Amyloid-beta peptide plaque in the brain is the primary diagnostic criterion of Alzheimer's disease . The physiological role of Abeta are poorly understood. We have previously determined an Abeta interacting domain in the promoters of AD-associated genes . This AbetaID interacts in a DNA sequence-specific manner with Abeta. We now demonstrate novel Abeta activity as a possible transcription factor. Herein, we detected Abeta-chromatin interaction in cell culture by ChIP assay. We observed that human neuroblastoma cells treated with FITC conjugated Abeta1-40 (...) localized Abeta to the nucleus in the presence of H2O2-mediated oxidative stress. Furthermore, primary rat fetal cerebrocortical cultures were transfected with APP and BACE1 promoter-luciferase fusions, and rat PC12 cultures were transfected with polymorphic APP promoter-CAT fusion clones. Transfected cells were treated with different Abeta peptides and/or H2O2. Abeta treatment of cell cultures produced a DNA sequence-specific response in cells transfected with polymorphic APP clones. Our results suggest the Abeta peptide may regulate its own production through feedback on its precursor protein and BACE1, leading to amyloidogenesis in AD. (shrink)

The sporadic nature of Alzheimer's disease argues for an environmental link that may drive AD pathogenesis; however, the triggering factors and the period of their action are unknown. Recent studies in rodents have shown that exposure to lead during brain development predetermined the expression and regulation of the amyloid precursor protein and its amyloidogenic beta-amyloid product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 ] as well as their transcriptional regulator were elevated in aged (...) monkeys exposed to Pb as infants. Furthermore, developmental exposure to Pb altered the levels, characteristics, and intracellular distribution of Abeta staining and amyloid plaques in the frontal association cortex. These latent effects were accompanied by a decrease in DNA methyltransferase activity and higher levels of oxidative damage to DNA, indicating that epigenetic imprinting in early life influenced the expression of AD-related genes and promoted DNA damage and pathogenesis. These data suggest that AD pathogenesis is influenced by early life exposures and argue for both an environmental trigger and a developmental origin of AD. (shrink)

Christopher Maloney offers an explanation of the fundamental nature of thought. He posits the idea that thinking involves the processing of mental representations that take the form of sentences in a covert language encoded in the mind. The theory relies upon traditional categories of psychology, including such notions as belief and desire. It also draws upon and thus inherits some of the problems of artificial intelligence which it attempts to answer, including what bestows meaning or content upon a thought (...) and what distinguishes genuine from simulated thought. (shrink)

Thought, including conscious perception, is representation. But perceptual representation is uniquely direct, permitting immediate acquaintance with the world and ensuring perception's distinctive phenomenal character. The perceptive mind is extended. It recruits the very objects perceived to constitute self-referential representations determinative of what it is like to perceive.

The Representational Theory of the Mind allows for psychological explanations couched in terms of the contents of propositional attitudes. Propositional attitudes themselves are taken to be relations to mental representations. These representations (partially) determine the contents of the attitudes in which they figure. Thus, Representationalism owes an explanation of the contents of mental representations. This essay constitutes an atomistic theory of the content of formally or syntactically simple mental representation, proposing that the content of such a representation is determined by (...) the intersection of the representation's correlational and control properties. The theory is distinguished from standard information-based accounts of mental content in allowing that the relevant correlations be contingent while insisting on an efferent aspect to mental content. The theory on offer allows for a natural explanation of misrepresentation, finds a niche for the notion of narrow content, welcomes radical first person fallibility with respect to questions of content, admits of mental ambiguity and recognizes that the future of a psychological agent is a factor in determining the content of the agent's present psychological states. (shrink)

An account of the contents of the propositional attitudes is fundamental to the success of the cognitive sciences if, as seems correct, the cognitive sciences do presuppose propositional attitudes. Fodor has recently pointed the way towards a naturalistic explication of mental content in his Psychosemantics (1987). Fodor's theory is a version of the causal theory of meaning and thus inherits many of its virtues, including its intrinsic plausibility. Nevertheless, the proposal may suffer from two deficiencies: (1) It seems not to (...) provide an adequate explanation of misrepresentation. (2) It may also fail, as a species of empiricism, to provide a correct explication of the content of observational concepts and those non-observational concepts whose meaning is to be traced to their causal connections with observational concepts. (shrink)

The task of this paper is to clarify the status and implications of Levinas's insistence on the necessity of subjectivity to the ethical relation. Focusing in particular on the discussion of substitution in Otherwise than Being, it is argued that the description of subjectivity as substitution enables Levinas to articulate the necessity of the subject to the approach of the other in a manner which avoids the transcendental character which such claims to necessity usually embody. This argument proceeds from an (...) initial characterization of substitution within the constellation of themes pursued by Levinas in Otherwise than Being to a detailed examination of the first four sections of the Substitution chapter. The essay concludes by noting the unity of the ethical exceeding of the transcendental character of subjectivity with the project which animates Levinas's work from its beginnings: the exceeding of the ontological by the ethical. (shrink)

Alzheimer's disease is characterized by plaques of amyloid-beta peptide, cleaved from amyloid-beta protein precursor . Our hypothesis is that lifespan profiles of AD-associated mRNA and protein levels in monkeys would differ from mice and that differential lifespan expression profiles would be useful to understand human AD pathogenesis. We compared profiles of AbetaPP mRNA, AbetaPP protein, and Abeta levels in rodents and primates. We also tracked a transcriptional regulator of the AbetaPP gene, specificity protein 1 , and the beta amyloid precursor (...) cleaving enzyme . In mice, AbetaPP and SP1 mRNA and their protein products were elevated late in life; Abeta levels declined in old age. In monkeys, SP1, AbetaPP, and BACE1 mRNA declined in old age, while protein products and Abeta levels rose. Proteolytic processing in both species did not match production of Abeta. In primates, AbetaPP and SP1 mRNA levels coordinate, but an inverse relationship exists with corresponding protein products as well as Abeta levels. Comparison of human DNA and mRNA sequences to monkey and mouse counterparts revealed structural features that may explain differences in transcriptional and translational processing. These findings are important for selecting appropriate models for AD and other age-related diseases. (shrink)

The present review highlights an association between autism, Alzheimer disease , and fragile X syndrome . We propose a conceptual framework involving the amyloid-beta peptide , Abeta precursor protein , and fragile X mental retardation protein based on experimental evidence. The anabolic effect of the secreted alpha form of the amyloid-beta precursor protein may contribute to the state of brain overgrowth implicated in autism and FXS. Our previous report demonstrated that higher plasma sAPPalpha levels associate with more severe symptoms of (...) autism, including aggression. This molecular effect could contribute to intellectual disability due to repression of cell-cell adhesion, promotion of dense, long, thin dendritic spines, and the potential for disorganized brain structure as a result of disrupted neurogenesis and migration. At the molecular level, APP and FMRP are linked via the metabotropic glutamate receptor 5 . Specifically, mGluR5 activation releases FMRP repression of APP mRNA translation and stimulates sAPP secretion. The relatively lower sAPPalpha level in AD may contribute to AD symptoms that significantly contrast with those of FXS and autism. Low sAPPalpha and production of insoluble Abeta would favor a degenerative process, with the brain atrophy seen in AD. Treatment with mGluR antagonists may help repress APP mRNA translation and reduce secretion of sAPP in FXS and perhaps autism. (shrink)

J. Christopher Maloney argues that free will is compatible with necessary laws of science and immutable history. For free will emerges from an akratic will that asymptotically approaches the ability to choose to act otherwise than it willfully does.

The Representational Theory of the Mind arises with the recognition that thoughts have contents carried by mental representations. For Abelard to think, for example, that Pegasus is winged is for Abelard to be related to a MENTAL REPRESENTATION whose content is that Pegasus is winged. Now, there are different kinds of representations: pictures, maps, models, and words ‐ to name only some. Exactly what sort of REPRESENTATION is mental representation? (see imagery; connectionism.) Sententialism distinguishes itself as a version of rep‐resentationalism (...) by positing that mental representations are themselves linguistic expressions within a ‘language of thought’ (FODOR, 1975, 1987; Field, 1978; Maloney, 1989). While some sententialists conjecture that the language of thought is just the thinker's spoken language internalized (Harman, 1982), others identify the language of thought with Mentalese, an unarticulated, internal language in which the computations supposedly definitive of cognition occur. Sententialism is certainly a bold and provocative thesis, and so we turn to the reasons that might be offered on its behalf. (shrink)

Metaphors are expressions in artificial, contrived, alien languages, and we understand metaphors by constructing translation schemes linking our natural, literal languages to these theoretically contrived metaphorical languages. The relation between a literal natural language and a metaphorical contrived language is like the relationship between a natively known language and a system of subsequently acquired languages etymologically emerging from that basic natural language. This model for understanding metaphorically contrived language is kin to the familiar model explaining how speakers of a language (...) such as Latin may come to decipher a language like Spanish through projecting to Spanish what they know of Latin without the aid of a translation manual. A metaphor is, thus, seen as a sentence in a nonnatural language, itself derived from and at least partially translatable with the natural, literal language of the metaphor's author or audience. (shrink)

Variations in levels of apolipoprotein E have been tied to the risk and progression of Alzheimer's disease . Our group has previously compared and contrasted the promoters of the mouse and human ApoE gene promoter sequences and found notable similarities and significant differences that suggest the importance of the APOE promoter's role in the human disease. We examine here three specific single-nucleotide polymorphisms within the human APOE promoter region, specifically at -491 , -427 , and at -219 upstream from the (...) +1 transcription start site. The -219 and -491 polymorphic variations have significant association with instance of AD, and -491AA has significant risk even when stratified for the APOEepsilon4 allele. We also show significant effects on reporter gene expression in neuronal cell cultures, and, notably, these effects are modified by species origin of the cells. The -491 and -219 polymorphisms may have an interactive effect in addition to any independent activity. DNA-protein interactions differ between each polymorphic state. We propose SP1 and GATA as candidates for regulatory control of the -491 and -219 polymorphic sites. This work's significance lies in drawing connection among APOE promoter polymorphisms' associations with AD to functional promoter activity differences and specific changes in DNA-protein interactions in cell culture-based assays. Taken together, these results suggest that APOE expression levels are a risk factor for AD irrespective of APOEepsilon4 allele status. (shrink)

Current computational psychology, especially as described by Fodor (1975, 1980, 1981), Pylyshyn (1980), and Stich (1983), is both a bold, promising program for cognitive science and an alternative to naturalistic psychology (Putnam 1975). Whereas naturalistic psychology depends on the general scientific framework to fix the meanings of general terms and, hence, the content of thoughts utilizing or expressed in those terms, computational cognitive theory banishes semantical considerations in psychological investigations, embracing methodological, not ontological, solipsism. I intend to argue that computational (...) psychology cannot individuate thoughts as it promises. For, semantics is fundamental in fixing an important subset of the computational relations that, according to the computational theory, are supposed both to obtain among thoughts and, thereby, to determine their identity conditions. If what I contend is correct, then contrary to what its advocates maintain, computational psychology is not preferable to naturalistic psychology as a research strategy in cognitive science. (shrink)

Alzheimer's disease is characterized by formation of neuritic plaque primarily composed of a small filamentous protein called amyloid-beta peptide . The rate-limiting step in the production of Abeta is the processing of Abeta precursor protein by beta-site APP-cleaving enzyme . Hence, BACE1 activity plausibly plays a rate-limiting role in the generation of potentially toxic Abeta within brain and the development of AD, thereby making it an interesting drug target. A phase II trial of the promising LY2886721 inhibitor of BACE1 was (...) suspended in June 2013 by Eli Lilly and Co., due to possible liver toxicity. This outcome was apparently a surprise to the study's team, particularly since BACE1 knockout mice and mice treated with the drug did not show such liver toxicity. Lilly proposed that the problem was not due to LY2886721 anti-BACE1 activity. We offer an alternative hypothesis, whereby anti-BACE1 activity may induce apparent hepatotoxicity through inhibiting BACE1's processing of beta-galactoside alpha-2,6-sialyltransferase I . In knockout mice, paralogues, such as BACE2 or cathepsin D, could partially compensate. Furthermore, the short duration of animal studies and short lifespan of study animals could mask effects that would require several decades to accumulate in humans. Inhibition of hepatic BACE1 activity in middle-aged humans would produce effects not detectable in mice. We present a testable model to explain the off-target effects of LY2886721 and highlight more broadly that so-called off-target drug effects might actually represent off-site effects that are not necessarily off-target. Consideration of this concept in forthcoming drug design, screening, and testing programs may prevent such failures in the future. (shrink)

BACKGROUND: Alzheimer's disease is intimately tied to amyloid-beta peptide. Extraneuronal brain plaques consisting primarily of Abeta aggregates are a hallmark of AD. Intraneuronal Abeta subunits are strongly implicated in disease progression. Protein sequence mutations of the Abeta precursor protein account for a small proportion of AD cases, suggesting that regulation of the associated gene may play a more important role in AD etiology. The APP promoter possesses a novel 30 nucleotide sequence, or "proximal regulatory element" , at -76/-47, from the (...) +1 transcription start site that confers cell type specificity. This PRE contains sequences that make it vulnerable to epigenetic modification and may present a viable target for drug studies. We examined PRE-nuclear protein interaction by gel electrophoretic mobility shift assay and PRE mutant EMSA. This was followed by functional studies of PRE mutant/reporter gene fusion clones. RESULTS: EMSA probed with the PRE showed DNA-protein interaction in multiple nuclear extracts and in human brain tissue nuclear extract in a tissue-type specific manner. We identified transcription factors that are likely to bind the PRE, using competition gel shift and gel supershift: Activator protein 2 , nm23 nucleoside diphosphate kinase/metastatic inhibitory protein , and specificity protein 1 . These sites crossed a known single nucleotide polymorphism . EMSA with PRE mutants and promoter/reporter clone transfection analysis further implicated PuF in cells and extracts. Functional assays of mutant/reporter clone transfections were evaluated by ELISA of reporter protein levels. EMSA and ELISA results correlated by meta-analysis. CONCLUSIONS: We propose that PuF may regulate the APP gene promoter and that AD risk may be increased by interference with PuF regulation at the PRE. PuF is targeted by calcium/calmodulin-dependent protein kinase II inhibitor 1, which also interacts with the integrins. These proteins are connected to vital cellular and neurological functions. In addition, the transcription factor PuF is a known inhibitor of metastasis and regulates cell growth during development. Given that APP is a known cell adhesion protein and ferroxidase, this suggests biochemical links among cell signaling, the cell cycle, iron metabolism in cancer, and AD in the context of overall aging. (shrink)

This is Putnam at his critical best; he is once again directing the shape of the philosophy of mind for years to come. Putnam scouts with dissatisfaction the prevailing functionalist/computationalist theory of mental states, a view he himself originated more than thirty years ago. Here he despairs of any reductionist theory of mental states, denying that there are naturalistically specifiable natures comprehending mental states of the same kind, although he continues to allow that token mental states may be emergent from (...) and supervenient upon computational states. Putnam is not, then, an eliminativist. Mentalistic eliminativism implies semantic eliminativism generally and, thus, the rejection of both reference and truth, amounting absurdly--by Putnam's lights--to the loss of logic. (shrink)

BACKGROUND: Serotonin transporter promoter genotype appears to increase risk for depression in the context of stressful life events. However, the effects of this genotype on measures of stress sensitivity are poorly understood. Therefore, this study examined whether 5-HTTLPR genotype was associated with negative information processing biases in early childhood. METHOD: Thirty-nine unselected seven-year-old children completed a negative mood induction procedure and a Self-Referent Encoding Task designed to measure positive and negative schematic processing. Children were also genotyped for the 5-HTTLPR gene. (...) RESULTS: Children who were homozygous for the short allele of the 5-HTTLPR gene showed greater negative schematic processing following a negative mood prime than those with other genotypes. 5-HTTLPR genotype was not significantly associated with positive schematic processing. LIMITATIONS: The sample size for this study was small. We did not analyze more recently reported variants of the 5-HTTLPR long alleles. CONCLUSIONS: 5-HTTLPR genotype is associated with negative information processing styles following a negative mood prime in a non-clinical sample of young children. Such cognitive styles are thought to be activated in response to stressful life events, leading to depressive symptoms; thus, cognitive styles may index the "stress-sensitivity" conferred by this genotype. (shrink)