Transforming growth factor-beta1 attenuates microglia-dependent enlargement of amyloid-beta-peptide aggregates and Smad signaling correlation

• Main Authors: Wei-Chao Huang, 黃威超
• Other Authors: Huey-Jen Tsay
• Format: Others
• Language: en_US
• Published: 2008
• Online Access: http://ndltd.ncl.edu.tw/handle/92855685578783741292

碩士 === 國立陽明大學 === 神經科學研究所 === 96 === The accumulation of amyloid-β peptide (Aβ) due to the overproduction and inefficient clearance of A�� leads to the formation of senile plaque of Alzheimer disease (AD) is hypothesized. The long duration and multiple steps involved in the A�� plaques formation remains unclear. The aim of this study is focused on the role of microglia on the accumulation of A�� deposition. Fibrillar and aggregated, but not oligomeric A�� induced the clustering of BV-2 microglia cells without affecting the cell viability. A��-treated microglia migrated in the random-walk pattern with the final destination toward the aggregated A��. A��-stimulated the chemotatic migration of BV-2 enlarged A�� aggregates. Neutralization antibodies of chemokines (CCL2, CCL3, and CCL5) attenuated the A��-induced microglial clustering. Transforming growth factor β1 (TGF-β1), an inflammation modifier, inhibited the A��-induced BV-2 microglia clustering and the enlargement of A�� aggregates. TGF-��1 attenuated the BV-2 chemotatic migration toward A�� aggregates without reducing the migration speed. Antagonist of ALK5, TGF-��1 receptor I, suppressed the inhibitory effect of TGF-��1 on A��-induced BV-2 microglia clustering and Smad phosphorylation. This study suggested that A�� deposition was further enlarged by the clustering microglia and TGF-��1 prevented the enlargement of A�� depositions by reducing the microglial chemotaxis toward A��. It was reported that overexpression of TGF-��1 in AD transgenic mice reduced the A�� burden and activated microglia in the hippocampus. The A�� clearance by microglia was implied. The novel function of microglia revealed in this study has reconciled with the previous result about TGF-��1 by preventing microglia gathering the scattered small A�� aggregates into large A�� deposits. In addition to enhancing microglial degradation of A�� deposition by TGF-��1, the alternative explanation of TGF-��1 function on reducing A�� burden is that TGF-��1 prevents the microglial clustering and consequently avoids the enlargement of the A�� deposits.