TGF-beta 1 protects against Abeta-neurotoxicity via the phosphatidylinositol-3-kinase pathway.
beta-Amyloid (A beta) 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 transforming growth factor-beta (TGF-beta) receptor. This suggested that TGF-beta acts as a factor limiting A beta toxicity. We examined the neuroprotective activity of TGF-beta1 in pure cultures of rat cortical neurons challenged with A beta. Neuronal death triggered by A beta is known to proceed along an aberrant re-activation of the cell cycle, and involves late beta-catenin degradation and tau hyperphosphorylation. TGF-beta1 was equally protective when added either in combination with, or 6 h after A beta. Co-added TGF-beta1 prevented A beta-induced cell cycle reactivation, whereas lately added TGF-beta1 had no effect on the cell cycle, but rescued the late beta-catenin degradation and tau hyperphosphorylation. The phosphatidylinositol-3-kinase (PI-3-K) inhibitor, LY294402, abrogated all effects. Thus, TGF-beta1 blocks the whole cascade of events leading to A beta neurotoxicity by activating the PI-3-K pathway.
Caraci
Filippo
F
Department of Pharmaceutical Sciences, University of Catania, 95125, Catania, Italy. carafil@hotmail.com
Battaglia
Giuseppe
G
Busceti
Carla
C
Biagioni
Francesca
F
Mastroiacovo
Federica
F
Bosco
Paolo
P
Drago
Filippo
F
Nicoletti
Ferdinando
F
Sortino
Maria Angela
MA
Copani
Agata
A
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D053773:Transforming Growth Factor beta1 / Q000008:administration & dosage / Q000502:physiology*
D016229:Amyloid beta-Peptides; D002867:Chromones; D009025:Morpholines; D018696:Neuroprotective Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D053773:Transforming Growth Factor beta1; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one