A canine model of human aging and Alzheimer's disease

AbstractThe aged dog naturally develops cognitive decline in many different domains (including learning and memory) but also exhibits human-like individual variability in the aging process. The neurobiological basis for cognitive dysfunction may be related to structural changes that reflect neurodegeneration. Molecular cascades that contribute to degeneration in the aging dog brain include the progressive accumulation of beta-amyloid (Aβ) in diffuse plaques and in the cerebral vasculature. In addition, neuronal dysfunction occurs as a consequence of mitochondrial dysfunction and cumulative oxidative damage. In combination, the aged dog captures key features of human aging, making them particularly useful for the development of preventive or therapeutic interventions to improve aged brain function. These interventions can then be translated into human clinical trials. This article is part of a Special Issue entitled: Animal Models of Disease

Structural brain correlates of serum and epigenetic markers of inflammation in major depressive disorder

Funding Information: Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006] and is currently supported by the Wellcome Trust [216767/Z/19/Z]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Edinburgh Clinical Research Facility, University of Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) Reference 104036/Z/14/Z). CG is supported by The Medical Research Council and The University of Edinburgh through the Precision Medicine Doctoral Training program. SRC is supported by the UK Medical Research Council [MR/R024065/1] and a National Institutes of Health (NIH) research grant R01AG054628. Acknowledgements The authors thank all of the STRADL and Generation Scotland participants for their time and effort taking part in this study. We would also like to thank all of the research assistants, clinicians and technicians for their help in the collecting this data.Peer reviewedPublisher PD

Glutamatergic neurotransmission in aging: a critical perspective.

Abstract The effects of aging on glutamate neurotransmission in the brain is reviewed and evaluated. Glutamate is the neurotransmitter in most of the excitatory synapses and appears to be involved in functions such as motor behaviour, cognition and emotion, which alter with age. However, relatively few studies have been conducted to study the relationship between glutamate and aging of the brain. The studies presented here indicate the existence of a number of changes in the glutamatergic system during the normal process of aging. First, an age-related decrease of glutamate content in tissue from cerebral cortex and hippocampus has been reported, although it may be mainly a consequence of changes in metabolic activity rather than glutamatergic neurotransmission. On the other hand, studies in vitro and in vivo have shown no changes in glutamate release during aging. Since glutamate sampled in most of these studies is the result of a balance between release and uptake processes, the lack of changes in glutamate release may be due to compensatory changes in glutamate uptake. In fact, a reduced glutamate uptake capacity, as well as a loss in the number of high affinity glutamate transporters in glutamatergic terminals of aged rats, have been described. However, the most significant and consistent finding is the decrease in the density of glutamatergic NMDA receptors with age. A new perspective, in which glutamate interacts with other neurotransmitters to conform the substrates of specific circuits of the brain and its relevance to aging, is included in this review. In particular, studies from our laboratory suggest the existence of age-related changes in the interaction between glutamate and other neurotransmitters, e.g. dopamine and GABA, which are regionally specific

Current and Future Issues in the Development of Spinal Agents for the Management of Pain.

Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety

Efecto de la edad y la inflamación sobre el sistema glutamatérgico en un modelo de isquemia cerebral en rata = Age and Inflammation Effect on the Glutamatergic System in a Rat Cerebral Ischemia Model

143 p.El objetivo de este estudio es analizar el papel de la edad en la respuesta a la isquemia cerebral, para lo que se utilizaron ratas Sprague-Dawley de 3 y 18 meses de edad en un modelo de isquemia global seguido de 48 horas de reperfusión, analizándose adicionalmente el efecto producido por el agente antiinflamatorio meloxicam. Para tener una medida de la actividad transcripcional y de la expresión de algunos de los genes implicados en la isquemia cerebral, se realizaron ensayos de PCR en tiempo real y de Western blot. También se realizaron estudios de inmunohistoquímica para observar la muerte neuronal retrasada y la respuesta inflamatoria. En este trabajo se concluye que la “parada transcripcional” de varios genes del sistema glutamatérgico actúa como un mecanismo protector frente al daño excitotóxico inducido por la isquemia-reperfusión. Este mecanismo sufre una atenuación dependiente de la edad que podría explicar la mayor mortalidad inducida por la isquemia, lo que se pone muy claramente de manifiesto en los animales 18 meses sometidos al tratamiento con meloxicam. La respuesta a la isquemia de l transportador GLT-1 parece ser más dependiente de cambios neuronales que gliales, a pesar del incremento de la gliosis. Las diferencias en los niveles de expresión y/o transcripción de algunos de los genes estudiados podrían explicar parcialmente la vulnerabilidad diferencial observada entre el hipocampo y la corteza cerebral, pero no explicarían la vulnerabilidad diferencial de las distintas áreas hipocampales. Nuestros datos apoyan la hipótesis de que existen cambios en la permeabilidad al calcio como respuesta a la isquemia-reperfusión, aunque estos cambios tampoco explican completamente la vulnerabilidad diferencial asociada a la edad o las diferentes áreas encefálica

A study of cortical and hippocampal NMDA and PCP receptors following selective cortical and subcortical lesions

The neuronal localization of glutamate and phencyclidine (PCP) receptors was evaluated in the cerebral cortex and hippocampal formation of rat CNS using quantitative autoradiography. Scatchard analysis of [3H]glutamate binding in the cortex (layers I and II and V and VI) showed no difference in the total number of binding sites (Bmax) or apparent affinity (Kd) 1 week, 1 month and 2 months following unilateral ibotenate lesions to nucleus basalis of Meynert (nbM) compared to the non-lesioned side. Quisqualic acid displacement of [3H]glutamate in layers I and II, 1 week following nbM destruction, revealed both high- and low-affinity binding sites (representing the quisqualate (QA) and (NMDA) sites, respectively). Compared to the control side, there was no difference in binding parameters for either of the receptors sites. In similarly lesioned animals, the NMDA receptor was specifically labelled with [3H]glutamate and the associated PCP receptor labelled with [3H]N-(1-[2-thienyl]cyclohexyl)3,4-piperidine ([3H]TCP) in adjacent brain sections. For both receptors, there was no change in the total number of binding sites in the cortex following destruction of nbM. On the other hand, virtually all binding to NMDA and PCP receptors was eliminated following chemical destruction of intrinsic cortical neurons. These results suggest that the NMDA/PCP receptor complex does not exist on the terminals of cortical cholinergic afferents. One week after knife cuts of the glutamatergic entorhinal pathway to the hippocampal formation only an approximate 10% reduction of NMDA and PCP receptors was seen in the dentate gyrus. Conversely, selective destruction of the dentate granule cells using colchicine caused a near identical loss of NMDA and PCP receptors (84% vs 92% respectively). It is concluded from these experiments that glutamate and PCP receptors exist almost exclusively on neurons intrinsic to the hippocampal formation and that no more than 10% of NMDA and PCP receptors exist as autoreceptors on glutamatergic terminals.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/29507/1/0000594.pd

Cortical neurones in Alzheimer's disease.

Two major neurotransmitter systems, cholinergic and glutamatergic, have been studied, mainly in the cortex of patients with Alzheimer's disease. Choline acetyltransferase (ChAT) activity was assayed in 15 areas of the cerebral cortex taken post-mortem from patients with Alzheimer's disease and controls. The number of neurofibrillary tangles was determined in an adjacent tissue sample. ChAT reduction and tangle numbers were maximal in structures of the medial temporal lobe (the uncus, amygdala, hippocampus and parahippocampal gyrus), severe in the neocortex on the lateral surface of the temporal lobe, moderate in the association cortex of the cortex of the parietal and frontal lobes and minimal in the primary somatic and visual sensory areas. These results are interpreted as providing support for the hypothesis that the pathological process in Alzheimer's disease may spread along a sequence of cortico-cortical connections between the main sensory area and the hippocampal formation. Earlier work in this laboratory suggested that glutamatergic neurones are involved in this process. Furthermore, tangles appear to be localized in pyramidal cells which probably use glutamate as their transmitter. Due to a lack of a suitable enzyme marker for glutamatergic cells, this type of cell is extremely difficult to investigate in humans. A drug with possible efficacy in Alzheimer's disease has been examined for effects on glutamatergic neurones (using laboratory animals). In addition a glutamate receptor subtype has been studied in detail, using post-mortem human tissue. Tetrahydro-9-aminoacridine (tacrine), an alleged drug for the treatment of Alzheimer's disease was examined for effects on glutamatergic neurones in rat brain. The Ca2+-dependent release and Na+-dependent uptake of amino acids in tissue prisms were inhibited by the drug. Extracellular amino acid concentrations (collected by in vivo microdialysis and measured by HPLC with fluorometric detection) were elevated by the drug. However, none of these effects were observed with concentrations thought to be clinically relevant suggesting that the alleged clinical benefit is dependent on the well documented cholinomimetic actions of this drug. The binding of [3H]-(+)-5-methyl-10 ,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10 imine maleate [3H]-MK-801) and [3H]-1-[1-(2-thienyl)cyclohexyl]piperidine [3H]- TCP) to the N-methyl D-aspartate (NMDA) receptor complex were studied in control post-mortem human brain taken from all cortical areas which was pooled before study. Binding of both ligands was stimulated by glutamate and glycine but the addition of both glutamate and glycine together resulted in an additional effect on [3H]-MK-801 binding only. Saturation analysis revealed approximately twice as many high affinity sites for [3H]-MK-801 than for [3H]-TCP binding. Cortical tissue from the temporal lobe, a severely affected area in Alzheimer's disease, and the frontal lobe, moderately affected, from a number of patients were assayed by radioligand binding for the density of the NMDA receptor complex using [3H]-MK- 801 and [3H]-TCP binding. There did not appear to be an alteration in the density of this receptor in Alzheimer's disease in the temporal cortex but there was a decrease in [3H]-MK-801 binding in the frontal cortex. The modulation of the NMDA receptor complex by glutamate, glycine, zinc and a polyamine, was examined in post-mortem human brain. In control brain the modulation by all four substances was similar to that in rat brain indicating that the NMDA receptor complex is similar in rat and human brain. In Alzheimer's disease tissue, there appeared to be a selective impairment of regulation by glycine and spermidine. These data are discussed in terms of a starting point for rational pharmacotherapy for Alzheimer's disease

Neuroinflammatory processes in cognitive disorders:Is there a role for flavonoids and n-3 polyunsaturated fatty acids in counteracting their detrimental effects?

Neuroinflammatory processes are known to contribute to the cascade of events culminating in the neuronal damage that underpins neurodegenerative disorders such as Parkinson's and Alzheimer's disease. With the ageing population and increased cases of neurodegenerative diseases, there is a crucial need for the development of new strategies capable to prevent, delay the onset or treat brain dysfunction and associated cognitive decline. Growing evidence sheds light on the use of dietary polyphenols and n-3 long chain polyunsaturated fatty acids to improve cognitive performances and reduce the neuroinflammatory and oxidative stress responses occurring with age and neurodegenerative pathologies. This review will summarise the most recent information related to the impact and mechanisms underlying the neuroinflammatory processes in neurodegenerative disorders. We will also detail the current evidence indicating that flavonoids and n-3 polyunsaturated fatty acids are strong candidate in preventing neuroinflammation and modulating age-related memory decline, and will describe the potential mechanisms of action underlying their neuroprotective effects. As such, these dietary bioactives represent important precursor molecules in the quest to develop of a new generation of drugs capable of counteracting neuroinflammation and neurodegenerative diseases