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Find video protocols related to scientific articles indexed in Pubmed.
Immunostaining of oxidized DJ-1 in human and mouse brains.
J. Neuropathol. Exp. Neurol.
PUBLISHED: 06-12-2014
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DJ-1, the product of a causative gene of a familial form of Parkinson disease, undergoes preferential oxidation of Cys106 (cysteine residue at position 106) under oxidative stress. Using specific monoclonal antibodies against Cys106 oxidized DJ-1 (oxDJ-1), we examined oxDJ-1 immunoreactivity in brain sections from DJ-1 knockout and wild-type mice and in human brain sections from cases classified into different Lewy body stages of Parkinson disease and Parkinson disease with dementia. Oxidized DJ-1 immunoreactivity was prominently observed in neuromelanin-containing neurons and neuron processes of the substantia nigra; Lewy bodies also showed oxDJ-1 immunoreactivity. Oxidized DJ-1 was also detected in astrocytes in the striatum, in neurons and glia in the red nucleus, and in the inferior olivary nucleus, all of which are related to regulation of movement. These observations suggest the relevance of DJ-1 oxidation to homeostasis in multiple brain regions, including neuromelanin-containing neurons of the substantia nigra, and raise the possibility that oxDJ-1 levels might change during the progression of Lewy body-associated neurodegenerative diseases.
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Lack of genetic association between TREM2 and late-onset Alzheimer's disease in a Japanese population.
J. Alzheimers Dis.
PUBLISHED: 04-26-2014
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Rare non-synonymous variants of TREM2 have recently been shown to be associated with Alzheimer's disease (AD) in Caucasians. We here conducted a replication study using a well-characterized Japanese sample set, comprising 2,190 late-onset AD (LOAD) cases and 2,498 controls. We genotyped 10 non-synonymous variants (Q33X, Y38C, R47H, T66M, N68K, D87N, T96K, R98W, H157Y, and L211P) of TREM2 reported by Guerreiro et al. (2013) by means of the TaqMan and dideoxy sequencing methods. Only three variants, R47H, H157Y, and L211P, were polymorphic (range of minor allele frequency [MAF], 0.0002-0.0059); however, no significant association with LOAD was observed in these variants. Considering low MAF of variants examined and our study sample size, further genetic analysis with a larger sample set is needed to firmly evaluate whether or not TREM2 is associated with LOAD in Japanese.
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The homologous carboxyl-terminal domains of microtubule-associated protein 2 and TAU induce neuronal dysfunction and have differential fates in the evolution of neurofibrillary tangles.
PLoS ONE
PUBLISHED: 01-01-2014
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Microtubule-associated protein 2 (MAP2) and Tau are abundant neuronal microtubule-associated proteins. Both proteins have highly homologous carboxyl-terminal sequences that function as microtubule-binding domains. Whereas Tau is widely accepted as a pathoetiological factor in human tauopathies, including Alzheimer's disease (AD), it is not known whether there is a relationship between MAP2 and tauopathy. To better understand the pathological roles of MAP2 and Tau, we compared their behaviors in transgenic Caenorhabditis elegans in which MAP2 or Tau was expressed pan-neuronally. Both MAP2 and Tau elicited severe neuronal dysfunction and neuritic abnormalities, despite the absence of detergent-insoluble aggregates in worm neurons. Biochemical analysis revealed that the expressed MAP2 or Tau in worms was highly phosphorylated and did not bind to microtubules. Newly raised antibodies to MAP2 that effectively distinguished between the highly homologous carboxyl-terminal sequences of MAP2 and Tau showed that MAP2 was not involved in the growth process of neurofibrillary tangles in the AD brain. These results indicate that Tau and MAP2 have different fates in the inclusion formation and raise the possibility that MAP2 plays a significant role in neurotoxicity in the AD brain despite the absence of MAP2-aggregates.
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?-Secretase associated with lipid rafts: multiple interactive pathways in the stepwise processing of ?-carboxyl terminal fragment.
J. Biol. Chem.
PUBLISHED: 12-28-2013
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??Secretase generates amyloid ??protein (A?), a pathogenic molecule in Alzheimers disease, through the intramembrane cleavage of the ??carboxyl terminal fragment (?CTF) of ??amyloid precursor protein. We previously showed the framework of the ??secretase cleavage: the stepwise successive processing of ?CTF at every three (or four) amino acids. However, the membrane integrity of ??secretase was not taken into consideration because of the use of the CHAPSO?solubilized reconstituted ??secretase system. Here, we sought to address how the membrane?integrated ??secretase cleaves ?CTF by using ??secretase associated with lipid rafts. Quantitative analyses using liquid chromatography?tandem mass spectrometry of the ?CTF transmembrane domain?derived peptides released along with A? generation revealed that the raft?associated ??secretase cleaves ?CTF in a stepwise sequential manner, but novel penta? and hexapeptides as well as tri- and tetrapeptides are released. The cropping of these peptides links the two major tripeptide?cleaving pathways generating A?40 and A?42 at several points, implying that there are multiple interactive pathways for the stepwise cleavages of ?CTF. It should be noted that A?38 and A?43 are generated through three routes, and ??secretase modulator 1 enhances all the three routes generating A?38, which results in decreases in A?42 and A?43 and an increase in A?38. These observations indicate that multiple interactive pathways for stepwise successive processing by ??secretase define the species and quantity of A? produced.
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Modulation of lipid kinase PI4KII? activity and lipid raft association of presenilin 1 underlies ?-secretase inhibition by ginsenoside (20S)-Rg3.
J. Biol. Chem.
PUBLISHED: 05-30-2013
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Amyloid ?-peptide (A?) pathology is an invariant feature of Alzheimer disease, preceding any detectable clinical symptoms by more than a decade. To this end, we seek to identify agents that can reduce A? levels in the brain via novel mechanisms. We found that (20S)-Rg3, a triterpene natural compound known as ginsenoside, reduced A? levels in cultured primary neurons and in the brains of a mouse model of Alzheimer disease. The (20S)-Rg3 treatment induced a decrease in the association of presenilin 1 (PS1) fragments with lipid rafts where catalytic components of the ?-secretase complex are enriched. The A?-lowering activity of (20S)-Rg3 directly correlated with increased activity of phosphatidylinositol 4-kinase II? (PI4KII?), a lipid kinase that mediates the rate-limiting step in phosphatidylinositol 4,5-bisphosphate synthesis. PI4KII? overexpression recapitulated the effects of (20S)-Rg3, whereas reduced expression of PI4KII? abolished the A?-reducing activity of (20S)-Rg3 in neurons. Our results substantiate an important role for PI4KII? and phosphoinositide modulation in ?-secretase activity and A? biogenesis.
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Substrate ectodomain is critical for substrate preference and inhibition of ?-secretase.
Nat Commun
PUBLISHED: 04-02-2013
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Understanding the substrate recognition mechanism of ?-secretase is a key step for establishing substrate-specific inhibition of amyloid ?-protein (A?) production. However, it is widely believed that ?-secretase is a promiscuous protease and that its substrate-specific inhibition is elusive. Here we show that ?-secretase distinguishes the ectodomain length of substrates and preferentially captures and cleaves substrates containing a short ectodomain. We also show that a subset of peptides containing the CDCYCxxxxCxCxSC motif binds to the amino terminus of C99 and inhibits A? production in a substrate-specific manner. Interestingly, these peptides suppress ?-secretase-dependent cleavage of APP, but not that of sialyltransferase 1. Most importantly, intraperitoneal administration of peptides into mice results in a significant reduction in cerebral A? levels. This report provides direct evidence of the substrate preference of ?-secretase and its mechanism. Our results demonstrate that the ectodomain of C99 is a potent target for substrate-specific anti-A? therapeutics to combat Alzheimers disease.
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SORL1 is genetically associated with late-onset Alzheimers disease in Japanese, Koreans and Caucasians.
PLoS ONE
PUBLISHED: 02-05-2013
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To discover susceptibility genes of late-onset Alzheimers disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n?=?1,008) and controls (n?=?1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values <2×10(-5) were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P?=?7.33×10(-7) in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P?=?1.77×10(-9)) and rs3781834 (P?=?1.04×10(-8)). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P?=?1.71×10(-5)) and rs744373 near BIN1 (P?=?1.39×10(-4)). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations.
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?-secretase modulators and presenilin 1 mutants act differently on presenilin/?-secretase function to cleave A?42 and A?43.
Cell Rep
PUBLISHED: 01-03-2013
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Deciphering the mechanism by which the relative A?42(43) to total A? ratio is regulated is central to understanding Alzheimer disease (AD) etiology; however, the mechanisms underlying changes in the A?42(43) ratio caused by familial mutations and ?-secretase modulators (GSMs) are unclear. Here, we show in vitro and in living cells that presenilin (PS)/?-secretase cleaves A?42 into A?38, and A?43 into A?40 or A?38. Approximately 40% of A?38 is derived from A?43. A?42(43) cleavage is involved in the regulation of the A?42(43) ratio in living cells. GSMs increase the cleavage of PS/?-secretase-bound A?42 (increase k(cat)) and slow its dissociation from the enzyme (decrease k(b)), whereas PS1 mutants and inverse GSMs show the opposite effects. Therefore, we suggest a concept to describe the A?42(43) production process and propose how GSMs act, and we suggest that a loss of PS/?-secretase function to cleave A?42(43) may initiate AD and might represent a therapeutic target.
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Homogamy and imprinting-like effect on mate choice preference for body height in the current Japanese population.
Ann. Hum. Biol.
PUBLISHED: 12-05-2011
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Homogamy for body height has been repeatedly documented in Western societies. Nevertheless, the underlying mechanism is unclear and the reasons for its apparent absence in non-Western societies remain unexplained.
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Central nervous system-specific deletion of transcription factor Nrf1 causes progressive motor neuronal dysfunction.
Genes Cells
PUBLISHED: 05-10-2011
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CapnCollar (CNC) proteins heterodimerize with small Maf proteins and regulate the transcription of various genes. Small Maf-deficient mice develop severe neurodegeneration, and it remains unclear whether CNC proteins are involved in this process. In this study, we examined the contribution of Nrf1, one of the CNC proteins, to neuronal homeostasis in vivo. As Nrf1 gene knockout mice are embryonic lethal, we developed a central nervous system (CNS)-specific Nrf1 knockout (CKO) mouse line using mice bearing an Nrf1(flox) allele and Nestin-Cre allele. At birth, the CKO mice appeared indistinguishable from control mice, but thereafter they showed progressive motor ataxia and severe weight loss. All Nrf1 CKO mice died within 3 weeks. These phenotypes are similar to those reported in small Maf-deficient mice, suggesting the presence of collaboration between Nrf1 and small Maf proteins. We also found aberrant accumulation of polyubiquitinated proteins in various CNS regions and apparent neuronal loss in the hippocampus of Nrf1 CKO mice. An oxidative stress marker was accumulated in the spinal cords of the mice, but the expression patterns of oxidative stress response genes regulated by Nrf2 did not change substantially. These results show that Nrf1 sustains the CNS homeostasis through regulating target genes distinct from those regulated by Nrf2.
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Potent amyloidogenicity and pathogenicity of A?43.
Nat. Neurosci.
PUBLISHED: 03-17-2011
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The amyloid-? peptide A?42 is known to be a primary amyloidogenic and pathogenic agent in Alzheimers disease. However, the role of A?43, which is found just as frequently in the brains of affected individuals, remains unresolved. We generated knock-in mice containing a pathogenic presenilin-1 R278I mutation that causes overproduction of A?43. Homozygosity was embryonic lethal, indicating that the mutation involves a loss of function. Crossing amyloid precursor protein transgenic mice with heterozygous mutant mice resulted in elevated A?43, impairment of short-term memory and acceleration of amyloid-? pathology, which accompanied pronounced accumulation of A?43 in plaque cores similar in biochemical composition to those observed in the brains of affected individuals. Consistently, A?43 showed a higher propensity to aggregate and was more neurotoxic than A?42. Other pathogenic presenilin mutations also caused overproduction of A?43 in a manner correlating with A?42 and with the age of disease onset. These findings indicate that A?43, an overlooked species, is potently amyloidogenic, neurotoxic and abundant in vivo.
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Classes of communication and the conditions for their evolution.
Theor Popul Biol
PUBLISHED: 03-02-2011
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Evolution of communication is conceptualized as a coevolutionary process in which evolution of signaler and that of receiver occur in an interdependent manner. Three classes of communication, mutualistic, altruistic, and exploiting, are distinguished depending on who gains a benefit or suffers a cost from successful communication. Communication is also dichotomized according to whether individuals are innately able to send and receive relevant signals or they have to acquire those signals culturally. We develop two-locus haploid models that represent the coevolutionary nature of the evolution of communication, and derive the conditions under which communicators can invade a population of non-communicators and those under which a population of communicators is evolutionarily stable against the invasion by non-communicators for each of the three classes of communication. Analysis of the models reveals that interaction among siblings enables the invasion of communication and that the optimal probability of interaction with siblings depends on the class of communication and the mode of signal transmission. In addition, cultural exploiting communication is more likely to invade a population of non-communicators than is genetic exploiting communication under certain circumstances.
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Evolution of culture-dependent discriminate sociality: a gene-culture coevolutionary model.
Philos. Trans. R. Soc. Lond., B, Biol. Sci.
PUBLISHED: 02-16-2011
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Animals behave cooperatively towards certain conspecifics while being indifferent or even hostile to others. The distinction is made primarily according to kinship as predicted by the kin selection theory. With regards to humans, however, this is not always the case; in particular, humans sometimes exhibit a discriminate sociality on the basis of culturally transmitted traits, such as personal ornaments, languages, rituals, etc. This paper explores the possibility that the human faculty of cultural transmission and resultant cultural variation among individuals may have facilitated the evolution of discriminate sociality in humans. To this end, a gene-culture coevolutionary model is developed focusing on competition over control of resource as a context in which discriminate sociality may have evolved. Specifically, two types of culture-dependent discriminate sociality are considered: ingroup favouritism, with ingroup and outgroup being distinguished by the presence or absence of a cultural trait; and prestige hierarchies, with the prestige being conferred on the bearer of a cultural trait. The model specifies the conditions under which emergence and evolutionary stability of the two types of discriminate sociality are promoted by the presence of cultural variation among individuals.
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Dissociation of ?-amyloid from lipoprotein in cerebrospinal fluid from Alzheimers disease accelerates ?-amyloid-42 assembly.
J. Neurosci. Res.
PUBLISHED: 01-11-2011
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Monoclonal 2C3 specific to ?-amyloid (A?) oligomers (A?Os) enabled us to test our hypothesis that the alteration of lipoprotein-A? interaction in the central nervous system (CNS) initiates and/or accelerates the cascade favoring A? assembly. Immunoprecipitation of frontal cortex employing 2C3 unequivocally detected soluble 4-, 8-, and 12-mers in Alzheimers disease (AD) brains. Immunoblot analysis of the entorhinal cortex employing 2C3 revealed that the accumulation of soluble 12-mers precedes the appearance of neuronal loss or cognitive impairment and is enhanced as the Braak neurofibrially tangle (NFT) stages progress. The dissociation of soluble A? from lipoprotein particles occurs in cerebrospinal fluid (CSF), and the presence of lipoprotein-free oligomeric 2C3 conformers (4- to 35-mers) was evident, which mimic CNS environments. Such CNS environments may strongly affect conformation of soluble A? peptides, resulting in the conversion of soluble A?(42) monomers into soluble A?(42) assembly. The findings suggest that functionally declined lipoproteins may accelerate the generation of metabolic conditions leading to higher levels of soluble A?(42) assembly in the CNS.
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The production ratios of AICD?51 and A?42 by intramembrane proteolysis of ?APP do not always change in parallel.
Psychogeriatrics
PUBLISHED: 09-24-2010
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During intramembrane proteolysis of ?-amyloid protein precursor (?APP) by presenilin (PS)/?-secretase, ?-cleavages at the membrane-cytoplasmic border precede ?-cleavages at the middle of the transmembrane domain. Generation ratios of A?42, a critical molecule for Alzheimers disease (AD) pathogenesis, and the major A?40 species might be associated with ?48 and ?49 cleavages, respectively. Medicines to downregulate A?42 production have been investigated by many pharmaceutical companies. Therefore, the ?-cleavages, rather than the ?-cleavage, might be more effective upstream targets for decreasing the relative generation of A?42. Thus, one might evaluate compounds by analyzing the generation ratio of the ?APP intracellular domain (AICD) species (?-cleavage-derived), instead of that of A?42.
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Estrous asynchrony causes low birth rates in wild female chimpanzees.
Am. J. Primatol.
PUBLISHED: 08-02-2010
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Estrous cycle asynchrony likely functions to elevate individual females sexual attractiveness during female mate choice. Female chimpanzees show physiological estrus as anogenital swelling. Copulations are concentrated during the period of maximal tumescence, which is called the estrous period. A group of female chimpanzees in Mahale Mountains National Park, Tanzania, was shown to display asynchrony in both maximal tumescence and periovulatory periods. We tested the hypothesis that females establish asynchronous maximal tumescence or periovulatory periods with respect to other females to increase copulation frequency and birth opportunities (Hypothesis 1). We analyzed differences in birth rates between four asynchronous years and five nonasynchronous years. Counter to Hypothesis 1, females in periovulatory periods during asynchronous years showed significantly lower birth rates than those in nonasynchronous years. In addition, periovulatory females copulated more frequently on days on which no other female in a periovulatory period was present. These results suggest that birth rates tend to decrease when females experience nonoverlapping ovulation cycles, although copulation frequency is high. Such a decrease in the birth rate may have resulted from the cost associated with multiple copulations. We tested two other hypotheses: paternity confusion (Hypothesis 2) and sperm competition (Hypothesis 3). Both of these hypotheses were partially supported. The highest-ranking male most effectively monopolized access to receptive females when relatively few other males and receptive females from the party (or subgroup) were present. The viability of Hypotheses 2 and 3 requires that dominant males are able to hinder a female from mating with other males. Given that the male-biased operational sex ratio created by female asynchrony is likely to reduce the efficiency of mate guarding by dominant males, an asynchronous female may gain a fitness benefit by increasing the probability of mating with at least one male who produces superior sperm.
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Generous cooperators can outperform non-generous cooperators when replacing a population of defectors.
Theor Popul Biol
PUBLISHED: 03-01-2010
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The evolution of cooperation has been a major challenge in evolutionary biology. Unconditional cooperators who help others at a cost to themselves are exploited by defectors who enjoy the benefits without any help in return. It has been argued that cooperation can be established in repeated dyadic interactions if cooperators punish defectors by withholding future cooperation. In social interactions involving more than two individuals, however, withholding future cooperation may result in penalizing not only defectors but also other cooperators. Hence, in such social interactions, it is unclear whether cooperation is most likely to evolve when cooperators are intolerant of any defectors. Here we show, by analyzing a stochastic model of n-player Prisoners Dilemma, that the evolution of cooperation can be more likely when cooperators tolerate some defection than when they have no such generosity. We also specify the optimal level of generosity that most likely facilitates the evolution of cooperation.
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gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment.
J. Neurosci.
PUBLISHED: 10-16-2009
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Amyloid beta protein (Abeta), a pathogenic molecule associated with Alzheimers disease, is produced by gamma-secretase, which cleaves the beta-carboxyl terminal fragment (betaCTF) of beta-amyloid precursor protein in the middle of its transmembrane domain. How the cleavage proceeds within the membrane has long been enigmatic. We hypothesized previously that betaCTF is cleaved first at the membrane-cytoplasm boundary, producing two long Abetas, Abeta(48) and Abeta(49), which are processed further by releasing three residues at each step to produce Abeta(42) and Abeta(40), respectively. To test this hypothesis, we used liquid chromatography tandem mass spectrometry (LC-MS/MS) to quantify the specific tripeptides that are postulated to be released. Using CHAPSO (3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxyl-1-propanesulfonate)-reconstituted gamma-secretase system, we confirmed that Abeta(49) is converted to Abeta(43/40) by successively releasing two or three tripeptides and that Abeta(48) is converted to Abeta(42/38) by successively releasing two tripeptides or these plus an additional tetrapeptide. Most unexpectedly, LC-MS/MS quantification revealed an induction period, 3-4 min, in the generation of peptides. When extrapolated, each time line for each tripeptide appears to intercept the same point on the x-axis. According to numerical simulation based on the successive reaction kinetics, the induction period exists. These results strongly suggest that Abeta is generated through the stepwise processing of betaCTF by gamma-secretase.
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GAB2 is not associated with late-onset Alzheimers disease in Japanese.
Eur. J. Hum. Genet.
PUBLISHED: 09-29-2009
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The varepsilon4 allele of the apolipoprotein E gene (APOE) is unequivocally recognized as a genetic risk factor for late-onset Alzheimers disease (LOAD). Recently, single-nucleotide polymorphisms (SNPs) of the GRB2-associated binding protein 2 gene (GAB2) were shown to be associated with LOAD in Caucasians carrying the APOE-varepsilon4 allele through a genome-wide association study. Here, we attempted to replicate the finding by genotyping these SNPs in a large clinical cohort of Japanese. We observed no association of any of the SNPs with LOAD. GAB2 may not be a disease susceptibility gene for LOAD in Japanese.
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Replicator-dynamics models of sexual conflict.
J. Theor. Biol.
PUBLISHED: 06-02-2009
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Evolutionary conflict between the sexes has been studied in various taxa and in various contexts. When the sexes are in conflict over mating rates, natural selection favors both males that induce higher mating rates and females that are more successful at resisting mating attempts. Such sexual conflict may result in an escalating coevolutionary arms race between males and females. In this article, we develop simple replicator-dynamics models of sexual conflict in order to investigate its evolutionary dynamics. Two specific models of the dependence of a females fitness on her number of matings are considered: in model 1, female fitness decreases linearly with increasing number of matings and in model 2, there is an optimal number of matings that maximizes female fitness. For each of these models, we obtain the conditions for a coevolutionary process to establish costly male and female traits and examine under what circumstances polymorphism is maintained at equilibrium. Then we discuss how assumptions in previous models of sexual conflict are translated to fit to our model framework and compare our results with those of the previous studies. The simplicity of our models allows us to consider sexual conflict in various contexts within a single framework. In addition, we find that our model 2 shows more complicated evolutionary dynamics than model 1. In particular, the population exhibits bistability, where the evolutionary outcome depends on the initial state, only in model 2.
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Collapsin response mediator protein-2 regulates neurite formation by modulating tubulin GTPase activity.
Cell. Signal.
PUBLISHED: 04-27-2009
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Collapsin response mediator protein-2 (CRMP-2) plays a key role in axonal development by regulating microtubule dynamics. However, the molecular mechanisms underlying this function have not been clearly elucidated. In this study, we demonstrated that hCRMP-2, specifically amino acid residues 480-509, is essential for stimulating tubulin GTPase activity. We also found that the GTPase-activating protein (GAP) activity of hCRMP-2 was important for microtubule assembly and neurite formation in differentiated PC12 pheochromocytoma cell lines. Mutant hCRMP-2, lacking arginine residues responsible for GAP activity, inhibited microtubule assembly and neurite formation. Interestingly, we found that the N-terminal region (amino acids150-299) of hCRMP-2 had an inhibitory role on GAP activity via a direct interaction with the C-terminal region (amino acids 480-509). Our results suggest that CRMP-2 as a tubulin direct binder may be a GAP of tubulin in neurite formation and that its GAP activity may be regulated by an intramolecular interaction with an N-terminal inhibitory region.
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Genetic association study on in and around the APOE in late-onset Alzheimer disease in Japanese.
Genomics
PUBLISHED: 01-20-2009
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The epsilon4 allele of APOE is a well-characterized genetic risk factor for late-onset Alzheimer disease (LOAD). Nevertheless, using high-density single nucleotide polymorphisms (SNPs), there have only been a few studies involving genetic association and linkage disequilibrium (LD) analyses of in and around the APOE. Here, we report fine mapping of a genomic region (about 200 kb) including the APOE in Japanese using 260 SNPs (mean intermaker distance, 0.77 kb). A case-control study demonstrated that 36 of these SNPs exhibited significance after adjustment for multiple testing. These SNPs are located in a genomic region including four genes, PVRL2, TOMM40, APOE and APOC1. Recombination rate estimation revealed that the associated region is firmly sandwiched between two recombination hotspots. Strong LD between these SNPs was observed (mean |D|=0.914). These data suggest that the three genes other than APOE, i.e. PVRL2, TOMM40 and APOC1, could also yield a predisposition to LOAD.
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Emergence of cooperation in public goods games.
Proc. Biol. Sci.
PUBLISHED: 01-13-2009
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Evolution of cooperation has been a major issue in evolutionary biology. Cooperation is observed not only in dyadic interactions, but also in social interactions involving more than two individuals. It has been argued that direct reciprocity cannot explain the emergence of cooperation in large groups because the basin of attraction for the cooperative equilibrium state shrinks rapidly as the group size increases. However, this argument is based on the analysis of models that consider the deterministic process. More recently, stochastic models of two-player games have been developed and the conditions for natural selection to favour the emergence of cooperation in finite populations have been specified. These conditions have been given as a mathematically simple expression, which is called the one-third law. In this paper, we investigate a stochastic model of n-player games and show that natural selection can favour a reciprocator replacing a population of defectors in the n-player repeated Prisoners Dilemma game. We also derive a generalized version of the one-third law (the {2/[n(n+1)]}1/(n-1) law). Additionally, contrary to previous studies, the model suggests that the evolution of cooperation in public goods game can be facilitated by larger group size under certain conditions.
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Evolution of social behavior in finite populations: a payoff transformation in general n-player games and its implications.
Theor Popul Biol
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The evolution of social behavior has been the focus of many theoretical investigations, which typically have assumed infinite populations and specific payoff structures. This paper explores the evolution of social behavior in a finite population using a general n-player game. First, we classify social behaviors in a group of n individuals based on their effects on the actors and the social partners payoffs, showing that in general such classification is possible only for a given composition of strategies in the group. Second, we introduce a novel transformation of payoffs in the general n-player game to formulate explicitly the effects of a social behavior on the actors and the social partners payoffs. Third, using the transformed payoffs, we derive the conditions for a social behavior to be favored by natural selection in a well-mixed population and in the presence of multilevel selection.
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Suspected limited efficacy of ?-secretase modulators.
Neurobiol. Aging
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Mild cognitive impairment and Alzheimers disease (AD) are associated with changes in ?-secretase activity in the brain, producing an amyloid ?-protein-42-lowering ?-modulator-like effect. We show here that this modulation occurs at the stage of amyloid deposition, presumably decades earlier than the onset of AD. In addition, ?-secretase modulator-1, a ?-modulator, altered ?-secretase activity in the AD brain but to a lesser extent than in the normal brain. These findings suggest that ?-modulators have limited efficacy against amyloid deposition and AD.
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The ubiquitin-proteasome system and the autophagic-lysosomal system in Alzheimer disease.
Cold Spring Harb Perspect Med
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As neurons age, their survival depends on eliminating a growing burden of damaged, potentially toxic proteins and organelles-a capability that declines owing to aging and disease factors. Here, we review the two proteolytic systems principally responsible for protein quality control in neurons and their important contributions to Alzheimer disease pathogenesis. In the first section, the discovery of paired helical filament ubiquitination is described as a backdrop for discussing the importance of the ubiquitin-proteasome system in Alzheimer disease. In the second section, we review the prominent involvement of the lysosomal system beginning with pathological endosomal-lysosomal activation and signaling at the very earliest stages of Alzheimer disease followed by the progressive failure of autophagy. These abnormalities, which result in part from Alzheimer-related genes acting directly on these lysosomal pathways, contribute to the development of each of the Alzheimer neuropathological hallmarks and represent a promising therapeutic target.
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Human homogamy in facial characteristics: does a sexual-imprinting-like mechanism play a role?
Hum Nat
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Human homogamy may be caused in part by individuals preference for phenotypic similarities. Two types of preference can result in homogamy: individuals may prefer someone who is similar to themselves (self-referent phenotype matching) or to their parents (a sexual-imprinting-like mechanism). In order to examine these possibilities, we compare faces of couples and their family members in two ways. First, "perceived" similarity between a pair of faces is quantified as similarity ratings given to the pair. Second, "physical" similarity between two groups of faces is evaluated on the basis of correlations in principal component scores generated from facial measurements. Our results demonstrate a tendency to homogamy in facial characteristics and suggest that the tendency is due primarily to self-referent phenotype matching. Nevertheless, the presence of a sexual-imprinting-like effect is also partially indicated: whether individuals are involved in facial homogamy may be affected by their relationship with their parents during childhood.
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Altered ?-secretase activity in mild cognitive impairment and Alzheimers disease.
EMBO Mol Med
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We investigated why the cerebrospinal fluid (CSF) concentrations of A?42 are lower in mild cognitive impairment (MCI) and Alzheimers disease (AD) patients. Because A?38/42 and A?40/43 are distinct product/precursor pairs, these four species in the CSF together should faithfully reflect the status of brain ?-secretase activity, and were quantified by specific enzyme-linked immunosorbent assays in the CSF from controls and MCI/AD patients. Decreases in the levels of the precursors, A?42 and 43, in MCI/AD CSF tended to accompany increases in the levels of the products, A?38 and 40, respectively. The ratios A?40/43 versus A?38/42 in CSF (each representing cleavage efficiency of A?43 or A?42) were largely proportional to each other but generally higher in MCI/AD patients compared to control subjects. These data suggest that ?-secretase activity in MCI/AD patients is enhanced at the conversion of A?43 and 42 to A?40 and 38, respectively. Consequently, we measured the in vitro activity of raft-associated ?-secretase isolated from control as well as MCI/AD brains and found the same, significant alterations in the ?-secretase activity in MCI/AD brains.
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In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.