Amyloid β (Aβ) and tau protein are both implicated in memory impairment, mild cognitive impairment (MCI), and early Alzheimer's disease (AD), but whether and how they interact is unknown. ...Consequently, we asked whether tau protein is required for the robust phenomenon of Aβ-induced impairment of hippocampal long-term potentiation (LTP), a widely accepted cellular model of memory. We used wild-type mice and mice with a genetic knock-out of tau protein and recorded field potentials in an acute slice preparation. We demonstrate that the absence of tau protein prevents Aβ-induced impairment of LTP. Moreover, we show that Aβ increases tau phosphorylation and that a specific inhibitor of the tau kinase glycogen synthase kinase 3 blocks the increased tau phosphorylation induced by Aβ and prevents Aβ-induced impairment of LTP in wild-type mice. Together, these findings show that tau protein is required for Aβ to impair synaptic plasticity in the hippocampus and suggest that the Aβ-induced impairment of LTP is mediated by tau phosphorylation. We conclude that preventing the interaction between Aβ and tau could be a promising strategy for treating cognitive impairment in MCI and early AD.
The concept of heritage relates to the ways in which contemporary society uses the past as a social, political or economic resource. However, heritage is open to interpretation and its value may be ...perceived from differing perspectives - often reflecting divisions in society. Moreover, the schism between the cultural and economic uses of heritage also gives rise to potential conflicts of interest.
Examining these issues in depth, this book is the first sustained attempt to integrate the study of heritage into contemporary human geography. It is structured around three themes: the diversity of use and consumption of heritage as a multi-sold cultural and economic resource; the conflicts and tensions arising from this multiplicity of uses, producers and consumers; and the relationship between heritage and identity at a variety of scales.
The prefrontal cortex (PFC) dopamine system, which is critical for modulating PFC function, undergoes remodeling until at least young adulthood in primates. Catechol-o-methyltransferase (COMT) alters ...extracellular dopamine levels in PFC, and its gene contains a functional polymorphism (Val158Met) that has been associated with variation in PFC function. We examined COMT enzyme activity and protein immunoreactivity in the PFC during human postnatal development. Protein was extracted from PFC of normal individuals from 6 age groups: neonates (1–4 months), infants (5–11 months), teens (14–18 years), young adults (20–24 years), adults (31–43 years), and aged individuals (68–86 years; n = 5–8 per group). There was a significant 2-fold increase in COMT enzyme activity from neonate to adulthood, paralleled by increases in COMT protein immunoreactivity. Furthermore, COMT protein immunoreactivity was related to Val158Met genotype, as has been previously demonstrated. The significant increase in COMT activity from neonate to adulthood complements previous findings of protracted postnatal changes in the PFC dopamine system and may reflect an increasing importance of COMT for PFC dopamine regulation during maturation.
Using heritage resources within local urban regeneration is rarely a simple matter of preserving some structures or relating some historical events and presuming that this will make some contribution ...to the contemporary objectives of regeneration. Buildings, spaces and historic narratives are not in themselves heritage but they can become it. This paper examines a single case seeking answers to the question, 'how does heritage happen?' and specifically explores the variety of ways in which built environmental forms in particular can be treated in order to use heritage to achieve contemporary regeneration objectives.
A decade ago, A Geography of Heritage: Power, Culture and Economy was published as an attempt to understand how the present invokes the past in the service of many and diverse contemporary needs and ...how such heritage functions within political, cultural and economic arenas. This article takes a retrospective view identifying those ideas that 'flew', by being developed and elaborated by others, those that 'stalled' being largely disregarded and those that were missed then but subsequently have received much attention. The burgeoning literature on heritage and a similar growth in academic courses in heritage studies prompts the prospective question, 'where are we going?' In particular, an increasing broadening of scope combined with an increasing diversity of academic approaches, promises both an enrichment of the study of heritage but also its fragmentation. Only the development of some core of accepted definitions, terminology and at least a modicum of grounded theory can bridge the widening gap between academics and practitioners, and prevent the different academic disciplinary perspectives retreating into mutually unintelligible solitudes.
A Geography of Heritage Graham, Brian; Ashworth, G. J.; Tunbridge, J. E.
2000, 2016-04-29
eBook
The concept of heritage relates to the ways in which contemporary society uses the past as a social, political or economic resource. However, heritage is open to interpretation and its value may be ...perceived from differing perspectives - often reflecting divisions in society. Moreover, the schism between the cultural and economic uses of heritage also gives rise to potential conflicts of interest.
Examining these issues in depth, this book is the first sustained attempt to integrate the study of heritage into contemporary human geography. It is structured around three themes: the diversity of use and consumption of heritage as a multi-sold cultural and economic resource; the conflicts and tensions arising from this multiplicity of uses, producers and consumers; and the relationship between heritage and identity at a variety of scales.
Comments on comments Tunbridge, J.E.; Ashworth, G.J.; Graham, B.J.
International journal of heritage studies : IJHS,
20/6/1/, Volume:
19, Issue:
4
Journal Article
Peer reviewed
This article is a comment on: Tubridge et al., 2012. Decennial reflections on a 'geography of heritage' (2000). International Journal of Heritage Studies, DOI: 10.1080/13527258.2012.695038
The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene affects activity of the enzyme and influences performance and efficiency of the prefrontal cortex (PFC); however, ...although catecholaminergic neurotransmission is implicated, the underlying mechanisms remain elusive because studies of the role of COMT in PFC function are sparse. This study investigated the effect of tolcapone, a brain-penetrant COMT inhibitor, on a rat model of attentional set shifting, which is dependent on catecholamines and the medial PFC (mPFC). Additionally, we investigated the effect of tolcapone on extracellular catecholamines in the mPFC using microdialysis in awake rats. Tolcapone significantly and specifically improved extradimensional (ED) set shifting. Tolcapone did not affect basal extracellular catecholamines, but significantly potentiated the increase in extracellular dopamine (DA) elicited by either local administration of the depolarizing agent potassium chloride or systemic administration of the antipsychotic agent clozapine. Although extracellular norepinephrine (NE) was also elevated by local depolarization and clozapine, the increase was not enhanced by tolcapone. We conclude that COMT activity specifically affects ED set shifting and is a significant modulator of mPFC DA but not NE under conditions of increased catecholaminergic transmission. These data suggest that the links between COMT activity and PFC function can be modeled in rats and may be specifically mediated by DA. The interaction between clozapine and tolcapone may have implications for the treatment of schizophrenia.
Genome-wide association studies (GWAS) of psychiatric phenotypes have tended to focus on categorical diagnoses, but to understand the biology of mental illness it may be more useful to study traits ...which cut across traditional boundaries. Here, we report the results of a GWAS of mood instability as a trait in a large population cohort (UK Biobank, n = 363,705). We also assess the clinical and biological relevance of the findings, including whether genetic associations show enrichment for nervous system pathways. Forty six unique loci associated with mood instability were identified with a SNP heritability estimate of 9%. Linkage Disequilibrium Score Regression (LDSR) analyses identified genetic correlations with Major Depressive Disorder (MDD), Bipolar Disorder (BD), Schizophrenia, anxiety, and Post Traumatic Stress Disorder (PTSD). Gene-level and gene set analyses identified 244 significant genes and 6 enriched gene sets. Tissue expression analysis of the SNP-level data found enrichment in multiple brain regions, and eQTL analyses highlighted an inversion on chromosome 17 plus two brain-specific eQTLs. In addition, we used a Phenotype Linkage Network (PLN) analysis and community analysis to assess for enrichment of nervous system gene sets using mouse orthologue databases. The PLN analysis found enrichment in nervous system PLNs for a community containing serotonin and melatonin receptors. In summary, this work has identified novel loci, tissues and gene sets contributing to mood instability. These findings may be relevant for the identification of novel trans-diagnostic drug targets and could help to inform future stratified medicine innovations in mental health.
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