Brain Advance Access originally published online on September 19, 2006
Brain 2006 129(11):3006-3019; doi:10.1093/brain/awl249
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Role of toll-like receptor signalling in Aß uptake and clearance
1 Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria Peoria, IL 2 Department of Medicine, Schools of Medicine, University of Alabama at Birmingham Birmingham, AL, USA
Correspondence to: Ken-ichiro Fukuchi, MD, PhD, Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, PO Box 1649, Peoria, IL 61656, USA E-mail: kfukuchi{at}uicomp.uic.edu
Deposits of amyloid ß-protein (Aß) in neuritic plaques and cerebral vessels are a pathological hallmark of Alzheimer's disease. Fibrillar Aß deposits are closely associated with inflammatory responses such as activated microglia in brain with this disease. Increasing lines of evidence support the hypothesis that activated microglia, innate immune cells in the CNS, play a pivotal role in the progression of the disease: either clearing Aß deposits by phagocytic activity or releasing cytotoxic substances and pro-inflammatory cytokines. Toll-like receptors (TLRs) are a family of pattern-recognition receptors in the innate immune system. Exogenous and endogenous TLR ligands activate microglia. To investigate the role of TLR4 in the amyloidogenesis in vivo, we determined the amounts of cerebral Aß in Alzheimer's disease mouse models with different genotypes of TLR4 using three distinct methods. We show that mouse models (Mo/Hu APPswe PS1dE9 mice) homozygous for a destructive mutation of TLR4 (TlrLps-d/TlrLps-d) had increases in diffuse and fibrillar Aß deposits by immunocytochemistry, fibrillar Aß deposits by thioflavine-S staining and buffer-soluble and insoluble Aß by ELISA in the cerebrum, as compared with TLR4 wild-type mouse models. Although the differences in these parameters were less significant, mouse models heterozygous for the mutation (TlrLps-d/
) showed co-dominant phenotypes. Consistent with these observations in vivo, cultured microglia derived from TlrLps-d/TlrLps-d mice failed to show an increase in Aß uptake after stimulation with a TLR4 ligand but not with a TLR9 ligand in vitro. Furthermore, activation of microglia (BV-2 cell) with a TLR2, TLR4 or TLR9 ligand, markedly boosted ingestion of Aß in vitro. These results suggest that TLR signalling pathway(s) may be involved in clearance of Aß-deposits in the brain and that TLRs can be a therapeutic target for Alzheimer's disease.
Key Words: Alzheimer's disease; amyloid; toll-like receptors; microglia; transgenic mouse
Abbreviations: Aß, amyloid ß-protein; APP, amyloid ß-protein precursor; LPS, lipopolysaccharide; PS1, presenilin 1; PTX, pertussis toxin; TLR, toll-like receptor
Received January 18, 2006. Revised August 10, 2006. Accepted August 11, 2006.
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