Neuronal TIMP-1 release accompanies astrocytic MMP-9 secretion and enhances astrocyte proliferation induced by beta-amyloid 25-35 fragment.
Academic Article
Overview
abstract
The neuropathology of Alzheimer's disease (AD) is accompanied by an inflammatory response that includes neurodegeneration and glial reactivity. Tissue remodeling proteins, such as matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs), are inflammatory mediators that might play a dual role in the AD brain. We aimed to investigate the effects of beta-amyloid (Abeta) on the MMP-9/TIMP-1 balance and its involvement in Abeta toxicity in neurons and glial cells. Our results demonstrate that the neurotoxic 25-35 Abeta fragment induces the activation of MMP-9 and the increase of proMMP-2/9 secretion and promotes the release of TIMP-1 in a mixed cortical neuroglial culture. The same treatments performed in pure neuronal or astrocytic cultures confirm that astroglial cells are the major source of MMP-9, whereas increased TIMP-1 levels have a neuronal origin. Moreover, 25-35 Abeta fragment not only induced a release of these molecules but also caused expressional changes in MMP-9 and TIMP-1, correlated with the neurotoxicity process. We also show that TIMP-1 promoted cell proliferation in a mixed neuroglial culture, and we confirm this effect in primary cultured astrocytes induced by rTIMP-1 and 25-35 Abeta. Because the proliferative effect caused by Abeta 25-35 was enhanced by the presence of TIMP-1, we suggest that the astroglial reactivity induced by chronic exposure of the peptide might be mediated in part by TIMP-1, which is secreted mainly by injured neurons. In conclusion, our data suggest that the Abeta 25-35 fragment stimulates the MMP-9-TIMP-1 pathway, promoting gliosis, in a self-defensive attempt to eliminate amyloid deposition from AD brains.
