Brain Cells Release Calreticulin That Attracts and Activates Microglia, and Inhibits Amyloid Beta Aggregation and Neurotoxicity

Abstract

Calreticulin is a chaperone, normally found in the endoplasmic reticulum, but can be released by macrophages into the extracellular medium. It is also found in cerebrospinal fluid bound to amyloid beta (Aβ). We investigated whether brain cells release calreticulin, and whether extracellular calreticulin had any effects on microglia and neurons relevant to neuroinflammation and neurodegeneration. We found that microglia release nanomolar levels of calreticulin when inflammatory-activated with lipopolysaccharide, when endoplasmic reticulum stress was induced by tunicamycin, or when cell death was induced by staurosporine, and that neurons release calreticulin when crushed. Addition of nanomolar levels of extracellular calreticulin was found to chemoattract microglia, and activate microglia to release cytokines TNF-α, IL-6 and IL-1β, as well as chemokine (C-C motif) ligand 2. Calreticulin blocked Aβ fibrillization and modified Aβ oligomerization, as measured by thioflavin T fluorescence and transmission electron microscopy. Extracellular calreticulin also altered microglial morphology and proliferation, and prevented Aβ-induced neuronal loss in primary neuron-glial cultures. Thus, calreticulin is released by microglia and neurons, and acts: as an alarmin to recruit and activate microglia, as an extracellular chaperone to prevent Aβ aggregation, and as a neuroprotectant against Aβ neurotoxicity.

Human Breast Milk microRNAs, Potential Players in the Regulation of Nervous System

“…Distinct variations in hub miRNA expression levels or patterns may initiate and/or progress various adult-onset nerve-related diseases [14]. Together with their gene regulation properties, the CLU gene and also CALR and KLK6 but less intensity, codify chaperone proteins implicated in Aβ clearance and α-Syn degradation [95][96][97][98][99][100], it implicates miRNAs to be the key regulators in the complex genetic network of the CNS [13]. Specific miRNAs have versatile functions in both invertebrates and vertebrates during neural development and brain activities.…”

Proteomic analysis of exosomes derived from human mature milk and colostrum of mothers with term, late preterm, or very preterm delivery

“…CALR is a chaperone found in the endoplasmic reticulum, which has been proposed as one of the major storage depots of releasable Ca 2+ . This protein in the brain is acting as a phagocytic signal to macrophages and microglia, [41][42][43] which can be a direct cause of neuronal death during inammation and might contribute to neurodegeneration. 44,45 Moreover, CALR is downregulated linked to Alzheimer's disease progression.…”

The Implications of Microglial Regulation in Neuroplasticity-Dependent Stroke Recovery

“…Calreticulin acts as an “eat me” signal or opsonin to trigger phagocytosis through low-density lipoprotein receptor-associated protein (LRP) on the surface of microglia [ 181 , 188 ]. The addition of nanomolar calreticulin could result in attraction of microglia, stimulation of microglia to release pro-inflammatory factors, alteration of microglial morphology and proliferation, and promotion of phagocytosis [ 188 , 221 ]. LPS-induced microglial phagocytosis can be inhibited by calreticulin or microglial surface LRP1 receptor blocker [ 222 ].…”