Toll-Like Receptor 2 Acts as a Natural Innate Immune Receptor to Clear Amyloid β1–42and Delay the Cognitive Decline in a Mouse Model of Alzheimer's Disease
Abstract
Microglia are the immune cells of the brain, they are activated in the brain of Alzheimer's disease (AD) patients and mouse models of AD, and they express the innate immune receptor toll-like receptor 2 (TLR2). The present study investigated role of this receptor in the progression of AD-like pathologies. Here we show that amyloid β (Aβ) stimulates TLR2 expression in a small proportion of microglia. We then generated triple transgenic mice that are deficient in TLR2 from mice that harbor a mutant human presenelin 1 and a chimeric mouse/human amyloid precursor protein (APP) genes. TLR2 deficiency accelerated spatial and contextual memory impairments, which correlated with increased levels of Aβ 1–42 and transforming growth factor β1 in the brain. NMDA receptors 1 and 2A expression levels were also lower in the hippocampus of APP–TLR2−/−mice. Gene therapy in cells of the bone marrow using lentivirus constructs expressing TLR2 rescued the cognitive impairment of APP–TLR2−/−mice. Indeed, lenti-green fluorescent protein/TLR2 treatment had beneficial effects by restoring the memory consolidation process disrupted by TLR2 deficiency in APP mice. These data suggest that TLR2 acts as an endogenous receptor for the clearance of toxic Aβ by bone-marrow-derived immune cells. The cognitive decline is markedly accelerated in a context of TLR2 deficiency. Upregulating this innate immune receptor may then be considered as a potential new powerful therapeutic approach for AD.
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Injection of amyloid into the hippocampus provokes increased TLR2 expression.
“Furthermore, an injection of amyloid into the hippocampus provokes increased TLR2 expression [41].”
From MicroRNA 146a (miR-146a) Is Over-Expressed during Prion Disease and Modulates the Innate Immune Response and the Microglial Activation State (2012) · cites this paper as [41]
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- Authors
- Richard, K. L., Filali, M., Préfontaine, P., & Rivest, S.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2008-05-28
- Volume
- 28
- Issue
- 22
- Pages
- 5784-5793
- ISSN
- 0270-6474
- 1529-2401
- Cited by
- 261
- References
- 10
- Language
- en
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