Different pathways of molecular pathophysiology underlie cognitive and motor tauopathy phenotypes in transgenic models for Alzheimer’s disease and frontotemporal lobar degeneration

2区 · 生物学

Article

作者: K. A. Harrington ; G. Riedel ; G. Niewiadomska ; F. Theuring ; V. Melis ; D. Horsley ; K. Davidson ; C. Zabke ; S. Bachmann ; J. E. Rickard ; K. Schwab ; P.-H. Moreau ; C. R. Harrington ; S. Deiana ; K. Stamer ; R. W. Veh ; M. Magbagbeolu ; M. Mazurkiewicz ; R. Garman ; P. Marschall ; C. M. Wischik

A poorly understood feature of the tauopathies is their very different clinical presentations. The frontotemporal lobar degeneration (FTLD) spectrum is dominated by motor and emotional/psychiatric abnormalities, whereas cognitive and memory deficits are prominent in the early stages of Alzheimer's disease (AD). We report two novel mouse models overexpressing different human tau protein constructs. One is a full-length tau carrying a double mutation [P301S/G335D; line 66 (L66)] and the second is a truncated 3-repeat tau fragment which constitutes the bulk of the PHF core in AD corresponding to residues 296-390 fused with a signal sequence targeting it to the endoplasmic reticulum membrane (line 1; L1). L66 has abundant tau pathology widely distributed throughout the brain, with particularly high counts of affected neurons in hippocampus and entorhinal cortex. The pathology is neuroanatomically static and declines with age. Behaviourally, the model is devoid of a higher cognitive phenotype but presents with sensorimotor impairments and motor learning phenotypes. L1 displays a much weaker histopathological phenotype, but shows evidence of neuroanatomical spread and amplification with age that resembles the Braak staging of AD. Behaviourally, the model has minimal motor deficits but shows severe cognitive impairments affecting particularly the rodent equivalent of episodic memory which progresses with advancing age. In both models, tau aggregation can be dissociated from abnormal phosphorylation. The two models make possible the demonstration of two distinct but nevertheless convergent pathways of tau molecular pathogenesis. L1 appears to be useful for modelling the cognitive impairment of AD, whereas L66 appears to be more useful for modelling the motor features of the FTLD spectrum. Differences in clinical presentation of AD-like and FTLD syndromes are therefore likely to be inherent to the respective underlying tauopathy, and are not dependent on presence or absence of concomitant APP pathology.

2011-12-02·Organic Letters1区 · 化学

Highly Efficient Synthesis of Quinoxalinone-N-oxide via Tandem Nitrosation/Aerobic Oxidative C–N Bond Formation

1区 · 化学

Article

作者: Kuroda, Mami ; Kobayashi, Yusuke ; Tanaka, Rie ; Kimachi, Tetsutaro ; Okada, Mari ; Toba, Natsuki

An efficient method for constructing quinoxalinone-N-oxides from cyanoacetanilides has been developed. This transformation can be achieved using inexpensive reagents and molecular oxygen under mild conditions, thus offering a practical pathway to quinoxalinone-containing pharmaceuticals such as ataquimast and opaviraline.

Pharmaceuticals

Hierarchical Virtual Screening of Potential Insectides Inhibitors of Acetylcholinesterase and Juvenile Hormone from Temephos

Article

作者: V da Costa, Glauber ; da S Ramos, Ryan ; M Lobato, Cássio ; B R Dos Santos, Cleydson ; M C Rosa, Joaquín ; N P Souto, Raimundo ; K P da Silva, Alicia ; M F de Sá, Ester ; Ferreira, Elenilze F B ; T de P da Silva, Carlos Henrique ; B da Silva, Luciane ; B Federico, Leonardo

Aedes aegypti (Linnaeus, 1762; Diptera: Culicidae) is the main vector transmitting viral diseases such as dengue fever, dengue haemorrhagic fever, urban yellow fever, zika and chikungunya. Worldwide, especially in the Americas and Brazil, many cases of dengue have been reported in recent years, which have shown significant growth. The main control strategy is the elimination of the vector, carried out through various education programs, to change human habits, but the most usual is biological control, together with environmental management and chemical control. The most commonly insecticide used is temephos (an organophosphorus compound), but Aedes aegypti populations have shown resistance and the product is highly toxic, so we chose it as a template molecule to perform a ligand-based virtual screening in the ChemBrigde (DIVERSet-CL subcollection) database, searching for derivatives with similarity in shape (ROCS) and electrostatic potential (EON). Thus, fourty-five molecules were filtered based on their pharmacokinetic and toxicological properties and 11 molecules were selected by a molecular docking study, including binding affinity and mode of interaction. The L46, L66 and L68 molecules show potential inhibitory activity for both the insect (−9.28, −10.08 and −6.78 Kcal/mol, respectively) and human (−6.05, 6.25 and 7.2 Kcal/mol respectively) enzymes, as well as the juvenile hormone protein (−9.2; −10.96 and −8.16 kcal/mol, respectively), showing a significant difference in comparison to the template molecule temephos. Molecules L46, L66 and L68 interacted with important amino acids at each catalytic site of the enzyme reported in the literature. Thus, the molecules here investigated are potential inhibitors for both the acetylcholinesterase enzymes and juvenile hormone protein–from insect and humans, characterizing them as a potential insecticide against the Aedes aegypti mosquito.

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