Comparative study of microglia activation induced by amyloid‐beta and prion peptides: Role in neurodegeneration

Abstract

The inflammatory responses in Alzheimer's disease (AD) and prion-related encephalopathies (PRE) are dominated by microglia activation. Several studies have reported that the amyloid-beta (Abeta) peptides, which are associated with AD, and the pathogenic isoform of prion protein (PrPSc) have a crucial role in neuronal death and gliosis that occur in both of these disorders. In this study, we investigate whether Abeta and PrPSc cause microglia activation per se and whether these amyloidogenic peptides differentially affect these immunoeffector cells. In addition, we also determined whether substances released by Abeta- and PrP-activated microglia induce neuronal death. Cultures of rat brain microglia cells were treated with the synthetic peptides Abeta1-40, Abeta1-42 and PrP106-126 for different time periods. The lipopolysaccharide was used as a positive control of microglia activation. Our results show that Abeta1-40 and PrP106-126 caused similar morphological changes in microglia and increased the production of nitric oxide and hydroperoxides. An increase on inducible nitric oxide synthase expression was also observed in microglia treated with Abeta1-40 or PrP106. However, these peptides affected in a different manner the secretion of interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) secretion. In cocultures of microglia-neurons, it was observed that microglia treated with Abeta1-40 or PrP106-126 induced a comparable extent of neuronal death. The neutralizing antibody for IL-6 significantly reduced the neuronal death induced by Abeta- or PrP-activated microglia. Taken together, the data indicate that Abeta and PrP peptides caused microglia activation and differentially affected cytokine secretion. The IL-6 released by reactive microglia caused neuronal injury.

Metallothionein Treatment Attenuates Microglial Activation and Expression of Neurotoxic Quinolinic Acid Following Traumatic Brain Injury

“…Microglia are known to express some of the same LRP receptors (Laporte et al 2004), which may provide a mechanism facilitating the action of MT upon microglia. Indeed it is well established that betaamyloid is internalised by microglia via interaction with LRP receptors (Laporte et al 2004), and that beta-amyloid induces reactive microglial phenotypes (Floden and Combs 2006;Garção et al 2006). Alternatively, Kauppinen et al (2008) have unexpectedly reported that zinc can directly induce microglial reactivity, and it is well established that extracellular levels of zinc are increased following traumatic brain injury (Choi and Koh 1998).…”

Inhibition of phagocytosis reduced the classical activation of BV2 microglia induced by amyloidogenic fragments of beta-amyloid and prion proteins

“…Experiments were conducted with final peptide concentrations of 5 mM [18]. PrP 106 -126 (KTNMKHMAGAAA AGAVVGGLG) and scramble PrP (Scr, AVGMHAGKG LANTAKAGAMVG) were purchased from Sangon BioTech (Shanghai, China) and dissolved in sterile PBS to a concentration of 1 mM and left to aggregate at 378C for 12 h. The experiments were conducted with final peptide concentrations of 50 mM [18,19].…”

CD36 Participates in PrP106–126-Induced Activation of Microglia

“…Primary microglial cell cultures were obtained from neonatal Wistar rats 5–7 days old, according to the method described by Garcao et al [9]. After sterilization with 75% ethanol for 3–5 min, the brain was dissected and the meninges were carefully removed under a stereomicroscope.…”

“…Mounting evidences also indicate that microglial activation contributes to neuronal damage in several neurodegenerative diseases including Alzheimer's disease, prion diseases, Parkinson's disease, multiple sclerosis, and Huntington's disease [5], [7]. In prion diseases and other neurodegenerative disorders, microglia can become overactivated and release ROS, NO, and cytokines, which might cause vascular damage in addition to neurodegeneration [7], [8], [9], [10]. Pattern recognition receptors expressed on the microglial surface, including Toll-like receptors and scavenger receptors seem to associate physically to form a receptor complex, which is one of the primary, common pathways through which diverse toxin signals are transduced into ROS production in microglia [4], [11].…”