Abstract
Deposits of amyloid β-protein (Aβ) in neuritic plaques and cerebral vessels are a pathological hallmark of Alzheimer's disease. Fibrillar Aβ 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 Aβ 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 Aβ 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/Tlr Lps-d) had increases in diffuse and fibrillar Aβ deposits by immunocytochemistry, fibrillar Aβ deposits by thioflavine-S staining and buffer-soluble and insoluble Aβ 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 (Tlr Lps-d/θ) 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 Aβ 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 Aβ in vitro. These results suggest that TLR signalling pathway(s) may be involved in clearance of Aβ-deposits in the brain and that TLRs can be a therapeutic target for Alzheimer's disease.
Original language | English (US) |
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Pages (from-to) | 3006-3019 |
Number of pages | 14 |
Journal | Brain |
Volume | 129 |
Issue number | 11 |
DOIs | |
State | Published - Nov 2006 |
Bibliographical note
Funding Information:We thank Drs David Borchelt and Joanna Jankowsky for providing the Mo/Hu APPswe PS1dE9 mice and Karen Minter for her help with preparing this manuscript. This study was supported in part by the National Institutes of Health grants to K.F. (NS43947) and to L.L. (AG025949) and the Alzheimer’s Association grant to K.F. (ZEN-03-5834).
Keywords
- Alzheimer's disease
- Amyloid
- Microglia
- Toll-like receptors
- Transgenic mouse