Regulation of adenosine triphosphate-sensitive potassium channels suppresses the toxic effects of amyloid-beta peptide(25-35)

In this study, we treated PC12 cells with 0-20 μM amyloid-β peptide （25-35） for 24 hours to induce cytotoxicity, and found that 5-20 μM amyloid-β peptide （25-35） decreased PC12 cell viability, but adenosine triphosphate-sensitive potassium channel activator diazoxide suppressed the decrease in PC12 cell viability induced by amyloid-β peptide （25-35）. Diazoxide protected PC12 cells against amyloid-β peptide （25-35）-induced increases in mitochondrial membrane potential and intracellular reactive oxygen species levels. These protective effects were reversed by the selective mitochondrial adenosine triphosphate-sensitive potassium channel blocker 5-hydroxydecanoate. An inducible nitric oxide synthase inhibitor, Nw-nitro-L-arginine, also protected PC12 cells from amyloid-β peptide （25-35）-induced increases in both mitochondrial membrane potential and intracellular reactive oxygen species levels. However, the H202-degrading enzyme catalase could not reverse the amyloid-β peptide （25-35）-induced increase in intracellular reactive oxygen species. A 24-hour exposure to amyloid-13 peptide （25-35） did not result in apoptosis or necrosis, suggesting that the increases in both mitochondrial membrane potential and reactive oxygen species levels preceded cell death. The data suggest that amyloid-β peptide （25-35） cytotoxicity is associated with adenosine triphosphate-sensitive potassium channels and nitric oxide. Regulation of adenosine triphosphate-sensitive potassium channels suppresses PC12 cell cytotoxicity induced by amyloid-β peptide （25-35）.

Amyloid-β depresses excitatory cholinergic synaptic transmission in Drosophila

Objective Decline, disruption, or alterations of nicotinic cholinergic mechanisms contribute to cognitive dysfunctions like Alzheimer＇s disease （AD）. Although amyloid-β （Aβ） aggregation is a pathological hallmark of AD, the mechanisms by which Aβ peptides modulate cholinergic synaptic transmission and memory loss remain obscure. This study was aimed to investigate the potential synaptic modulation by Aβ of the cholinergic synapses between olfactory receptor neurons and projection neurons （PNs） in the olfactory lobe of the fruit fly. Methods Cholinergic spontaneous and miniature excitatory postsynaptic current （mEPSC） were recorded with whole-cell patch clamp from PNs in Drosophila AD models expressing Aβ40, Aβ42, or Aβ42Arc peptides in neural tissue. Results In fly pupae （2 days before eclosion）, overexpression of Aβ42 or Aβ42Arc, but not Aβ40, led to a significant decrease of mEPSC frequency, while overexpression of Aβ40, Aβ42, or Aβ42Arc had no significant effect on mEPSC amplitude. In contrast, Pavlovian olfactory associative learning and lifespan assays showed that both short-term memory and lifespan were decreased in the Drosophila models expressing Aβ40, Aβ42, or Aβ42Arc. Conclusion Both electrophysiological and behavioral results showed an effect of Aβ peptide on cholinergic synaptic transmission and suggest a possible mechanism by which Aβ peptides cause cholinergic neuron degeneration and the consequent memory loss.

Rational design of a ＂sense and treat＂ system to target amyloid aggregates related to AIzheimer＇s disease

The aggregation of amyloid-β peptide （Aβ） is implicated in the pathology of Alzheimer＇s disease （AD）, and Aβ oligomers are considered the most toxic species. Therefore, the detection and clearance of Aβ oligomers are crucial for the theranostic strategies for AD. However, effective methods for the detection of Aβ oligomers are rare, and only few of the oligomer-specific sensors have therapeutic functions as well. Recent studies have demonstrated that the toxicity of Aβ oligomers is related to the number of exposed hydrophobic residues. In this study, an oligomer-specific fluorescent probe, which was based on the hydrophobic regions that are exposed on Aβ oligomer surfaces was designed and synthesized. For improving the ability to recognize Aβ oligomers, the in situ treatment of AD symptoms and the ability to penetrate the blood-brain barrier, the probe and KLVFF peptide （an Aβ-target peptide） were modified on the surfaces of magnetic nanoparticles （MNP@NFP-pep）. This complex could detect Aβ oligomers specifically, and achieve the wireless deep magnetothermally mediated disaggregation of Aβ aggregates with an alternating magnetic field. This work provides new insights into the development of a ＂sense and treat＂ system for AD therapy.

Interaction Between Baicalein and Amyloid-β Fibrils Studied by Fluorescence Spectroscopy

The interaction between baicalein and amyloid-β（Aβ） polypeptide was investigated by fluorescence and UV-Vis absorbance spectroscopy. The absence of the characteristic peak of tyrosinate（Tyr） in the absorption spectra of Afl-baicalein complexes provided evidence that the sole Tyr residue in Aβis not bound to baicalein, but remains close to it. The intrinsic fluorescence of Tyr residues in Aβ1-42 aggregates was quenched strongly by the excited-state ionization of baicalein. In this complex the hydroxyl group was not ionized, but to ionize immediately upon excitation. Absorbance, fluorescence and synchronous spectroscopies show that the formation of Schiff base between the quinone of baicalein and the lysine（Lys） side chains ofAβ1-42 is another major reason in the depolymerization of Aβ1-42 aggregates by baicalein. It is desirable that our research would offer some valuable reference for the application of flavonoid derivants in Alzheimer＇s disease（AD） treatment.