Role of the Toll-Like Receptor 4 in Neuroinflammation in Alzheimer’s Disease

Abstract

Microglial activation is a key feature in Alzheimer’s disease and is considered to contribute to progressive neuronal injury by release of neurotoxic products. The innate immune receptor Toll-like-receptor 4 (TLR4), localized on the surface of microglia, is a first-line host defense receptor against invading microorganisms. Here, we show that a spontaneous loss-of-function mutation in the Tlr4 gene strongly inhibits microglial and monocytic activation by aggregated Alzheimer amyloid peptide resulting in a significantly lower release of the inflammatory products IL-6, TNFα and nitric oxide. Treatment of primary murine neuronal cells with supernatant of amyloid peptide-stimulated microglia demonstrates that Tlr4 contributes to amyloid peptide-induced microglial neurotoxicity. In addition, stimulation experiments in transfected HEK293 cells allowed to define a tri-molecular receptor complex consisting of TLR4, MD-2 and CD14 necessary for full cellular activation by aggregated amyloid peptide. A clinical relevance of these findings is supported by a marked upregulation of Tlr4 mRNA in APP transgenic mice and by an increased expression of TLR4 in Alzheimer’s disease brain tissue associated with amyloid plaque deposition. Together, these observations provide the first evidence for a role of the key innate immune receptor, TLR4, in neuroinflammation in Alzheimer’s disease.

Evaluating the role of Toll-like receptors in diseases of the central nervous system

“…For example animal models of AD and patients with AD exhibit increased expression of CD14, (a co-receptor for TLR4), TLR4 and TLR2 [33][34][35][36], which are thought to occur independently in response to the presence of Aβ. Interestingly a polymorphism in TLR4 Asp299Gly resulted in a 2.7 fold reduction in risk for late onset AD [37].…”

Shock Wave Treatment Protects From Neuronal Degeneration via a Toll‐Like Receptor 3 Dependent Mechanism: Implications of a First‐Ever Causal Treatment for Ischemic Spinal Cord Injury

“…It is well described that TLR4 is involved in neurodegeneration 12, 14. It was also found that TLR4‐dependent microglial activation mediates spinal cord ischemia–reperfusion injury 11.…”

“…TLR3 also causes downregulation of TLR4 17. TLR4 has been shown to trigger neuronal degeneration and to be involved in several kinds of neurological disorders 12, 14, 15. TLR3 activation with the synthetic RNA analogue poly(I:C) and simultaneous TLR4 downregulation have been described as protective against ischemia– reperfusion injury of the spinal cord 11…”

“…Effects were as strong as in wild types, showing that shock waves are not TLR4 dependent; however, we observed a decrease of TLR4 protein in wild types. TLR4 had been described as being involved in the pathogenesis of several kinds of neurological disorders 14. The main mechanism of action of shock waves in spinal cord ischemia is apparently the same as in ischemic muscle tissue, namely, TLR3 stimulation and subsequent TLR4 downregulation.…”

“…Microglia are spinal resident macrophages and the main cell type in the resting central nervous system that expresses TLR3 and TLR4 12, 13. TLR4 activation has even been shown to trigger neurodegeneration and is thought to be involved in the pathogenesis of several kinds of neurological disorders such as Alzheimer's disease 14. The absence of TLR4 in TLR4‐knockout mice showed neuroprotective effects against focal cerebral ischemia.…”