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Abstract
Available evidence shows that human cortical neurons’ and astrocytes’ calcium-sensing receptors (CaSRs) bind Amyloid-beta (Aβ) oligomers triggering the overproduction/oversecretion of several Alzheimer’s disease (AD) neurotoxins—effects calcilytics suppress. We asked whether Aβ•CaSR signaling might also play a direct pro-neuroinflammatory role in AD. Cortical nontumorigenic adult human astrocytes (NAHAs) in vitro were untreated (controls) or treated with Aβ25–35 ± NPS 2143 (a calcilytic) and any proinflammatory agent in their protein lysates and growth media assayed via antibody arrays, enzyme-linked immunosorbent assays (ELISAs), and immunoblots. Results show Aβ•CaSR signaling upregulated the synthesis and release/shedding of proinflammatory interleukin (IL)-6, intercellular adhesion molecule-1 (ICAM-1) (holoprotein and soluble [s] fragment), Regulated upon Activation, normal T cell Expressed and presumably Secreted (RANTES), and monocyte chemotactic protein (MCP)-2. Adding NPS 2143 (i) totally suppressed IL-6′s oversecretion while remarkably reducing the other agents’ over-release; and (ii) more effectively than Aβ alone increased over controls the four agents’ distinctive intracellular accumulation. Conversely, NPS 2143 did not alter Aβ-induced surges in IL-1β, IL-3, IL-8, and IL-16 secretion, consequently revealing their Aβ•CaSR signaling-independence. Finally, Aβ25–35 ± NPS 2143 treatments left unchanged MCP-1′s and TIMP-2′s basal expression. Thus, NAHAs Aβ•CaSR signaling drove four proinflammatory agents’ over-release that NPS 2143 curtailed. Therefore, calcilytics would also abate NAHAs’ Aβ•CaSR signaling direct impact on AD’s neuroinflammation.
Highlights
Alzheimer’s disease (AD) is the world’s most prevalent form of dementia [1]
These findings revealed for the first time that the AD-typical chronic neuroinflammation can be advanced by the nontumorigenic adult human astrocytes (NAHAs)’ AβCaSR signaling-elicited secretion of proinflammatory cytokine IL-6, chemokines RANTES and monocyte chemotactic protein (MCP)-2, and of the s-intercellular adhesion molecule-1 (ICAM-1) fragment
The present findings show that AβCaSR signaling strongly increases both the synthesis and off or remarkably mitigates
Summary
The main AD’s neuropathology hallmarks are amyloid-β (Aβ) senile plaques, hyperphosphorylated. Tau (hp-Tau) protein neurofibrillary tangles (NFTs), and a chronic diffuse neuroinflammation due to activated innate immune pathways in glial cells [2,3]. Cells 2020, 9, 1386 and oligodendrocytes, which eventually causes the patients’ memory loss, cognitive decline, and ultimate demise [4,5]. The mainstream research focused on the pathogenetic roles played by Aβ peptides (Aβs) and hp-Tau proteins, the two main AD drivers [4,5]. AD’s neuroinflammation mechanisms have been attracting increasing attention [2,3]. Some authors posit that the induced reactive astrogliosis plays a prominent role in AD’s neuroinflammation [6]. Astrocytes are the most abundant brain cell type
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