Danger-Sensing/Patten Recognition Receptors and Neuroinflammation in Alzheimer's Disease

Abstract

Fibrillar aggregates and soluble oligomers of both Amyloid-β peptides (Aβs) and hyperphosphorylated Tau proteins (p-Tau-es), as well as a chronic neuroinflammation are the main drivers causing progressive neuronal losses and dementia in Alzheimer's disease (AD). However, the underlying pathogenetic mechanisms are still much disputed. Several endogenous neurotoxic ligands, including Aβs, and/or p-Tau-es activate innate immunity-related danger-sensing/pattern recognition receptors (PPRs) thereby advancing AD's neuroinflammation and progression. The major PRR families involved include scavenger, Toll-like, NOD-like, AIM2-like, RIG-like, and CLEC-2 receptors, plus the calcium-sensing receptor (CaSR). This quite intricate picture stresses the need to identify the pathogenetically topmost Aβ-activated PRR, whose signaling would trigger AD's three main drivers and their intra-brain spread. In theory, the candidate might belong to any PRR family. However, results of preclinical studies using in vitro nontumorigenic human cortical neurons and astrocytes and in vivo AD-model animals have started converging on the CaSR as the pathogenetically upmost PRR candidate. In fact, the CaSR binds both Ca²⁺ and Aβs and promotes the spread of both Ca²⁺ dyshomeostasis and AD's three main drivers, causing a progressive neurons' death. Since CaSR's negative allosteric modulators block all these effects, CaSR's candidacy for topmost pathogenetic PRR has assumed a growing therapeutic potential worth clinical testing.

Keywords: Alzheimer’s disease; calcium signaling; danger-sensing receptors; inflammasomes; neuroinflammation; pattern recognition receptors.

Figure 1

Top: A summary representation of the main cell types and proinflammatory factors each of them releases into the extracellular matrix in the course of AD. Neurons, blue. Astrocytes, green. Oligodendrocytes, yellow. Microglia, black. Endothelial cells (ECs), red. Monocytes, colorless. A black arrow indicates the migration of a monocyte into the nervous tissue. Senile plaques, ## Aβs. Most of the abbreviations as in the text. CHM, chemokines. PICs, proinflammatory cytokines. CaSR, calcium-sensing receptor. Bottom: Schematic diagram of the reciprocal interactions between the three main neural cell types involved in Alzheimer-related neuroinflammation. The bidirectional interaction with amyloid senile plaques is also indicated.

Figure 2

A schematic representation of some of the main PRRs and their signaling pathways involved in AD’s neuroinflammation. The cell represented could belong to any neural cell type. Aβs, soluble and/or fibrillar amyloid-β peptides; FPR2, formyl peptide receptor 2; IP3, inositol triphosphate; LT, lethal toxin; ↑, upregulation; ↓, downregulation. For further details and abbreviations see the text.