutamate (mGlu) receptors, that cross the blood-brain-barrier and are potentially able to increase the production of TGF-ß1. Interestingly, lithium, a mood stabilizer used for the treatment of bipolar disorder,induced at therapeutic concentrations (0.5-1mM) both the synthesis and the release of TGF-β1 from cultured astrocytes and also prevented Aβ-induced neurodegeneration in mixed neuronal cultures.
The dual mGlu2/3 receptor agonist, LY379268 (0.1-1 μM) was neuroprotective in mixed cultures via a paracrine mechanism mediated by TGF-β1. LY379268 lost its protective activity in neurons grown with astrocytes lacking mGlu3 receptors, indicating that protection against Aβneurotoxicity was entirely mediated by glial mGlu3 receptors (2).
Our data demonstrate that TGF-β1 is neuroprotective in vitro and in vivo against Aß-induced neurodegeneration and suggest that drugs able to increase TGF-β1, such as lithium and dual mGlu2/3 receptor agonists, might represent new neuroprotective tools for the treatment of AD.
REFERENCES
1) Tesseur I et al. 2006, Deficiency in neuronal TGF-beta signaling promotes neurodegeneration and Alzheimer's pathology. J. Clin. Invest. 116: 3060-9.
2) Caraci F. et al. 2011, Targeting group-II metabotropic glutamate receptors for the treatment of psychosis associated with Alzheimer’s disease: selective activation of mGlu2 receptors amplifies b-amyloid toxicity in cultured neurons whereas dual activation of mGlu2 and mGlu3 receptors is neuroprotective. Molecular Pharmacology 79:618-26.
We examined the neuroprotective activity of TGF-β1 in pure cultures of rat cortical neurons challenged with synthetic β-amyloid (Aβ). Aβ induced the apoptosis of about 30-40% of the total neuronal population. TGF-β1 was equally protective when added either in combination with, or 6 hours after Aβ. Co-added TGF-ß1 prevented Aβ-induced cell cycle reactivation, whereas lately added TGF-β1 rescued late β-catenin degradation and tau hyperphosphorylation. We also assessed the neuroprotective activity of endogenous TGF-β1 in vivo. Aβ injection into the rat dorsal hippocampus had a small neurotoxic effect that was amplified by i.c.v. injection of SB431542, a selective inhibitor of TGF-β1 receptor, thus suggesting that endogenous TGF-β1 acts as a factor limiting Aβ toxicity.
We then examined the neuroprotective activity of different drugs, such as lithium and agonists of group II metabotropic glutamate (mGlu) receptors, that cross the blood-brain-barrier and are potentially able to increase the production of TGF-ß1. Interestingly, lithium, a mood stabilizer used for the treatment of bipolar disorder,induced at therapeutic concentrations (0.5-1mM) both the synthesis and the release of TGF-β1 from cultured astrocytes and also prevented Aβ-induced neurodegeneration in mixed neuronal cultures.
The dual mGlu2/3 receptor agonist, LY379268 (0.1-1 μM) was neuroprotective in mixed cultures via a paracrine mechanism mediated by TGF-β1. LY379268 lost its protective activity in neurons grown with astrocytes lacking mGlu3 receptors, indicating that protection against Aβneurotoxicity was entirely mediated by glial mGlu3 receptors (2).
Our data demonstrate that TGF-β1 is neuroprotective in vitro and in vivo against Aß-induced neurodegeneration and suggest that drugs able to increase TGF-β1, such as lithium and dual mGlu2/3 receptor agonists, might represent new neuroprotective tools for the treatment of AD.
REFERENCES
1) Tesseur I et al. 2006, Deficiency in neuronal TGF-beta signaling promotes neurodegeneration and Alzheimer's pathology. J. Clin. Invest. 116: 3060-9.
2) Caraci F. et al. 2011, Targeting group-II metabotropic glutamate receptors for the treatment of psychosis associated with Alzheimer’s disease: selective activation of mGlu2 receptors amplifies b-amyloid toxicity in cultured neurons whereas dual activation of mGlu2 and mGlu3 receptors is neuroprotective. Molecular Pharmacology 79:618-26.