The role of calcium-permeable AMPA receptors and arc in secreted amyloid precursor protein alpha-mediated plasticity

The orchestrated regulation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-subtype of glutamate receptors by neuronal activity and neuromodulators is critical to the expression of both long-term potentiation (LTP) and memory. In particular, GluA1-containing, Ca2+-permeable AMPAR (CP-AMPAR) comprise a unique role in these processes due to their transient, activity-regulated expression at the synapse. Importantly, many of the mechanisms which govern these processes are negatively affected in neurodegenerative disorders such as Alzheimer’s disease, suggesting that understanding the mode of action of neuromodulatory molecules may reveal much needed novel therapeutic interventions. Secreted amyloid precursor protein-alpha (sAPPα), a metabolite of the parent amyloid precursor protein (APP) has been previously shown to enhance hippocampal LTP and facilitate memory formation. Accordingly, we hypothesised that sAPPα may act via modulation of AMPAR synthesis and cell surface expression. Using primary hippocampal neurons grown in culture, we found that sAPPα (1 nM) differentially regulates the expression of cell surface GluA1-, GluA2-, and GluA3-containing AMPAR. Interestingly, using fluorescent non-canonical amino acid tagging with proximity ligation assay (FUNCAT-PLA), we found that short-term sAPPα treatments (1 nM, 30 min) rapidly enhanced the cell surface expression of newly synthesised extrasynaptic GluA1-, but not GluA2-containing AMPAR, while long-term treatments of sAPPα (1 nM, 120 min) increased levels of pre-existing GluA1/2-containing heteromers at the cell surface, indicating a dynamic regulation of distinct AMPARs following treatment. Moreover, using electrophysiology in area CA1 of acute hippocampal slices, we provide evidence that the expression of CP-AMPAR is important in the induction of sAPPα-enhanced LTP. Using immunocytochemistry and siRNA knockdown, we provide evidence that internalization of CP-AMPARs may be governed, at least in part by sAPPα-driven expression of the activity-regulated cytoskeletal-associated protein (Arc). Further, we show that Arc expression is not induced by the related APP metabolite sAPPβ, but is dependent on synergistic activation of N-Methyl-D-Aspartate and α7-nicotinic acetylcholine receptors, as well as downstream activation of CaMKII, MAPK, and PKG. Together, these findings suggest that application of sAPPα to hippocampal neurons engages a cascade of mechanisms which enhance the synthesis and expression of AMPAR and Arc protein, in the regulation of synaptic strength and the expression of hippocampal LTP. These experiments expand upon our current knowledge underlying mechanisms of synaptic plasticity in hippocampal neurons

Neurochemistry

Neurochemistry is a flourishing academic field that contributes to our understanding of molecular, cellular and medical neurobiology. As a scientific discipline, neurochemistry studies the role of chemicals that build the nervous system, it explores the function of neurons and glial cells in health and disease, it discovers aspects of cell metabolism and neurotransmission, and it reveals how degenerative processes are at work in the nervous system. Accordingly, this book contains chapters from a variety of topics that fall into the following broad sections: I. Neural Membranes and Intracellular Signaling, II. Neural Processing and Intercellular Signaling, III. Growth, Development and Differentiation, and IV. Neurodegenerative Diseases. The book presents comprehensive reviews in these different areas written by experts in their respective fields. Neurodegeneration and neuronal diseases are featured prominently and are a recurring theme throughout most chapters. This book will be a most valuable resource for neurochemists and other scientists alike. In addition, it will contribute to the training of current and future neurochemists and, hopefully, will lead us on the path to curing some of the biggest challenges in human health

Activation of the pro-resolving receptor Fpr2 attenuates inflammatory microglial activation

Poster number: P-T099 Theme: Neurodegenerative disorders & ageing Activation of the pro-resolving receptor Fpr2 reverses inflammatory microglial activation Authors: Edward S Wickstead - Life Science & Technology University of Westminster/Queen Mary University of London Inflammation is a major contributor to many neurodegenerative disease (Heneka et al. 2015). Microglia, as the resident immune cells of the brain and spinal cord, provide the first line of immunological defence, but can become deleterious when chronically activated, triggering extensive neuronal damage (Cunningham, 2013). Dampening or even reversing this activation may provide neuronal protection against chronic inflammatory damage. The aim of this study was to determine whether lipopolysaccharide (LPS)-induced inflammation could be abrogated through activation of the receptor Fpr2, known to play an important role in peripheral inflammatory resolution. Immortalised murine microglia (BV2 cell line) were stimulated with LPS (50ng/ml) for 1 hour prior to the treatment with one of two Fpr2 ligands, either Cpd43 or Quin-C1 (both 100nM), and production of nitric oxide (NO), tumour necrosis factor alpha (TNFα) and interleukin-10 (IL-10) were monitored after 24h and 48h. Treatment with either Fpr2 ligand significantly suppressed LPS-induced production of NO or TNFα after both 24h and 48h exposure, moreover Fpr2 ligand treatment significantly enhanced production of IL-10 48h post-LPS treatment. As we have previously shown Fpr2 to be coupled to a number of intracellular signaling pathways (Cooray et al. 2013), we investigated potential signaling responses. Western blot analysis revealed no activation of ERK1/2, but identified a rapid and potent activation of p38 MAP kinase in BV2 microglia following stimulation with Fpr2 ligands. Together, these data indicate the possibility of exploiting immunomodulatory strategies for the treatment of neurological diseases, and highlight in particular the important potential of resolution mechanisms as novel therapeutic targets in neuroinflammation. References Cooray SN et al. (2013). Proc Natl Acad Sci U S A 110: 18232-7. Cunningham C (2013). Glia 61: 71-90. Heneka MT et al. (2015). Lancet Neurol 14: 388-40

COMING TO THE SURFACE: THE ENVIRONMENT, HEALTH, AND CULTURE IN BUTTE, MONTANA

Butte is a small town in southwest Montana that was profoundly shaped by over a century of mining and smelting activities. Today, Butte is a post-industrial city that is the focal point of America\u27s largest Superfund site as well as the nation\u27s largest National Historic District. There are two types of remediation occurring in Butte: environmental and cultural. Environmental remediation occurs throughout the city, most notably at the operable units of the Butte Superfund sites. This remediation does not restore the environment to its original state but instead reclaims it to a level of risk deemed acceptable by the EPA. Much like environmental remediation, community members practice acts of reclaiming history, landscape, and community. These are acts of cultural reclamation. To understand the current interrelationship between the environment, health, and culture in Butte, it is first necessary to understand the cultural foundations. Butte is a mining town that practices mining culture. A mining culture has several characteristics: physical and/or cultural isolation; pride in resilience, toughness, and craftsmanship; strong sense of community and kin networks; distrust of institutions, politics, and positions of power; historic pride and romanticizing the past; and gender division. These cultural values are at the core of Butte\u27s culture and heritage. These values are a basis for historic preservationists who oppose environmental remediation and promote the preservation of the historic mining landscape. This is in sharp contrast to the environmental groups that promote environmental remediation and cite elevated risk levels and potential health effects in their reasoning. Debate about risk levels and the consequences of living in a toxic landscape do not provide answers regarding health issues, however. The community does not track disease rates and has never performed a longitudinal epidemiology study. By remaining unaware of disease rates, the community and those in positions of power are left with only opinions. As a remedy, this study set out to investigate mortality rates in Butte and compare them to the state of Montana and the United States. This study showed that the majority of the mortality rates in Butte are greater than the state of Montana and United States rates for all disease groups, and that mortality rates fluctuate over time but are consistently elevated. It also showed that mortality rates correlate with the target systems of concern. It did not show a clear reduction in mortality rates after remediation. Several diseases, such as neurological disease, did decrease after remediation, and this potentially correlates to the extensive lead abatement program in the city

Positive adaptation to Dementia: A Realist Evaluation of family carers’ journey towards Resilience

Background: Prevalence of dementia and especially Alzheimer’s disease (AD) is increasing exponentially, both in the U.K. and more globally. Reliance on family carers of people living with AD (FCOPWA) to provide the backbone of care remains critical and continued reliance on such carers also represents current governmental policy. However, carers are vulnerable to salient health inequalities and chronic variable stress in particular as a direct consequence of taking on the carer role. The numbers of those family carers whose own health and wellbeing might be affected has reached unprecedented levels which are set to increase further in future. Aims: This study therefore aims to investigate ways in which FCOPWA can be optimally supported to maintain and sustain family care over the course of the AD trajectory. Research questions: ‘What works’ ‘when’ and ‘in what circumstances’ to enable the FCOPWA?’ Design: this study adopted a scientific realist methodology to identify ‘generative mechanisms’ which support the long-term maintenance and sustenance of FCOPWA. A rapid realist review (RRR) is employed to investigate a comprehensive range of candidates for ‘what enables the FCOPWA,’ draw up a new conceptual framework based on ‘what works’ and formulate candidate Program Theories (CPTs) to be empirically tested. Testing comprised eighteen in-depth interviews with family carers to gather data which could be analysed to further investigate the CPTs. This led to the establishment of more specific and narrowly defined Program Theories (PTs). Findings: Five PTs emerged, presenting an adaptive carer pathway covering the three main stages of the AD trajectory. This adaptive pathway was underpinned by resilience as a key mechanism and facilitated by the adaptive and differentiated employment of a range of problem and emotion-focused coping approaches and strategies. Hope was also found to provide a pivotal positive and motivating influence throughout the FCOPWA. The pathway offered a way to promote the sustainability of FCOPWA. Conclusions: The adaptive pathway outlined by this study may also prove useful in similar adult care contexts beyond AD and dementia. Additionally, the three main emergent strands: resilience, coping and salutogenesis might be usefully combined to represent an alternative paradigm to the traditional Medical model as part of the solution to the burgeoning question of how diseases which are chronic and life-limiting but not life-threatening such as dementia, but also other diseases with similar criteria, can be better served and supported in future by health and social care system

Effects of cholinesterase inhibition on brain function

Pharmacological-functional imaging provides a non-invasive method by which the actions of neurotropic drugs on the human brain can be explored. Simply put, it assesses how neural activity patterns associated with cognitive functions of interest are modified by a drug challenge. Since one of the most widely-used cognitive-enhancing drugs in clinical practice are cholinesterase inhibitors, this thesis applies pharmacological functional imaging to the question of understanding how such drugs work - both in healthy people and dementia. The experiments in this thesis describe how brain activations – as revealed by functional magnetic resonance imaging (fMRI) – are modulated by the cholinesterase inhibitor physostigmine, during tasks designed to isolate sensory, attentional, and memory processes. While non-human and human psychophysical studies suggest that all three of these cognitive functions are under the control of the endogenous cortical cholinergic system, understanding how neurobiological models of cholinergic function translate into human brain activation modulations is unclear. One main question that is particularly relevant in this regard, that recurs through all the experiments, is how physostigmine-induced neuromodulations differ between sensory-driven ‘bottom-up’, and task-driven ‘top-down’, brain activations. The results are discussed with reference both to non-human physiological data and to existing human cholinergic-functional imaging studies (fifty studies published to date), which are themselves reviewed at the outset. Furthermore, assumptions based upon the physical and physiological principles of pharmacological functional imaging, being critical to interpretation, are discussed in detail within a general methods section