Biochimica et biophysica acta
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Biochim. Biophys. Acta · Dec 2013
Activation of the endoplasmic reticulum stress response by the amyloid-beta 1-40 peptide in brain endothelial cells.
Neurovascular dysfunction arising from endothelial cell damage is an early pathogenic event that contributes to the neurodegenerative process occurring in Alzheimer's disease (AD). Since the mechanisms underlying endothelial dysfunction are not fully elucidated, this study was aimed to explore the hypothesis that brain endothelial cell death is induced upon the sustained activation of the endoplasmic reticulum (ER) stress response by amyloid-beta (Aβ) peptide, which deposits in the cerebral vessels in many AD patients and transgenic mice. Incubation of rat brain endothelial cells (RBE4 cell line) with Aβ1-40 increased the levels of several markers of ER stress-induced unfolded protein response (UPR), in a time-dependent manner, and affected the Ca(2+) homeostasis due to the release of Ca(2+) from this intracellular store. ⋯ Enhanced release of cytochrome c from mitochondria and activation of the downstream caspase-9 were observed in cells treated with Aβ1-40 concomitantly with caspase-12 activation. Furthermore, Aβ1-40 activated the apoptosis effectors' caspase-3 and promoted the translocation of apoptosis-inducing factor (AIF) to the nucleus demonstrating the involvement of caspase-dependent and -independent mechanisms during Aβ-induced endothelial cell death. In conclusion, our data demonstrate that ER stress plays a significant role in Aβ1-40-induced apoptotic cell death in brain endothelial cells suggesting that ER stress-targeted therapeutic strategies might be useful in AD to counteract vascular defects and ultimately neurodegeneration.
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Biochim. Biophys. Acta · Nov 2013
ReviewUse of model organisms for the study of neuronal ceroid lipofuscinosis.
Neuronal ceroid lipofuscinoses are a group of fatal progressive neurodegenerative diseases predominantly affecting children. Identification of mutations that cause neuronal ceroid lipofuscinosis, and subsequent functional and pathological studies of the affected genes, underpins efforts to investigate disease mechanisms and identify and test potential therapeutic strategies. ⋯ In this review, we will discuss the ethical issues associated with experiments using model organisms, the factors underlying the choice of model organism, the disease models and genetic tools available, and the contributions of those disease models and tools to neuronal ceroid lipofuscinosis research. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.
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Biochim. Biophys. Acta · Nov 2013
ReviewBioinformatic perspectives in the neuronal ceroid lipofuscinoses.
The neuronal ceroid lipofuscinoses (NCLs) are a group of rare genetic diseases characterised clinically by the progressive deterioration of mental, motor and visual functions and histopathologically by the intracellular accumulation of autofluorescent lipopigment - ceroid - in affected tissues. The NCLs are clinically and genetically heterogeneous and more than 14 genetically distinct NCL subtypes have been described to date (CLN1-CLN14) (Haltia and Goebel, 2012 [1]). In this review we will chronologically summarise work which has led over the years to identification of NCL genes, and outline the potential of novel genomic techniques and related bioinformatic approaches for further genetic dissection and diagnosis of NCLs. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.
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Biochim. Biophys. Acta · Nov 2013
ReviewPathogenesis and therapies for infantile neuronal ceroid lipofuscinosis (infantile CLN1 disease).
The neuronal ceroid lipofuscinoses (NCL, Batten disease) are a group of inherited neurodegenerative diseases. Infantile neuronal ceroid lipofuscinosis (INCL, infantile Batten disease, or infantile CLN1 disease) is caused by a deficiency in the soluble lysosomal enzyme palmitoyl protein thioesterase-1 (PPT1) and has the earliest onset and fastest progression of all the NCLs. Several therapeutic strategies including enzyme replacement, gene therapy, stem cell-mediated therapy, and small molecule drugs have resulted in minimal to modest improvements in the murine model of PPT1-deficiency. ⋯ Different therapeutic targets will need to be identified and novel strategies developed in order to effectively treat forms of NCL caused by deficiencies in integral membrane proteins such as juvenile neuronal ceroid lipofuscinosis. Finally, the challenge with all of the NCLs will lie in early diagnosis, improving the efficacy of the treatments, and effectively translating them into the clinic. This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or Batten Disease.
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Biochim. Biophys. Acta · Nov 2013
Neutral liposomes containing crown ether-lipids as potential DNA vectors.
Three crown ether derivatives, 1,2-O-dioleoyl-3-O-{2-[(12-crown-4)methoxy]ethyl}-sn-glycerol (12C4L), 1,2-O-dioleoyl-3-O-{2-[(15-crown-5)methoxy]ethyl}-sn-glycerol (15C5L) and 2,3-naphtho-15-crown-5 (NAP5), have been incorporated into 1-palmitoyl-2-oleoyl-phosphatydilcholine (POPC) liposomes. The size of the crown ether and the lipophilic moiety of 12C4L, 15C5L and NAP5 influence the stability and the properties of the extruded POPC liposomes determined at 25°C in buffered aqueous solution at pH7.4. The investigated liposomes are zwitterionic for POPC headgroups but can be turned into cationic aggregates in the presence of divalent cations. The capability of these systems to complex DNA has been demonstrated by SAXS experiments.