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.
Highlights
Alzheimer’s disease (AD) is a devastating neurodegenerative illness that slowly yet diffusely kills neurons in cognitively critical cerebral cortical areas, eventually inducing the world’s most prevalent form of dementia
The concept generally accepted in recent years is that the interactions between soluble Aβ oligomers (sAβ-os) and a number of multiligand cellular receptors grouped under the denomination of “Pattern Recognition Receptors” (PRRs) may mediate via their intracellular signaling pathways all the noxious effects proper of AD’s neuropathology, including the associated neuroinflammation, involving activated microglia and astrocytes [72] and the other central nervous system (CNS) cell types too
Abundant evidences show that a trio of mutually interacting pathogenetic factors, i.e., oligomers and polymers of Aβ peptides (Aβs) and p-Tau, and a concurrent chronic neuroinflammation drive the progressive development and spreading of human AD
Summary
According to the “Amyloid Hypothesis of AD”, the neuropathology starts within the layer II of the temporal lobe lateral entorhinal allocortex and thence via its neuritic projections spreads out towards cognitively crucial upper neocortical areas [52]. The concept generally accepted in recent years is that the interactions between sAβ-os and a number of multiligand cellular receptors grouped under the denomination of “Pattern Recognition Receptors” (PRRs) may mediate via their intracellular signaling pathways all the noxious effects proper of AD’s neuropathology, including the associated neuroinflammation, involving activated microglia and astrocytes [72] and the other CNS cell types too. RAGE extracellular domain binds several AGEs, including Aβs, S100β proteins, high-mobility group box B1 (HMGB1) protein, heat shock (HS) proteins, and other endogenous danger-associated molecular patterns (DAMPs) that damaged or dying cells release in non-infectious conditions [124,125] (Figure 2) The expression of these various DAMPs increases in course of chronic inflammatory ailments [126]. The infusion of a dominant-negative soluble RAGE form into the same animals decreased the brain’s Aβs load while improving synaptic transmission and learning and memory faculties [152,153]
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