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Review
. 2020 Aug 26:11:1588.
doi: 10.3389/fimmu.2020.01588. eCollection 2020.

Role of Toll Like Receptor 4 in Alzheimer's Disease

Maria Calvo-Rodriguez  1 , Carmen García-Rodríguez  2 , Carlos Villalobos  2 , Lucía Núñez  2   3
Affiliations
Review

Role of Toll Like Receptor 4 in Alzheimer's Disease

Maria Calvo-Rodriguez et al. Front Immunol. .

Abstract

Long-term evidence has confirmed the involvement of an inflammatory component in neurodegenerative disorders including Alzheimer's disease (AD). This view is supported, in part, by data suggesting that selected non-steroidal anti-inflammatory drugs (NSAIDs) provide protection. Additionally, molecular players of the innate immune system have recently been proposed to contribute to these diseases. Toll-like receptors (TLRs) are transmembrane pattern-recognition receptors of the innate immune system that recognize different pathogen-derived and tissue damage-related ligands. TLR4 mediated signaling has been reported to contribute to the pathogenesis of age-related neurodegenerative diseases, including AD. Although the pathophysiology of AD is not clear, soluble aggregates (oligomers) of the amyloid β peptide (Aβo) have been proven to be key players in the pathology of AD. Among others, Aβo promote Ca2+ entry and mitochondrial Ca2+ overload leading to cell death in neurons. TLR4 has recently been found to be involved in AD but the mechanisms are unclear. Our group recently reported that lipopolysaccharide (LPS), a TLR4 receptor agonist, increases cytosolic Ca2+ concentration leading to apoptosis. Strikingly, this effect was only observed in long-term cultured primary neurons considered a model of aging neurons, but not in short-term cultured neurons resembling young neurons. These effects were significantly prevented by pharmacological blockade of TLR4 receptor signaling. Moreover, TLR4 expression in rat hippocampal neurons increased significantly in aged neurons in vitro. Therefore, molecular patterns associated with infection and/or brain cell damage may activate TLR4 and Ca2+ signaling, an effect exacerbated during neuronal aging. Here, we briefly review the data regarding the involvement of TLR4 in AD.

Keywords: Alzheimer’s disease; TLR4; aging; amyloid beta oligomers; calcium; hippocampal neurons.

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Figures

FIGURE 1
FIGURE 1
Effects of aging and amyloid oligomers on TLR4 induced Ca2+ signaling and death in rat hippocampal neurons aged in vitro. Short-term cultures of rat hippocampal neurons, resembling young neurons, display low expression of TLR4, and the TLR4 agonist LPS has no effect on cytosolic Ca2+ concentration or cell death. However, long-term cultured neurons resembling aged neurons display enhanced TLR4 expression, increased Ca2+ responses to LPS, and neuronal cell death. All three of these effects are exacerbated in aged neurons treated with amyloid β oligomers involved in Alzheimer’s disease, suggesting a crosstalk between TLR4 and amyloid β-induced Ca2+ signaling pathways.
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