The LPS receptor (CD14) links innate immunity with Alzheimer's disease

Abstract

To rapidly respond to invading microorganisms, humans call on their innate immune system. This occurs by microbe-detecting receptors, such as CD14, that activate immune cells to eliminate the pathogens. Here, we link the lipopolysaccharide receptor CD14 with Alzheimer`s disease, a severe neurodegenerative disease resulting in dementia. We demonstrate that this key innate immunity receptor interacts with fibrils of Alzheimer amyloid peptide. Neutralization with antibodies against CD14 and genetic deficiency for this receptor significantly reduced amyloid peptide induced microglial activation and microglial toxicity. The observation of strongly enhanced microglial expression of the LPS receptor in brains of animal models of Alzheimer's disease indicates a clinical relevance of these findings. These data suggest that CD14 may significantly contribute to the overall neuroinflammatory response to amyloid peptide, highlighting the possibility that the enormous progress currently being made in the field of innate immunity could be extended to research on Alzheimer's disease.

CD14 Protein Acts as an Adaptor Molecule for the Immune Recognition of Salmonella Curli Fibers

“…It is interesting to note that several amyloids with a similar quaternary structure rich in ␤-sheets are also produced in humans, leading to inflammatory responses through the activation of TLRs. In the case of Alzheimer's disease, ␤-amyloid that forms plaques in the brain of the patients elicits nitric oxide and cytokine activation (49,57,76,77). Although various TLRs have been implicated in this inflammatory process, caused by the accumulation of ␤-amyloid (56,57,78), TLR2 has been demonstrated convincingly to recognize the quaternary fibrillar structure of ␤-amyloid as well as curli fibers (46,48).…”

“…Interestingly, blocking CD14 by neutralizing antibodies or genetic deficiency for this molecule on microglia results in reduced levels of immune activation by ␤-amyloid (76). Furthermore, deletion of CD14 attenuates the progression of Alzheimer's disease pathology in the brain in mouse models of Alzheimer's disease (57).…”

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].…”

Deletion of the Prostaglandin E2EP2 Receptor Reduces Oxidative Damage and Amyloid Burden in a Model of Alzheimer's Disease

“…The amyloid hypothesis of AD suggests that dysregulation of amyloid-␤ (A␤) peptide metabolism triggers the innate immune response, in which microglial cells are activated to clear and phagocytose A␤, producing free radical species and neurotoxic cytokines. The CD14-dependent innate immune response to LPS is directly relevant to the immune response to accumulating A␤ peptide, in which microglial activation, phagocytosis, and elaboration of inflammatory mediators are, in part, CD14 dependent (Fassbender et al, 2004;Milatovic et al, 2004). Given that A␤ accumulation can elicit an innate immune response similar to that of LPS, we hypothesized that the EP2 receptor functioned similarly in mediating inflammatory oxidative damage in a transgenic model of familial AD.…”