TGFβ signaling in Glia: Effect of aging on glial activation and Aβ clearance in a murine model of Alzheimer Disease.

von Bernhardi R, Tichauer J.

Neuroscience Laboratory, Neurology Department, Faculty of Medicine, Pontificia Universidad Católica de Chile.

Glial cell activation and neuroinflammation play a key role in Alzheimer’s disease (AD). I propose that glial dysfunction and the resulting imbalance between the cytotoxic inflammatory and neuroprotective-modulator activity is the pathological mechanism behind AD. Such imbalance can be promoted by conditions like hypoxia and chronic inflammation, which are frequently observed in aged individuals. Astrocytes play a major role both promoting damage and mediating neuroprotection. We have shown that astrocytes can modulate microglial cytotoxicity through secretion of TGFβ. However, in AD patients TGFβ levels are increased whereas Smad3, its principal effector, is decreased, suggesting the existence of major changes in inflammatory modulation that could affect the activity of microglia. Here we will discuss changes on TGFβ-Smad3 signaling pathway in aging and in a mice model of AD subjected to pro-inflammatory stimulus and the involvement of TGFβ-Smad3 pathway on scavenger receptor expression and amyloid uptake. Smad3 expression increases in young mice, but not in adult mice exposed to chronic inflammatory stimulus. We found that chronic inflammation increases plaque load in transgenic mice. Under such conditions, there is also an increase of TGFβ levels, and a decrease in pSmad3 levels in the hippocampus; difference that is more evident in AD transgenic mice. TGFβ increases Aβ uptake and modifies the expression pattern of scavenger receptor in microglia, inducing an increase on SRA, and a decrease of SRBI expression. Inhibition of Smad3 results in the inhibition of TGFβ-mediated induction of SRA expression and Aβ uptake. Altogether, we propose that persistent inflammation impairs protective functions of microglia, favoring microglia-mediated neurotoxicity. Induction of Aβ uptake by TGFβ appears to be mediated by SR expression and is mediated, at least partially, on the Smad pathway, being modulated by age and proinflammatory conditions.

Supported by grant FONDECYT 1090353 and grant VRAID-PUENTE 01/08 from the Pontificia Universidad Católica de Chile to RvB.