Dataset Information

The antidiabetic drug troglitazone protects against PrP (106‑126)‑induced neurotoxicity via the PPARγ‑autophagy pathway in neuronal cells.

ABSTRACT: Prion diseases, which involve the alteration of cellular prion protein into a misfolded isoform, disrupt the central nervous systems of humans and animals alike. Prior research has suggested that peroxisome proliferator‑activator receptor (PPAR)γ and autophagy provide some protection against neurodegeneration. PPARs are critical to lipid metabolism regulation and autophagy is one of the main cellular mechanisms by which cell function and homeostasis is maintained. The present study examined the effect of troglitazone, a PPARγ agonist, on autophagy flux in a prion peptide (PrP) (106‑126)‑mediated neurodegeneration model. Western blot analysis confirmed that treatment with troglitazone increased LC3‑II and p62 protein expression, whereas an excessive increase in autophagosomes was verified by transmission electron microscopy. Troglitazone weakened PrP (106‑126)‑mediated neurotoxicity via PPARγ activation and autophagy flux inhibition. A PPARγ antagonist blocked PPARγ activation as well as the neuroprotective effects induced by troglitazone treatment, indicating that PPARγ deactivation impaired troglitazone‑mediated protective effects. In conclusion, the present study demonstrated that troglitazone protected primary neuronal cells against PrP (106‑126)‑induced neuronal cell death by inhibiting autophagic flux and activating PPARγ signals. These results suggested that troglitazone may be a useful therapeutic agent for the treatment of neurodegenerative disorders and prion diseases.

SUBMITTER: Moon JH

PROVIDER: S-EPMC8047904 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Microglial activation is a characteristic feature of the pathogenesis of prion diseases. The molecular mechanisms that underlie prion-induced microglial activation are not very well understood. In the present study, we investigated the role of the class B scavenger receptor CD36 in microglial activation induced by neurotoxic prion protein (PrP) fragment 106-126 (PrP(106-126)). We first examined the time course of CD36 mRNA expression upon exposure to PrP(106-126) in BV2 microglia. We then analyzed different parameters of microglial activation in PrP(106-126)-treated cells in the presence or not of anti-CD36 monoclonal antibody (mAb). The cells were first incubated for 1 h with CD36 monoclonal antibody to block the CD36 receptor, and were then treated with neurotoxic prion peptides PrP(106-126). The results showed that PrP(106-126) treatment led to a rapid yet transitory increase in the mRNA expression of CD36, upregulated mRNA and protein levels of proinflammatory cytokines (IL-1β, IL-6 and TNF-α), increased iNOS expression and nitric oxide (NO) production, stimulated the activation of NF-κB and caspase-1, and elevated Fyn activity. The blockade of CD36 had no effect on PrP(106-126)-stimulated NF-κB activation and TNF-α protein release, abrogated the PrP(106-126)-induced iNOS stimulation, downregulated IL-1β and IL-6 expression at both mRNA and protein levels as well as TNF-α mRNA expression, decreased NO production and Fyn phosphorylation, reduced caspase-1 cleavage induced by moderate PrP(106-126)-treatment, but had no effect on caspase-1 activation after treatment with a high concentration of PrP(106-126). Together, these results suggest that CD36 is involved in PrP(106-126)-induced microglial activation and that the participation of CD36 in the interaction between PrP(106-126) and microglia may be mediated by Src tyrosine kinases. Our findings provide new insights into the mechanisms underlying the activation of microglia by neurotoxic prion peptides and open perspectives for new therapeutic strategies for prion diseases by modulation of CD36 signaling.

Project description:Prion-related encephalopathies are characterized by the intracerebral accumulation of an abnormal isoform of the cellular prion protein (PrPC) named scrapie prion protein (PrPSc). The pathological forms of this protein and its cellular precursor are not only expressed in the brain but also, at lower concentrations, in peripheral tissues. We recently showed that a synthetic peptide corresponding to residues 106-126 [PrP-(106-126)] of the human PrP is toxic to neurons and trophic to astrocytes in vitro. Our experiments were aimed at verifying whether PrP-(106-126) and other peptides corresponding to fragments of the amyloid protein purified from brains of patients with Gerstmann-Sträussler-Scheinker disease-namely PrP-(89-106), PrP-(106-114), PrP-(127-147)-were capable of stimulating circulating leucocytes. Native PrP expression in human lymphocytes, monocytes and neutrophils was first confirmed using PCR amplification of total RNA, after reverse transcription, and immunoblot analysis of cell extracts with anti-PrP antibodies. PrP-(106-126), but not the other peptides, increased membrane microviscosity, intracellular Ca2+ concentration and cell migration in circulating leucocytes, and O2-. production in monocytes and neutrophils. Membrane microviscosity was determined by the fluorescence polarization technique, using diphenylhexatriene as a probe, 300 s after the addition of PrP-(106-126) to the cell suspension in the concentration range 5-50 microM. The increase in intracellular Ca2+ elicited by PrP-(106-126) was dose-dependent in the range 5-500 microM. PrP-(106-126) stimulated O2-. production in monocytes and neutrophils in a dose- (10-300 microM) and time-(5-30 min) dependent manner in the presence of 10 microM dihydrocytochalasin B. Both the increase in Ca2+ concentration and the O2-. production were partially sensitive to pertussis toxin. PrP-(106-126) stimulated leucocyte migration in a dose-dependent (30-300 microM) manner and, at the highest concentration used, this migration was comparable with that elicited by 2.5 nM interleukin 8 or 10 nM fMet-Leu-Phe peptide.

Dataset Information

The antidiabetic drug troglitazone protects against PrP (106‑126)‑induced neurotoxicity via the PPARγ‑autophagy pathway in neuronal cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets