Muramyl dipeptide promotes Aβ1-42 oligomer production via the nod2/p-p38 mapk/bace1 signaling pathway in the sh-sy5y cells

Abstract

The relationship between chronic bacterial colonization in the brain and Alzheimer's disease is attracting extensive attention. Recent studies indicated that the components of bacterial biofilm drive the amyloid-β production. Muramyl dipeptide, the minimal bioactive peptidoglycan motif common to all bacteria, contributes to the development of many central inflammatory and neurodegenerative disorders. However, the involvement of Muramyl dipeptide in amyloid-β production is not completely defined. In our present study, wild type mice received an intracerebroventricular injection of normal saline or Muramyl dipeptide. Data showed that the production of Aβ1-42 oligomers was significantly increased after Muramyl dipeptide injection in the wild type mice or incubation of the SH-SY5Y cells with Muramyl dipeptide. Moreover, the action of Muramyl dipeptide was dose-and timedependent. The above results suggested a possibility that the Muramyl dipeptide -induced Aβ1-42 oligomer production might be related to the NOD2/p-p38 MAPK/BACE1 pathway. To confirm this, the SH-SY5Y cells were transfected with siRNA NOD2. Data showed that the transfected SH-SY5Y cells exhibited decreased expression of Aβ1-42 oligomer, NOD2, p-p38 MAPK, and BACE1 after treatment with Muramyl dipeptide. Finally, SH-SY5Y cells were pretreated with SB203580, an inhibitor of the p-38-MAPK pathway. The results indicated that these pretreated SH-SY5Y cells exhibited decreased expression of Aβ1-42 oligomer, p-p38 MAPK, and BACE1 after treatment with Muramyl dipeptide. In conclusion, these results suggested that Muramyl dipeptide was the trigger factor for Aβ1-42 oligomer production, which probably acts via the NOD2/p-p38 MAPK/BACE1 signaling pathway.

Genes associated with amyloid-beta-induced inflammasome-mediated neuronal death identified using functional gene trap mutagenesis approach

“…showed that MDP at 10 µg/ml induced the upregulation of phosphorylated-p38 mitogenactivated protein kinase (MAPK; Chen et al, 2020). In neurons, the MAPK signalling pathway plays an important role in the regulation of NLRP1 inflammasome expression and activation (Fann et al, 2018).…”

“…MDP (InvivoGen, USA) was prepared as a 10 mg/mL stock in endotoxin-free water. When used in experiments, the MDP was diluted to 100 µg/mL with serum-free media before further diluted in the samples to a final working concentration of 10 µg/mL (Chen et al, 2020).…”

Neuroprotection of Food Bioactives in Neurodegenerative Diseases: Role of the Gut Microbiota and Innate Immune Receptors

“…In turn, MDP promotes inflammatory cell infiltration in the CNS, destroys the neurovascular integrity, down-regulates cognitionrelated receptors, exacerbates the production of Aβ, and eventually contributes to neuronal damage and memory impairment. 39,40 Nod1 and Nod2 have synergistic functions in the detection of bacteria and in the inflammatory response. Early research revealed that Nod1 and Nod2 induced the activation of the NF-κB and MAPKs following recognition of bacterial components, resulting in proinflammatory cytokine and chemokine secretion.…”

“…The higher expression of Nod2 agitated by MDP (the muropeptide ligand of Nod2) stimulates a cascade of reactions, such as the inflammatory response and ROS. In turn, MDP promotes inflammatory cell infiltration in the CNS, destroys the neurovascular integrity, down-regulates cognition-related receptors, exacerbates the production of Aβ, and eventually contributes to neuronal damage and memory impairment. , …”

Investigating the Therapeutic Effects of Novel Compounds Targeting Inflammasome and IL-1β and IL-6 Signaling Pathways in Spinocerebellar Ataxia Type 3

“…To clarify the in ammatory priming role of IL-1β and IL-6 in BV-2 conditioned medium, IL-1β in 8 pg/mL or IL-6 in 10 µg/mL was added to ATXN3/Q 75 -GFP-expressing SH-SY5Y cells to mimic the concentration of IL-1β or IL-6 in BV-2 conditioned medium added to SH-SY5Y cells. MDP, a NLRP1 agonist upregulating Aβ-associated in ammation in the SH-SY5Y cells [29], was also included for comparison. After induction of ATXN3/Q 75 -GFP expression in SH-SY5Y cells for 6 days, the culture medium was removed and replaced with new cultural medium/conditioned medium (± LPS/IFN-γ stimulation, 2:1 ratio), MDP (0.1 µg/mL), IL-1β (8 pg/mL) or IL-6 (10 µg/mL), and further incubated for 48 h (Fig.…”