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 Frontiers in Cellular Neuroscience , 2014, DOI: 10.3389/fncel.2014.00427 Abstract: One of the most critical pathological features of Alzheimer’s disease (AD) is the accumulation of β-amyloid (Aβ) peptides that form extracellular senile plaques in the brain. Aβ is derived from β-amyloid precursor protein through sequential cleavage by β- and γ-secretases. γ-secretase is a high molecular weight complex minimally composed of four components: presenilins, nicastrin, anterior pharynx defective 1, and presenilin enhancer 2. In addition to APP, γ-secretase also cleaves many other type I transmembrane protein substrates. As a crucial enzyme for Aβ production, γ-secretase is an appealing therapeutic target for AD. Here, we summarize current knowledge on the structure and function of γ-secretase, as well as recent progress in developing γ-secretase targeting drugs for AD treatment.
 PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019430 Abstract: Neurexins are a large family of neuronal plasma membrane proteins, which function as trans-synaptic receptors during synaptic differentiation. The binding of presynaptic neurexins to postsynaptic partners, such as neuroligins, has been proposed to participate in a signaling pathway that regulates synapse formation/stabilization. The identification of mutations in neurexin genes associated with autism and mental retardation suggests that dysfunction of neurexins may underlie synaptic defects associated with brain disorders. However, the mechanisms that regulate neurexin function at synapses are still unclear. Here, we show that neurexins are proteolytically processed by presenilins (PS), the catalytic components of the γ-secretase complex that mediates the intramembraneous cleavage of several type I membrane proteins. Inhibition of PS/γ-secretase by using pharmacological and genetic approaches induces a drastic accumulation of neurexin C-terminal fragments (CTFs) in cultured rat hippocampal neurons and mouse brain. Neurexin-CTFs accumulate mainly at the presynaptic terminals of PS conditional double knockout (PS cDKO) mice lacking both PS genes in glutamatergic neurons of the forebrain. The fact that loss of PS function enhances neurexin accumulation at glutamatergic terminals mediated by neuroligin-1 suggests that PS regulate the processing of neurexins at glutamatergic synapses. Interestingly, presenilin 1 (PS1) is recruited to glutamatergic terminals mediated by neuroligin-1, thus concentrating PS1 at terminals containing β-neurexins. Furthermore, familial Alzheimer's disease (FAD)-linked PS1 mutations differentially affect β-neurexin-1 processing. Expression of PS1 M146L and PS1 H163R mutants in PS？/？ cells rescues the processing of β-neurexin-1, whereas PS1 C410Y and PS1 ΔE9 fail to rescue the processing defect. These results suggest that PS regulate the synaptic function and processing of neurexins at glutamatergic synapses, and that impaired neurexin processing by PS may play a role in FAD.
 Genome Biology , 2002, DOI: 10.1186/gb-2002-3-11-reviews3014 Abstract: The presenilin 1 (PS1) gene on human chromosome 14 (14q24.3) was initially discovered by genetic analysis of a subset of pedigrees in which the Alzheimer's disease is transmitted as a pure autosomal dominant trait [1]. The closely related PS2 gene on chromosome 1 (1q42.2) was identified subsequently by sequence homology [2,3]. Both PS1 and PS2 genes are organized into ten translated exons that display tissue-specific alternative splicing [2,4,5,6,7]. The functions and biological importance of differentially spliced presenilin variants are poorly understood; differential expression of isoforms may lead to differential regulation of the proteolytic processing of the β-amyloid precursor protein (βAPP; see later). For example, aberrant PS2 transcripts lacking exon 5 increase the rate of production of amyloid β peptide (Aβ, the neurotoxic peptide implicated in Alzheimer's disease) [8], whereas naturally occurring isoforms without exons 3 and 4 and/or without exon 8 do not affect production of Aβ [6,9].GenBank database searches using the full length PS1 sequence suggest that presenilin-like proteins are phylogenetically ancient and well-conserved across diverse eukaryote species, including plants, molluscs, insects, fish, birds, and mammals [10,11,12,13,14,15,16]. Functional conservation of presenilins in most non-human species is undetermined, except in the nematode Caenorhabditis elegans, in which a deficiency in Sel-12, the PS1 homolog, induces an egg-laying defect that can be rescued by expression of human PS1 [17,18]. Additional presenilin homologs were recently identified in disparate eukaryotes by their homology to the PS1 transmembrane domains, suggesting that the presenilin family may be more common than previously contemplated [19,20].Mammalian PS1 and PS2 are synthesized as 50 kDa polypeptides, each predicted to traverse the membrane 6-10 times; the ammo and carboxyl termini are both oriented towards the cytoplasm [21]. The current model, with eight transmembra
 Molecular Neurodegeneration , 2009, DOI: 10.1186/1750-1326-4-19 Abstract: Alzheimer's disease (AD) is the most common cause of dementia among elderly people and it has no known cure. Compelling evidence from histological and biochemical studies support the idea that the accumulation of amyloid-β (Aβ) aggregates in the brain plays a seminal role in the pathogenesis of AD [1]. Likewise, the genetic evidence regarding familial mutations of the amyloid precursor protein (APP) and presenilins support the pathogenic role of Aβ accumulation [2]. Aβ deposits as compact or dense core plaques that are sources of focal neurotoxicity in transgenic mice and in AD [3]. In this regard, senile plaques are associated with neuritic dystrophies and synaptic loss [4-6] and it has also been shown that senile plaques may disrupt cortical synaptic integration[7].Aβ is generated after sequential cleavage of APP by β and γ-secretases. Therefore, both β-secretase [8] and γ-secretase inhibitors are primary pharmacological targets in the treatment of AD (for review see [9-11]). The γ-secretase complex is constituted by at least four integral membrane proteins including presenilin, nicastrin, APH-1 and PEN-2. The activity of γ-secretase determines the solubility of the Aβ fragments, with Aβ42 more prone to aggregation than the shorter cleavage products [10]. Due to these considerations, different approaches towards modulating γ-secretase activity towards producing shorter peptide fragments are being developed. There has been considerable success in generating small molecules capable of entering the central nervous system that inhibit γ-secretase activity potently leading to a sustained reduction in brain Aβ levels [12]. In both humans and animal models, the use of γ-secretase inhibitors to reduce Aβ levels and slow Aβ deposition has been demonstrated. Administration of γ-secretase inhibitors significantly reduced Aβ levels in plasma in control and AD patients [13,14], as well as in CSF [15]. Similarly, it has also been shown that inhibiting γ-secretase activity can r
 Molecular Neurodegeneration , 2006, DOI: 10.1186/1750-1326-1-4 Abstract: In 1995 independent groups identified genetic linkage and mutations within PSEN1 (chromosome 14) and PSEN2 (chromosome 1) genes in several early onset familial Alzheimer's disease (FAD) kindreds [1-3]. Since then a number of research groups have focused on FAD-linked mutations and the biology of proteins encoded by these homologous genes. So far 140 and 10 mutations that co-segregate with FAD (in most cases before 60 years of age) have been identified in PSEN1 and PSEN2, respectively. PSEN1 and PSEN2 encode 467 and 448 amino acid-long polytopic transmembrane proteins, termed presenilin 1 (PS1) and presenilin 2 (PS2), respectively. The sequence identity between these two highly conserved proteins is greater than 65%. PS1 is expressed earlier than PS2 during mouse embryonic development indicating differential regulation of these proteins during development [4]. Although PS1 is relatively expressed at higher levels than PS2, both proteins are ubiquitously expressed in the brain and peripheral tissues in adult human and rodent.Mutations in PSEN1 and PSEN2 are autosomal dominant, highly penetrant, and cause Alzheimer's disease (AD) symptoms before age 65, in some cases with onset of symptoms less than 30 years of age. Even though FAD-linked mutations in amyloid precursor protein (APP) and PSEN genes account for less than 5% of total AD cases, the phenocopies of these FAD mutations are reminiscent of late onset sporadic AD. As discussed below, PS1 and PS2 are subunits of a protein complex, termed γ-secretase, which cleaves several type I membrane proteins including APP within their transmembrane domain. In the case of APP, γ-secretase cleavage predominantly generates 39–43 amino acid-long peptides, termed β-amyloid peptides (Aβ), which accumulate in the brains of aged individuals and patients with AD. Although the mode of action (gain of function or loss of function) is still debated, FAD-linked mutations in PS selectively elevate the levels of highly amyloidogenic Aβ42 p
 Science China Life Sciences , 2011, DOI: 10.1007/s11427-011-4201-y Abstract: Alzheimer disease (AD) is the most common neurodegenerative disorder worldwide and is at present, incurable. The accumulation of toxic amyloid-beta (Aβ) peptide aggregates in AD brain is thought to trigger the extensive synaptic loss and neurodegeneration linked to cognitive decline, an idea that underlies the ‘amyloid hypothesis’ of AD etiology in both the familal (FAD) and sporadic forms of the disease. Genetic mutations causing FAD also result in the dysregulation of neuronal calcium (Ca2+) handling and may contribute to AD pathogenesis, an idea termed the ‘calcium hypothesis’ of AD. Mutations in presenilin proteins account for majority of FAD cases. Presenilins function as catalytic subunit of γ-secretase involved in generation of Aβ peptide Recently, we discovered that presenilns function as low-conductance, passive ER Ca2+ leak channels, independent of γ-secretase activity. We further discovered that many FAD mutations in presenilins result in loss of ER Ca2+ leak function activity and Ca2+ overload in the ER. These results provided potential explanation for abnormal Ca2+ signaling observed in FAD cells with mutations in presenilns. Our latest work on studies of ER Ca2+ leak channel function of presenilins and implications of these findings for understanding AD pathogenesis are discussed in this article.
 Physics , 2000, DOI: 10.1016/j.physletb.2003.08.058 Abstract: The role of a chiral U(1) phase in the quark mass in QCD is analysed from first principles. In operator formulation, there is a parity symmetry and the phase can be removed by a change in the representation of the Dirac gamma matrices. Moreover, these properties are also realized in a Pauli-Villars regularized version of the theory. In the functional integral scenario, attempts to remove the chiral phase by a chiral transformation are thought to be obstructed by a nontrivial Jacobian arising from the fermion measure and the chiral phase may therefore seem to break parity. But if one starts from the regularized action with the chiral phase also present in the regulator mass term, the Jacobian for a combined chiral rotation of quarks and regulators is seen to be trivial and the phase can be removed by a combined chiral rotation. This amounts to a taming of the strong CP problem.
 Journal of Toxicology , 2012, DOI: 10.1155/2012/187297 Abstract: Alzheimer disease (AD) is a heterogeneous neurodegenerative disorder characterized by (1) progressive loss of synapses and neurons, (2) intracellular neurofibrillary tangles, composed of hyperphosphorylated Tau protein, and (3) amyloid plaques. Genetically, AD is linked to mutations in few proteins amyloid precursor protein (APP) and presenilin 1 and 2 (PS1 and PS2). The molecular mechanisms underlying neurodegeneration in AD as well as the physiological function of APP are not yet known. A recent theory has proposed that APP and PS1 modulate intracellular signals to induce cell-cycle abnormalities responsible for neuronal death and possibly amyloid deposition. This hypothesis is supported by the presence of a complex network of proteins, clearly involved in the regulation of signal transduction mechanisms that interact with both APP and PS1. In this review we discuss the significance of novel finding related to cell-signaling events modulated by APP and PS1 in the development of neurodegeneration. 1. Introduction Alzheimer disease (AD) is a neurodegenerative disease clinically characterized by progressive dementia, and, neuropathologically, by loss of synapses and neurons, gliosis, and the presence of both amyloid plaques and neurofibrillary tangles. The main amyloid components of plaques are a family of short peptides (Aβ) of 40 or 42 amino acids, in the most common forms, derived from the proteolysis of the type I protein, amyloid β precursor protein (AβPP), upon sequential cleavage by β- and γ-secretases [1]. γ-secretase has been characterized as a multiprotein complex in which presenilins 1 and 2 have a regulatory role [1]. Familial AD forms (FADs) are caused by the overexpression or by mutations in the AβPP gene, or by mutations on the presenilins (presenilins 1 and 2). The molecular mechanisms underlying the development of AD are not yet known, and also the physiological role of AβPP is still unclear [2]. In particular, it is still debated whether presenilins (PSs) familial mutations cause gain or loss of function in the γ-secretase complex. PS mutations have been presumed to cause FAD by enhancing production of the more toxic Aβ42 over the Aβ40 isoform, thereby conferring a toxic gain of function [3]. However, a number of recent studies have shown that clinically relevant PS mutations impair Aβ40 production without affecting Aβ42 production, leading to the revised view that pathogenic PS mutations consistently shift the cleavage specificity of the mutant protein to favor production of Aβ42 at the cost of Aβ40 [4, 5]. On the other hand, it has
 Noam D. Elkies Mathematics , 1999, Abstract: A "still Life" is a subset S of the square lattice Z^2 fixed under the transition rule of Conway's Game of Life, i.e. a subset satisfying the following three conditions: 1. No element of Z^2-S has exactly three neighbors in S; 2. Every element of S has at least two neighbors in S; 3. Every element of S has at most three neighbors in S. Here a neighbor'' of any x \in Z^2 is one of the eight lattice points closest to x other than x itself. The "still-Life conjecture" is the assertion that a still Life cannot have density greater than 1/2 (a bound easily attained, for instance by {(x,y): x is even}). We prove this conjecture, showing that in fact condition 3 alone ensures that S has density at most 1/2. We then consider variations of the problem such as changing the number of allowed neighbors or the definition of neighborhoods; using a variety of methods we find some partial results and many new open problems and conjectures.
 D. L. Stein Physics , 2003, Abstract: Spin glasses are magnetic systems exhibiting both quenched disorder and frustration, and have often been cited as examples of complex systems.' In this talk I review some of the basic notions of spin glass physics, and discuss how some of our recent progress in understanding their properties might lead to new viewpoints of how they manifest complexity'.
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