Transforming growth factor-β stimulates β amyloid uptake by microglia through Smad3-dependent mechanisms.
Inflammatory cytokines and β amyloid (Aβ) induce activation of glial cells, leading to both protective and deleterious changes that are relevant for the pathogenesis of Alzheimer disease (AD). We have shown that astrocytes downregulate microglial cell cytotoxic activation through secretion of transforming growth factor-β (TGFβ1), and there is evidence that TGFβ1 modifies Aβ removal through the modulation of microglia. However, inflammatory activation of microglia is increased and Aβ clearance is reduced in AD patients, regardless of the fact that TGFβ1 is increased in their nervous system. We propose that changes in TGFβ Smad3 signal transduction could modify the regulation mediated by TGFβ1. Here we evaluated the participation of the TGFβ Smad3 pathway in regulation of the expression pattern of scavenger receptors (SR) and activation of microglia through nitric oxide (NO·) secretion and phagocytosis of Aβ. We found that TGFβ1 increased SR-A by 2.4-fold and decreased SR-BI expression by 79% at 48 hr, whereas it did not change SR-MARCO or CD36 expression. In addition, we observed a 51% increase of Aβ uptake and an 83% decrease of NO· production induced by lipopolysaccharide in microglial cell cultures. Increased expression of SR-A, phagocytosis, and downregulation of NO· by TGFβ1 were prevented by the inhibition of the TGFβ Smad3 pathway. Our results indicate that the modulation of microglial cell activation by TGFβ1, leading to increased clearance of Aβ and reduced cytotoxicity, is at least partially mediated by the Smad pathway.
Department of Neurology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
Juan E
JE
Tichauer
Rommy
R
von Bernhardi
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D005609:Free Radicals / Q000378:metabolism; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D007150:Immunohistochemistry; D017628:Microglia / Q000187:drug effects / Q000378:metabolism*; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D010957:Plasmids / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D051116:Receptors, Scavenger / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*; D014404:Tubulin / Q000378:metabolism
D016229:Amyloid beta-Peptides; D005609:Free Radicals; D051116:Receptors, Scavenger; D051900:Smad3 Protein; C497787:Smad3 protein, rat; D053773:Transforming Growth Factor beta1; D014404:Tubulin; D009569:Nitric Oxide; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases