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/, Letnik:
19, Številka:
4
Journal Article
Recenzirano
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.
•We examined whether groups that differ in the activity of catechol-O-methyltransferase (COMT), either genetically or as the result of a pharmacological challenge, show differences in regional ...cerebral blood flow (CBF).•COMT genotype influenced frontal CBF, whilst COMT inhibition altered CBF in parietal and temporal regions.•Our findings demonstrate that both acute and trait differences in dopamine signalling influence regional CBF.•We recommend the inclusion of CBF measures in fMRI studies of the impact of dopaminergic manipulations on BOLD signal.
Dopamine has direct and complex vasoactive effects on cerebral circulation. Catechol-O-methyltransferase (COMT) regulates cortical dopamine, and its activity can be influenced both genetically and pharmacologically. COMT activity influences the functional connectivity of the PFC at rest, as well as its activity during task performance, determined using blood oxygen level-dependent (BOLD) fMRI. However, its effects on cerebral perfusion have been relatively unexplored. Here, 76 healthy males, homozygous for the functional COMT Val158Met polymorphism, were administered either the COMT inhibitor tolcapone or placebo in a double-blind, randomised design. We then assessed regional cerebral blood flow at rest using pulsed arterial spin labelling. Perfusion was affected by both genotype and drug. COMT genotype affected frontal regions (Val158 > Met158), whilst tolcapone influenced parietal and temporal regions (placebo > tolcapone). There was no genotype by drug interaction. Our data demonstrate that lower COMT activity is associated with lower cerebral blood flow, although the regions affected differ between those affected by genotype compared with those altered by acute pharmacological inhibition. The results extend the evidence for dopaminergic modulation of cerebral blood flow. Our findings also highlight the importance of considering vascular effects in functional neuroimaging studies, and of exercising caution in ascribing group differences in BOLD signal solely to altered neuronal activity if information about regional perfusion is not available.
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