Vol 1-2 Mini Review

Long-term window of ischemic tolerance: An evolutionarily conserved form of metabolic plasticity regulated by epigenetic modifications?

Nathalie Khoury, Kevin B. Koronowski and Miguel A. Perez-Pinzon*

Department of Neurology and Neuroscience Program, Cerebral Vascular Disease Research Laboratories, Miller School of Medicine, University of Miami, Miami, Florida, USA

In the absence of effective neuroprotective agents in the clinic, ischemic and pharmacological preconditioning are gaining increased interest in the field of cerebral ischemia. Our lab recently reported that resveratrol preconditioning affords tolerance against a focal cerebral ischemic insult in mice that can last for at least 14 days in vivo making it the longest window of ischemic tolerance discovered to date by a single administration of a pharmacological agent. The mechanism behind this novel extended window of ischemic tolerance remains elusive. In the below commentary we discuss potential mechanisms that could explain this novel extended window of ischemic tolerance in the context of previously identified windows and the known mechanisms behind them. We also draw parallels from the fields of hibernation and hypoxia-tolerance, which are chronic adaptations to severe conditions of hypoxia and ischemia known to be mediated by a form of metabolic depression. We also briefly discuss the importance of epigenetic modifications in maintaining this depressed state of metabolism.

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Vol 1-2 Commentary

Commentary: A systematic review of the characteristics and validity of monitoring technologies to assess Parkinson's disease

Domingos J1,3, Godinho C1,2,3, Ferreira JJ1,3,4*

1Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028, Lisboa, Portugal
2Center for Interdisciplinary Research Egas Moniz (CiiEM), Instituto Superior de Ciências da Saúde Egas Moniz, Monte de Caparica, Portugal
3CNS-Campus Neurológico Sénior, Portugal
4Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, Lisbon, Portugal

Technologies may have implications for improving clinical diagnosis and prognosis, and for the development of therapeutic interventions, specific biomarkers, and preventive strategies. Given the amount of existing and ever-growing quantitative assessments using technology in PD, clinicians, patients and researchers are faced with the challenge of deciding which assessment tool to use in the laboratory, clinic and home environment. In order to facilitate this decision-making a systematic review was done to identify and classify the available monitoring technologies for individuals with PD over the last 2 decades. This is a commentary on the systematic review which adds on discussion on some controversial issues in the area. It tackles some of current open-to-discussion topics in the technology field, such as: which definitions to use, the heterogeneity of the clinimetric properties among technologies, standardization of a validation process, how to group different measuring technologies, and the need to conduct further studies on existing technologies before developing new ones. The strength of this comprehensive, timely and useful review is the detailed and robust approach taken by authors to classify technologies as listed, suggested, or recommended for the assessment of individuals with PD.

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Vol 1-2 Mini Review

Genetic risk factors of Alzheimer's disease and cell-to-cell transmission of Tau

Riikka-Liisa Uronen, Henri J. Huttunen*

Neuroscience Center, University of Helsinki, FI-00014 Helsinki, Finland

In Alzheimer’s disease (AD), loss of neurons and synapses parallels the formation of neurofibrillary tangles, protein aggregates mainly composed of hyperphosphorylated and aggregated Tau protein. Tau is mostly a cytosolic protein but can also be secreted by neurons. Cell-to-cell transfer of misfolded Tau protein plays a key role in the spread of neurofibrillary pathology between brain regions in AD and other tauopathies. Advances in genome-wide technologies have identified a large number of genetic risk factors for late-onset AD (LOAD). Currently, it remains unknown if genetic factors influence disease risk or progression rate by altering cell-to-cell propagation of Tau. Several LOAD risk genes are functionally associated with endocytic trafficking providing a potential link to Tau secretion and uptake. Recently, a LOAD risk gene FRMD4A was shown to regulate Tau secretion via a pathway linked to presynaptic vesicle machinery and polarity signaling. Tau release is linked to neuronal activity, and genetic factors that affect presynaptic vesicle release in the aging brain may also influence disease progression in AD and other tauopathies. In this mini review, we summarize the recent literature with a focus on the role of FRMD4A-cytohesin-Arf6 pathway and presynaptic vesicle machinery in the secretion of Tau.

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Vol 1-2 Mini Review

Does telomerase protein protect our neurons?

Gabriele C Saretzki

Institute for Cell and Molecular Biosciences, Newcastle Institute for Ageing, Campus for Ageing and Vitality, Newcastle University, UK

Telomerase is best known for its canonical function in telomere maintenance. However, a growing number of non-telomeric functions have been described. Several groups have found the telomerase protein TERT to persist in adult brain neurons. A protective role for the telomerase protein TERT had been demonstrated in cultivated mouse neurons during brain development, against excitotoxic stresses from N-methyl-D-aspartate (NMDA) and glutamate and agents known to be involved in neurodegenerative diseases such as beta amyloid peptides and hyperphosphorylated tau. In contrast, lack of telomerase and TERT protein increase oxidative stress and decrease neuronal survival. Research on telomerase and TERT protein in human neurodegenerative diseases is a relatively new field. However, there is emerging evidence of a beneficial role of telomerase in human brains and animal models of neurodegenerative diseases that suggests to explore the possibility of using telomerase activators as neuroprotective agents to combat brain ageing and to ameliorate neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases. The current mini-review summarises the knowledge about this developing novel area of brain research.

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Vol 1-2 Review

Substance P and Antagonists of the Neurokinin-1 Receptor in Neuroinflammation Associated with Infectious and Neurodegenerative Diseases of the Central Nervous System

Alejandra N. Martinez1, Mario T. Philipp1,2

1Division of Bacteriology & Parasitology, Tulane National Primate Research Center, Covington, LA, USA
2Department of Microbiology and Immunology, Tulane University Medical School, New Orleans, LA, USA

This review addresses the role that substance P (SP) and its preferred receptor neurokinin-1 (NK1R) play in neuroinflammation associated with select bacterial, viral, parasitic, and neurodegenerative diseases of the central nervous system. The SP/NK1R complex is a key player in the interaction between the immune and nervous systems. A common effect of this interaction is inflammation. For this reason and because of the predominance in the human brain of the NK1R, its antagonists are attractive potential therapeutic agents. Preventing the deleterious effects of SP through the use of NK1R antagonists has been shown to be a promising therapeutic strategy, as these antagonists are selective, potent, and safe. Here we evaluate their utility in the treatment of different neuroinfectious and neuroinflammatory diseases, as a novel approach to clinical management of CNS inflammation.

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Vol 1-2 Mini Review

Can the Brain Benefits of Exercise Be Enhanced Without Additional Exercise?

J. Leigh Leasure1,2*, Rebecca West1

1Department of Psychology, University of Houston, 126 Heyne Building, Houston, TX 77204-5022, United States
2Department of Biology & Biochemistry, 3455 Cullen Boulevard, Room 342, Houston, TX 77204-5001, United States

Exercise has long been considered a useful means by which to maintain brain health and treat brain diseases. Yet many of the neural benefits of exercise, such as enhanced hippocampal neurogenesis, take weeks to manifest. Moreover, the brains most in need of the restorative effects of exercise are often paired with bodies that can tolerate very little physical activity, such as those deconditioned by stroke. It would therefore be of great utility to pinpoint ways in which the brain benefits of exercise could be augmented without adding additional exercise time. Exercise represents a significant challenge to the brain because of the heat produced by exercising muscles, but physical activity in the cold attenuates this physiological burden. Using a rat model of voluntary exercise, we recently tested the hypothesis that exercise in cold ambient temperature (4.5°C) would stimulate hippocampal neurogenesis more effectively than exercise at room temperature. We found that, compared to animals that ran at room temperature, animals that exercised in the cold ran a shorter distance and for less total time. Nonetheless, they had more significantly more newly generated neurons in the hippocampal dentate gyrus, indicating that running in the cold may be an effective means by which to maximize brain exercise benefits, yet minimize exercise time.

Exercise is increasingly becoming accepted as “medicine” for diseases of both brain and body1. For the brain, exercise offers chemical, cellular and structural benefits, including enhanced generation of new neurons, glia and blood vessels2-5, increased expression of neurotrophins (such as brain-derived neurotrophic factor (BDNF)6,7), dendritic remodeling8,9 and stabilization of stress responses10 and inflammatory signaling11. These mechanisms of action directly counteract those present in disease states. For example, the depressed brain is characterized by decreased synaptic plasticity, hippocampal neurogenesis and BDNF12, all of which can be reversed by exercise.

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Vol 1-2 Research

The Female mdx Mouse: An Unexpected Vascular Story

Lorna Guéniot1a, Claire Latroche1ab, Cédric Thépenier1,2a, Laurent Chatre3,4, Aurélien Mazeraud1, Daniel Fiole1,2, Pierre L. Goossens1, Fabrice Chrétien1,5,6c and Gregory Jouvion1,5c

1Institut Pasteur, Histopathologie Humaine et Modèles Animaux, Paris, France
2Institut de Recherche Biomédicale des Armées, Interactions Hôte-Agents Pathogènes, Brétigny-sur-Orge, France
3Groupe Stabilité de l’ADN Nucléaire et Mitochondrial, CNRS UMR 3525, Paris, France
4Institut Pasteur, Cellules Souches et Développement, Paris, France
5Université Paris Descartes, PRES Sorbonne-Paris-Cité, Paris, France
6CH Sainte-Anne, Neuropathology Department, Paris, France
aGuéniot L, Latroche C, and Thépenier C contributed equally to this work
bPresent address: San Raffaele Telethon Institute for Gene Therapy; Division of Regenerative Medicine, Stem Cells and Gene Therapy; San Raffaele Scientific Institute; Milano, Italia.
cChrétien F and Jouvion G share senior co-authorship

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease, caused by absence of functional dystrophin and inevitably leading to death. A variable proportion of women carriers (2.5 to 19%) can also manifest symptoms ranging from myalgia to cardiomyopathy, and pathophysiological mechanisms are still not completely understood. Our study focused on 12 month-old female mdx mice, displaying marked chronic muscle lesions, similar to the lesions observed in human DMD. Our aim was to focus on the alterations of the vascular network organisation, and functional repercussions using a combination of histology/morphometry techniques and totally non-invasive functional approach (multiparametric and functional nuclear magnetic resonance), clearly relevant for clinical diagnosis and research, combining arterial spin labeling imaging of perfusion, and 31P-spectroscopy of phosphocreatine kinetics. Collectively, our results demonstrate that the vasculature, both in its steady state organisation and dynamic behaviour after an ischemia-reperfusion stress, is altered in the 12 month-old female mdx mouse: increased density of vascular sections in histology, modification of the post-ischemic hyperemia profile, increase in mitochondrial oxidative rephosphorylation capacity, in striking opposition to what was observed in age-matched male mdx mice. We believe the apparent discordance between vascular and muscular features in the female mdx mouse make it an interesting tool to decipher further dystrophinopathy pathophysiological mechanisms.

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