Destabilization of plasma and inner mitochondrial membranes by extra-and intracellular amyloid β peptide (Aβ42) aggregates may lead to dysregulated calcium flux through the plasma membrane, mitochondrial-mediated apoptosis, and neuronal cell death in patients with Alzheimer's disease. In the current study, experiments performed with artificial membranes, isolated mitochondria, and neuronal cells allowed us to understand the mechanism by which a nonaggregating Aβ42 double mutant (designated Aβ42 DM ) exerts its neuroprotective effects. Specifically, we showed that Aβ42 DM protected neuronal cells from Aβ42induced accumulation of toxic intracellular levels of calcium and from apoptosis. Aβ42 DM also inhibited Aβ42-induced mitochondrial membrane potential depolarization in the cells and abolished the Aβ42-mediated decrease in cytochrome c oxidase activity in purified mitochondrial particles. These results can be explained in terms of the amelioration by Aβ42 DM of Aβ42-mediated changes in membrane fluidity in DOPC and cardiolipin/DOPC phospholipid vesicles, mimicking plasma and mitochondrial membranes, respectively. These observations are also in agreement with the inhibition by Aβ42 DM of phospholipid-induced conformational changes in Aβ42 and with the fact that, unlike Aβ42, the Aβ42− Aβ42 DM complex could not permeate into cells but instead remained attached to the cell membrane. Although most of the Aβ42 DM molecules were localized on the cell membrane, some penetrated into the cytosol in an Aβ42-independent process, and, unlike Aβ42, did not form intracellular inclusion bodies. Overall, we provide a mechanistic explanation for the inhibitory activity of Aβ42 DM against Aβ42-induced membrane permeability and cell toxicity and provide confirmatory evidence for its protective function in neuronal cells.

Although various fluorescent‐based nanoparticles are treated as cellular imaging probes, approaching the construction of a biocompatible subcellular imaging probe is challenging. At the same time, the recognition of wasted pharmaceutical drugs by some fluorescent nanoprobes is important and urgently required. We report a “structural memory” concept for simple one‐pot synthesis of bright green fluorescent (quantum yield of up to 61%) carbon dots (C‐dots) from triphenylphosphonium (TPP) as a carbon precursor that will simultaneously act as an effective vehicle for mitochondria labeling in cancer cells and as a selective tetracycline sensor. The ubiquitous TPP residues upon the C‐dots’ surface easily recognize the cellular mitochondria. Tetracycline has been selectively and instantaneously detected through rapid fluorescence on‐off response from C‐dots where other drugs remained silent in nature, even after longer incubation. This quenching response is ascribed to the static quenching effect and position of functional groups of the targeted drug which can play a dominating role. The reason for strong fluorescence exhibition from C‐dots has been well explained by considering different factors. Such types of C‐dots have been shown to be universal mitochondria‐targeting nanoprobes, non‐cytotoxic, and effective as a tetracycline detector. This finding should open a new avenue for in‐vivo therapeutic application and sensing of pharmaceutical drugs in real clinical applications.

Carbon dots prepared from tyrosine and citric acid inhibit fibrillation, membrane interactions and toxicity of hIAPP.

Reactive aldehydes generated in cells and tissues are associated with adverse physiological effects. Dihydroxyphenylacetaldehyde (DOPAL), the biogenic aldehyde enzymatically produced from dopamine, is cytotoxic, generates reactive oxygen species, and triggers...

No abstract

It is currently believed that molecular agents that specifically bind to and neutralize the toxic proteins/peptides, amyloid β (Aβ42), tau, and the tau-derived peptide PHF6, hold the key to attenuating the progression of Alzheimer's disease (AD). We thus tested our previously developed nonaggregating Aβ42 double mutant (Aβ42 DM ) as a multispecific binder for three ADassociated molecules, wild-type Aβ42, the tau K174Q mutant, and a synthetic PHF6 peptide. Aβ42 DM acted as a functional inhibitor of these molecules in in vitro assays and in neuronal cell-based models of AD. The double mutant bound both cytotoxic tau K174Q and synthetic PHF6 and protected neuronal cells from the accumulation of tau in cell lysates and mitochondria. Aβ42 DM also reduced toxic intracellular levels of calcium and the overall cell toxicity induced by overexpressed tau, synthetic PHF6, Aβ42, or a combination of PHF6and Aβ42. Aβ42 DM inhibited PHF6-induced overall mitochondrial dysfunction: In particular, Aβ42 DM inhibited PHF6-induced damage to submitochondrial particles (SMPs) and suppressed PHF6-induced elevation of the ζ-potential of inverted SMPs (proxy for the inner mitochondrial membrane, IMM). PHF6 reduced the lipid fluidity of cardiolipin/DOPC vesicles (that mimic the IMM) but not DOPC (which mimics the outer mitochondrial membrane), and this effect was inhibited by Aβ42 DM . This inhibition may be explained by the conformational changes in PHF6 induced by Aβ42 DM in solution and in membrane mimetics. On this basis, the paper presents a mechanistic explanation for the inhibitory activity of Aβ42 DM against Aβ42-and tauinduced membrane permeability and cell toxicity and provides confirmatory evidence for its protective function in neuronal cells.