a11-positive-amyloid-oligomer-preparation-assessment-using-dot

A11-positive &#946;-amyloid Oligomer Preparation and Assessment Using Dot Blotting Analysis

&#946;-amyloid (A&#946;) is a hydrophobic peptide with an intrinsic tendency to self-assemble into aggregates. Among various aggregates, A&#946; oligomer ...

Ningbo University

The oligomer of β-amyloid (Aβ) is considered the main neurotoxin in Alzheimer's disease (AD). Therefore, the inhibition of the formation of Aβ oligomer could be a target for AD therapy. In this study, with the help of the dot blotting assay and transmission electronic microscopy, it was have discovered that 5-hydroxycyclopenicillone, a cyclopentenone recently isolated from a sponge-associated fungus, effectively reduced the formation of Aβ oligomer from Aβ peptide in vitro. Molecular dynamics simulations suggested hydrophobic interactions between 5-hydroxycyclopenicillone and Aβ peptide, which might prevent the conformational transition and oligomerization of Aβ peptide. Moreover, Aβ oligomer pre-incubated with 5-hydroxycyclopenicillone was less toxic when added to neuronal SH-SY5Y cells compared to the normal Aβ oligomer. Although 5-hydroxycyclopenicillone is not bioavailable in the brain in its current form, further modification or encapsulation of this chemical might improve the penetration of 5-hydroxycyclopenicillone into the brain. Based on the current findings and the anti-oxidative stress properties of 5-hydroxycyclopenicillone, it is suggested that 5-hydroxycyclopenicillone may have potential therapeutic efficacy in treating AD.

5-Hydroxycyclopenicillone Inhibits β-Amyloid Oligomerization and Produces Anti-β-Amyloid Neuroprotective Effects In Vitro.

Indirubins are natural occurring alkaloids extracted from indigo dye-containing plants. Indirubins could inhibit various kinases, and might be used to treat chronic myelocytic leukemia, cancer and neurodegenerative disorders. 7-bromoindirubin-3-oxime (7Bio), an indirubin derivative derived from indirubin-3-oxime, possesses inhibitory effects against cyclin-dependent kinase-5 (CDK5) and glycogen synthase kinase-3β (GSK3β), two pharmacological targets of Alzheimer's disease (AD). In this study, we have discovered that 2.3-23.3 μg/kg 7Bio effectively prevented β-amyloid (Aβ) oligomer-induced impairments of spatial cognition and recognition without affecting bodyweight and motor functions in mice. Moreover, 7Bio potently inhibited Aβ oligomer-induced expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Furthermore, 7Bio significantly prevented the decreased expression of synapsin-1 and PSD-95, biomarkers of pre-synaptic and post-synaptic proteins in Aβ oligomer-treated mice. The mean optical density (OD) with hyper-phosphorylated tau (pTau), glial fibrillary acidic protein (GFAP) and CD45 positive staining in the hippocampus of 7Bio-treated mice were significantly decreased compared to those of Aβ oligomer-treated mice. In addition, Western blotting analysis showed that 7Bio attenuated Aβ oligomer-decreased expression of pSer9-GSK3β. Those results suggested that 7Bio could potently inhibit Aβ oligomer-induced neuroinflammation, synaptic impairments, tau hyper-phosphorylation, and activation of astrocytes and microglia, which may contribute to the neuroprotective effects of 7Bio. Based on these findings, we expected that 7Bio might be developed as a novel anti-AD lead compound.

Indirubin Derivative 7-Bromoindirubin-3-Oxime (7Bio) Attenuates Aβ Oligomer-Induced Cognitive Impairments in Mice.

Taxifolin is a potent flavonoid with anti-inflammatory activity. Taxifolin has been reported to decrease the accumulation of β-amyloid (Aβ), and reduce Aβ-induced neurotoxicity. However, the detail molecular mechanism of taxifolin against Aβ-induced neurotoxicity is largely unknown. In this study, we revealed the protective effects and the underlying mechanisms of taxifolin on the impairments of cognitive function and synapse formation induced by soluble Aβ oligomers. Our results showed that taxifolin prevented neuronal cell death in a concentration-dependent manner. The recognition memory in novel object recognition tasks and the spatial memory in Morris water maze tests are significantly lower in the Alzheimer's disease (AD) model mice induced by hippocampal injection of Aβ. Taxifolin treatment prevented the recognitive and spatial memory deficits of the AD mice. 10 mg/kg taxifolin treatment also significantly prevented the decreased expression levels of PSD 95 induced by Aβ. Live cell imaging study showed that 2 h pre-treatment of taxifolin prevented the decrease in the number of filopodium and spine induced by Aβ oligomers. Aβ oligomers significantly increased the production of cytosolic phospholipase A (cPLA), a crucial enzyme of pro-inflammatory mediator, and prostaglandin E (PGE), a neuroinflammatory molecule. Taxifolin significantly reduced the content of cPLA and PGE induced by Aβ both in the primary hippocampal neurons and hippocampal tissues. These results indicated that taxifolin might prevent Aβ oligomer-induced synapse and cognitive impairments through decreasing cPLA and PGE. Our study provided novel insights into the cellular mechanisms for the protective effects of taxifolin on AD.

Taxifolin prevents β-amyloid-induced impairments of synaptic formation and deficits of memory via the inhibition of cytosolic phospholipase A/prostaglandin E content.

Article	Year
5-Hydroxycyclopenicillone Inhibits β-Amyloid Oligomerization and Produces Anti-β-Amyloid Neuroprotective Effects In Vitro. Molecules (Basel, Switzerland)\| PubMed ID: 28974023	2017
Indirubin Derivative 7-Bromoindirubin-3-Oxime (7Bio) Attenuates Aβ Oligomer-Induced Cognitive Impairments in Mice. Frontiers in molecular neuroscience\| PubMed ID: 29234273	2017
Taxifolin prevents β-amyloid-induced impairments of synaptic formation and deficits of memory via the inhibition of cytosolic phospholipase A/prostaglandin E content. Metabolic brain disease\| PubMed ID: 29542038	2018

Shentu Jieyi

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