Role of toll-like receptor signalling in Abeta uptake and clearance.

Role of toll-like receptor signalling in Abeta uptake and clearance. Research Abstract Details 

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Role of toll-like receptor signalling in Abeta uptake and clearance. Abstract Text:

Kazuki Tahara,Hong-Duck Kim,Jing-Ji Jin,J Adam Maxwell,Ling Li,Ken-ichiro Fukuchi,

Deposits of amyloid beta-protein (Abeta) in neuritic plaques and cerebral vessels are a pathological hallmark of Alzheimer's disease. Fibrillar Abeta 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 Abeta 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 Abeta 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 (Tlr(Lps-d)/Tlr(Lps-d)) had increases in diffuse and fibrillar Abeta deposits by immunocytochemistry, fibrillar Abeta deposits by thioflavine-S staining and buffer-soluble and insoluble Abeta 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)/) showed co-dominant phenotypes. Consistent with these observations in vivo, cultured microglia derived from Tlr(Lps-d)/Tlr(Lps-d) mice failed to show an increase in Abeta 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 Abeta in vitro. These results suggest that TLR signalling pathway(s) may be involved in clearance of Abeta-deposits in the brain and that TLRs can be a therapeutic target for Alzheimer's disease.

Role of toll-like receptor signalling in Abeta uptake and clearance. Publishing Authors By Initials

K Tahara,HD Kim,JJ Jin,JA Maxwell,L Li,K Fukuchi,

For similar proteins: dna-binding proteins: toll-like receptor 9 research abstracts see: proteins: dna-binding proteins: toll-like receptor 9 research

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Role of toll-like receptor signalling in Abeta uptake and clearance. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Brain : a journal of neurology

VOLUME: 129

Page Numbers: 3006-19

Journal Abbreviation: Brain

ISSN: 1460-2156

DAY: 19

MONTH: 09

YEAR: 2006

Role of toll-like receptor signalling in Abeta uptake and clearance. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 372537

Role of toll-like receptor signalling in Abeta uptake and clearance. Keywords Mesh Terms:

KEYWORDS: Toll-Like Receptor 9

MESH TERMS: physiology

Chemical & Substance for Abstract: Role of toll-like receptor signalling in Abeta uptake and clearance. Information

Substance Name: amyloid beta-protein (1-42)

Registry Number: 0

Grant and Affiliation Information for Role of toll-like receptor signalling in Abeta uptake and clearance.

AFFILIATION: Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61656, USA.

Country: England

AGENCY: United States NINDS

GRANT: NS43947

ACRONYM: NS

MEDLINETA: Brain

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