Determination of the Kinetic Constants of the Telomerization of 10‐Undecenol with Alkyl Hydrogenphosphonate

Summary: The telomerization of 10‐undecenol with alkyl hydrogenphosphonate was studied in order to synthesize telomers of different molecular weights. The study showed that telomers from 10‐undecenol could be obtained despite the fact that the double bond has a low reactivity. The kinetic constant Kp²/K_Te was determined to be 7 × 10^?4 l · mol^?1 · s^?1 at 135 °C and the transfer constant C_T was 0.057. These values are normal for a low activity telogen such as hydrogenphosphonate and for slightly reactive monomers like 10‐undecenol.

SEC chromatogram of telomers obtained in the reaction of 10‐undecenol addition.     

Solution‐Processable Donor‐Acceptor‐Donor Oligomers with Cross‐Linkable Functionality

Electron‐acceptor units, combined with bithiophene substituted with flexible chains end‐functionalized with cross‐linkable moieties, provide soluble donor‐acceptor‐donor (DAD) π‐conjugated oligomer‐type molecules with cross‐linking ability and broad absorption in the visible spectrum. A study on the cross‐linking conditions of the new oligomers to yield insoluble polymer networks is presented, including conditions for obtaining polymer films over poly(3,4‐ethylenedioxythiophene):polystyrene sulfonate‐covered substrates. The combination of the DAD molecular design and cross‐linking functionality opens prospects for applications in solution‐processed small‐molecule solar cells with morphologically‐stable organic layers.

     

一种新型混杂多官能团齐聚物的固化反应

以N,N,N′,N′-四缩水甘油基-4,4′-二氨基二苯甲烷(TGDDM)和丙烯酸(AA)为原料,合成了一种既含有环氧基又含有乙烯基酯基团的新型混杂多官能团齐聚物树脂(MEVO)。以过氧化甲乙酮(MEKP)为引发剂、甲基四氢苯酐(MeTHPA)为环氧固化剂与MEVO共混制备了MEVO-MEKP、MEVO-MeTHPA和MEVO-MEKP-MeTHPA 3种固化体系。通过非等温DSC和FT-IR研究了MEVO的固化反应,求得了各体系表观反应活化能。结果表明：在MEVO-MEKP固化体系中,乙烯基酯按照自由基聚合机理固化,对环氧基没有影响;在MEVO-MeTHPA固化体系中,环氧基固化过程中乙烯基酯会发生热固化;在MEVO-MEKP-MeTHPA固化体系中,乙烯基酯和环氧基按各自机理固化并互相影响。     

Age-related impairment of cerebral blood flow response to KATP channel opener in Alzheimer’s disease mice with presenilin-1 mutation

Local cerebral blood flow (CBF) responses to neuronal activity are essential for cognition and impaired CBF responses occur in Alzheimer’s disease (AD). In this study, regional CBF (rCBF) responses to the K_ATP channel opener diazoxide were investigated in 3xTgAD, WT and mutant Presenilin 1(PS1_M146V) mice from three age groups using Laser-Doppler flowmetry. The rCBF response was reduced early in young 3xTgAD mice and almost absent in old 3xTgAD mice, up to 30%–40% reduction with altered CBF velocity and mean arterial pressure versus WT mice. The impaired rCBF response in 3xTgAD mice was associated with progression of AD pathology, characterized by deposition of intracellular and vascular amyloid-β (Aβ) oligomers, senile plaques and tau pathology. The nitric oxide synthase (NOS) inhibitor N^ω-nitro-L-arginine abolished rCBF response to diazoxide suggesting NO was involved in the mediation of vasorelaxation. Levels of phosphor-eNOS (Ser1177) diminished in 3xTgAD brains with age, while the rCBF response to the NO donor sodium nitroprusside remained. In PS1_M146V mice, the rCBF response to dizoxide reduced and high molecular weight Abeta oligomers were increased indicating PS1_M146V contributed to the dysregulation of rCBF response in AD mice. Our study revealed an Aβ oligomer-associated compromise of cerebrovascular function in rCBF response to diazoxide in AD mice with PS1_M146V mutation.     

Crucial role of nonspecific interactions in amyloid nucleation

Protein oligomers have been implicated as toxic agents in a wide range of amyloid-related diseases. However, it has remained unsolved whether the oligomers are a necessary step in the formation of amyloid fibrils or just a dangerous byproduct. Analogously, it has not been resolved if the amyloid nucleation process is a classical one-step nucleation process or a two-step process involving prenucleation clusters. We use coarse-grained computer simulations to study the effect of nonspecific attractions between peptides on the primary nucleation process underlying amyloid fibrillization. We find that, for peptides that do not attract, the classical one-step nucleation mechanism is possible but only at nonphysiologically high peptide concentrations. At low peptide concentrations, which mimic the physiologically relevant regime, attractive interpeptide interactions are essential for fibril formation. Nucleation then inevitably takes place through a two-step mechanism involving prefibrillar oligomers. We show that oligomers not only help peptides meet each other but also, create an environment that facilitates the conversion of monomers into the β-sheet–rich form characteristic of fibrils. Nucleation typically does not proceed through the most prevalent oligomers but through an oligomer size that is only observed in rare fluctuations, which is why such aggregates might be hard to capture experimentally. Finally, we find that the nucleation of amyloid fibrils cannot be described by classical nucleation theory: in the two-step mechanism, the critical nucleus size increases with increases in both concentration and interpeptide interactions, which is in direct contrast with predictions from classical nucleation theory.During the process of amyloid formation, normally soluble proteins assemble into fibrils that are enriched in β-sheet content and have diameters of a few nanometers and lengths up to several micrometers. This phenomenon has been implicated in a variety of pathogenic processes, including Alzheimer’s and Parkinson’s diseases, type 2 diabetes, and systemic amyloidoses (1–3). The association with human diseases has largely motivated a long-standing effort to probe the assembly process, and numerous studies have aimed at elucidating the mechanism of amyloid aggregation (4). The basic nature of the aggregation reaction has emerged as a nucleation and growth process (5, 6), where the aggregates are created through a not well-understood primary nucleation event and can grow by recruiting additional peptides or proteins to their ends (7, 8). In this paper, we focus on the nature of this primary step in amyloid nucleation and the fundamental initial events that underlie amyloid formation.Amyloidogenic peptides and proteins, when in their nonpathological cellular form, can range in the structures from mainly α-helical to β-sheet and even random coil, whereas the amyloid forms of proteins possess a generic cross–β-structure (9–14). The formation of amyloid is, hence, accompanied by marked changes in the conformations of the peptides and proteins that undergo this process. A pertinent question is whether this conformational change takes place simultaneously with the nucleation process or whether nucleation takes place first and is then followed by conformational change. These two possible scenarios of nucleation have been extensively discussed in the experimental and theoretical literature (5, 8, 15–19). We will refer in this work to the two scenarios simply as one-step nucleation (1SN), in which the β-sheet–enriched nucleus forms directly from the solution, and two-step nucleation (2SN), where soluble monomers first assemble into disordered oligomers, which subsequently convert into a β-sheet nucleus. Disordered oligomers, ranging in size between dimers and micrometer-sized particles, have been observed in some experiments (20–28). These findings highlight a central question regarding the role of disordered oligomers in fibril formation: are such clusters a necessary step in the process of fibril formation or just a byproduct?From a biological and biomedical perspective, it is important to understand the conditions under which oligomeric clusters form, because such species exhibit high cytotoxicity (1, 29–31). Indeed, there is strong evidence that the disordered oligomers rather than fully grown fibrils are the main pathogenic species in protein aggregation diseases (31–33). As such, defining the role of the prefibrillar oligomers during amyloid formation will be crucial to develop intervention strategies that target these species (1, 30, 34, 35).Mutations in the polypeptide sequence and extrinsic changes in the experimental conditions are known to alter the concentrations of aggregated species, their size, and their cytotoxicity (25, 36–39). For instance, mutations that increase hydrophobicity of the Alzheimer’s β-peptide (Aβ1–42) have a pronounced effect on its aggregation behavior and the size distribution of the resulting oligomers (23–26, 40), promoting toxicity and expediting the fibrillization process. In the same spirit, two extra hydrophobic residues in Aβ1–42 are believed to contribute to the more pronounced oligomerization and faster fibrillization compared with its alloform Aβ1–40 (24, 25, 40). Temperature, pH, and concentration of certain metals also affect oligomerization and pathways of fibrillization (41–44).The common feature of the above experiments is that they modify the internal free energy difference between the soluble and the β-sheet–forming state, also called the β-sheet propensity, which has been extensively studied in the literature (45–48). However, they also modify interactions between peptides that aggregate, a crucial contribution that has not yet been systematically addressed.In this paper, we study the effect of nonspecific interactions between peptides on the amyloid nucleation process. Such nonspecific interactions do not depend on the atomistic details of the amino acids involved, allowing us to address question about amyloid aggregation and nucleation using a coarse-grained model. In particular, generic hydrophobic stretches in the sequence of Aβ have been shown to be sufficient to promote aggregation (49, 50). Mutations of nonpolar residues to other nonpolar residues had little or no effect on aggregation, whereas mutations that reduce charge and/or increase hydrophobicity enhanced it (50, 51). Furthermore, atomic force microscopy measurements have shown that the strength of overall interactions between amyloidogenic proteins correlates with their tendency to aggregate (52, 53).We have performed extensive computer simulations that allowed us to observe both the 1SN and the 2SN mechanisms. These simulations reveal that 1SN and 2SN can be viewed as two limits of the same process, something that several previous studies have suspected (16, 18). Importantly, we observe that only 2SN is possible at low peptide concentrations, comparable with the levels that are found in vivo. Another key observation is that fibril nucleation typically does not proceed through the most prevalent oligomeric species but rather, through an oligomer with a size that is only observed as a result of rare fluctuations. As a consequence, such oligomers will be hard to capture experimentally, although their presence is required for nucleation to take place. Our simulations show that the free energy barrier for fibril nucleation through the two-step mechanism decreases with increasing strength of the interpeptide interactions. Furthermore, the critical nucleus size in the two-step mechanism is found to grow with the increase in the peptide concentrations as well as with stronger interpeptide interactions, which is in direct contrast with the classical nucleation. These results imply that weakening the nonspecific interactions between peptide monomers in solution and thereby, simultaneously increasing both the free energy barrier for oligomer formation and the free energy barrier for peptide conversion at a given oligomer size may be a crucial step in preventing amyloid aggregation.     

β‐amyloid and ATP‐induced diffusional trapping of astrocyte and neuronal metabotropic glutamate type‐5 receptors

β‐Amyloid (Aβ) oligomers initiate synaptotoxicity following their interaction with the plasma membrane. Several proteins including metabotropic glutamate type 5 receptors (mGluR5s) contribute to this process. We observed an overexpression of mGluR5s in reactive astrocytes surrounding Aβ plaques in brain sections from an Alzheimer's disease mouse model. In a simplified cell culture system, using immunocytochemistry and single molecule imaging, we demonstrated a rapid binding of Aβ oligomers on the plasma membrane of astrocytes. The resulting aggregates of Aβ oligomers led to the diffusional trapping and clustering of mGluR5s. Further, Aβ oligomers induced an increase in ATP release following activation of astroglial mGluR5s by its agonist. ATP slowed mGluR5s diffusion in astrocytes as well as in neurons co‐cultured with astrocytes. This effect, which is purinergic receptor‐dependent, was not observed in pure neuronal cultures. Thus, Aβ oligomer‐ and mGluR5‐dependent ATP release by astrocytes may contribute to the overall deleterious effect of mGluR5s in Alzheimer's disease. GLIA 2013;61:1673–1686     

Lavender and coriander essential oils and their main component linalool exert a protective effect against amyloid‐β neurotoxicity

Alzheimer's disease (AD) is a neurodegenerative disorder leading to cognitive deficits and cognitive decline. Since no cure or preventing therapy is currently available to counteract AD, natural‐derived compounds are investigated to find new potential neuroprotective agents for its treatment. In the present study, we tested the neuroprotective effect of lavender and coriander essential oils (EOs) and their main active constituent linalool, against the neurotoxicity elicited by Aβ_1‐42 oligomers, a key molecular factor in the neurodegeneration of AD. Importantly, our findings on neuronally differentiated PC12 cells exposed to Aβ_1‐42 oligomers are in accordance with previous in vivo studies reporting the neuroprotective potential of lavender and coriander EOs and linalool. We found that lavender and coriander EOs at the concentration of 10 μg/mL as well as linalool at the same concentration were able to improve viability and to reduce nuclear morphological abnormalities in cells treated with Aβ_1‐42 oligomers for 24 hours. Lavender and coriander EOs and linalool also showed to counteract the increase of intracellular reactive oxygen species production and the activation of the pro‐apoptotic enzyme caspase‐3 induced by Aβ_1‐42 oligomers. Our findings provide further evidence that these EOs and their main constituent linalool could be natural agents of therapeutic interest against Aβ_1‐42‐induced neurotoxicity.     

Calcium-Sensing Receptors of Human Astrocyte-Neuron Teams: Amyloid-β-Driven Mediators and Therapeutic Targets of Alzheimer’s Disease

It is generally assumed that the neuropathology of sporadic (late-onset or nonfamilial) Alzheimer’s disease (AD) is driven by the overproduction and spreading of first Amyloid-β_x-42 (Aβ₄₂) and later hyperphosphorylated (hp)-Tau oligomeric “infectious seeds”. Hitherto, only neurons were held to make and spread both oligomer types; astrocytes would just remove debris. However, we have recently shown that exogenous fibrillar or soluble Aβ peptides specifically bind and activate the Ca²⁺-sensing receptors (CaSRs) of untransformed human cortical adult astrocytes and postnatal neurons cultured in vitro driving them to produce, accrue, and secrete surplus endogenous Aβ₄₂. While the Aβ-exposed neurons start dying, astrocytes survive and keep oversecreting Aβ₄₂, nitric oxide (NO), and vascular endothelial growth factor (VEGF)-A. Thus astrocytes help neurons’ demise. Moreover, we have found that a highly selective allosteric CaSR agonist (“calcimimetic”), NPS R-568, mimics the just mentioned neurotoxic actions triggered by Aβ●CaSR signaling. Contrariwise, and most important, NPS 2143, a highly selective allosteric CaSR antagonist (“calcilytic”), fully suppresses all the Aβ●CaSR signaling-driven noxious actions. Altogether our findings suggest that the progression of AD neuropathology is promoted by unceasingly repeating cycles of accruing exogenous Aβ₄₂ oligomers interacting with the CaSRs of swelling numbers of astrocyte-neuron teams thereby recruiting them to overrelease additional Aβ₄₂ oligomers, VEGF-A, and NO. Calcilytics would beneficially break such Aβ/CaSR-driven vicious cycles and hence halt or at least slow the otherwise unstoppable spreading of AD neuropathology     

Highly Efficient Synthesis of 1,3-Dihydroxy-2-carboxycarbazole and Its Neuroprotective Effects

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