Background: There is currently no strong evidence for a linkage between glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Alzheimer disease (AD). Results: GAPDH aggregates enhanced amyloid- peptide (A) amyloidogenesis and augmented A40-induced neurotoxicity, both in vitro and in vivo, concomitant with mitochondrial dysfunction. Conclusion: GAPDH aggregates accelerate A amyloidogenesis. Significance: A amyloidogenesis associated with GAPDH aggregation might underlie AD pathogenesis.
Botulinum neurotoxin type A
(BoNT/A) cleaves SNAP-25 and interrupts the release of acetylcholine. We previously
reported that BoNT/A subtype 2 (BoNT/A2) ameliorates pathologic behavior more effectively
than subtype 1 (BoNT/A1) in a rat Parkinson’s disease model. Here, we further show BoNT/A2
has fewer adverse effects than BoNT/A1. We first confirmed that intrastriatal treatments
of both BoNT/As had no-effect on dopaminergic terminals in the striatum. SNAP-25 cleaved
by BoNT/A2 was strictly localized to the striatum on the injected side; however, SNAP-25
cleaved by BoNT/A1 diffused contralaterally. Furthermore, treatment with BoNT/A1 caused a
significant reduction in body weight, while BoNT/A2 treatment did not. These results
suggest that BoNT/A2 is more beneficial for clinical application against Parkinson’s
disease than BoNT/A1.
The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has multiple functions, including mediating oxidative stress-induced neuronal cell death. This process is associated with disulfide-bonded GAPDH aggregation. Some reports suggest a link between GAPDH and the pathogenesis of several oxidative stress-related diseases. However, the pathological significance of GAPDH aggregation in disease pathogenesis remains unclear due to the lack of an effective GAPDH aggregation inhibitor. In this study, we identified a GAPDH aggregation inhibitor (GAI) peptide and evaluated its biological profile. The decapeptide GAI specifically inhibited GAPDH aggregation in a concentration-dependent manner. Additionally, the GAI peptide did not affect GAPDH glycolytic activity or cell viability. The GAI peptide also exerted a protective effect against oxidative stress-induced cell death in SH-SY5Y cells. This peptide could potentially serve as a tool to investigate GAPDH aggregation-related neurodegenerative and neuropsychiatric disorders and as a possible therapy for diseases associated with oxidative stress-induced cell death.
ABSTRACT. Macrophages are essential for controlling the majority of infections, and are mediators of natural immunity. During infection, lipopolysaccharide (LPS) stimulates macrophages to produce pro-inflammatory cytokines. Adenosine and ATP released into the extracellular space by immunological stimuli have been shown to regulate various immune functions. More recently, it has been shown adenosine and ATP have a critical role on the physiological negative feedback mechanism for limitation and termination of tissue-specific and systemic inflammatory responses. It was useful and meaningful to gain information about interaction between LPS, which generates the inflammation, and adenosine and ATP, which terminate the inflammation. We evaluate effects of adenosine and ATP on the production of cytokines related to inflammation in canine macrophage cell line DH82 cells. Adenosine and ATP respectively increased the production of IL-10 without affecting the production of IL-6, TNF- and IL-12 in DH82 cells. In addition, adenosine and ATP prevented the production of LPS-induced IL-6, TNF- and IL-12 in DH82 cells. In contrast, adenosine and ATP potentiated LPS-induced IL-10 production in DH82 cells. Moreover, adenosine, but not ATP inhibited LPS-induced expression of TLR4 in DH82 cells. These results suggest that conditions related to increased adenosine and/or ATP may play an important role in the inflammatory reactions.
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