ABOUT EVENT

This International Symposium and Workshop is an integral part of a novel Uruguay-UK research network with the aim to identify and characterize the role of nutraceuticals in age-related neurodegenerative disease. It has been funded by the Science and Innovation Open Call from the UK Foreign and Commonwealth Office through the UK Embassy in Montevideo in association with Agencia Nacional de Investigación en Innovación (ANII). The objective proposed is to implement a collaborative research network for the characterization of therapeutically relevant nutraceuticals through an innovative approach combining bioinformatics with cellular and molecular biology. The combined application of cutting-edge technical approaches, along with the transference of knowledge and expertise among each participant group, will contribute to the development of translational research in Uruguay. The activities proposed will increase our understanding of the neuroprotective mechanisms of nutraceuticals, while consolidating bilateral ties in academic and translational research between Uruguay and the UK.

SCHEDULE
  • 31 march
    Thursday
  • 01 april
    Friday
  • 04 april
    Monday
  • 05 april
    Tuesday
  • 06 april
    Wednesday
9:00 - 11:00
Workshop* - Day 1

Introduction to the microfluidic culture techniques Cortical neuronal cultures
Federico Dajas-Bailador | Florencia Arredondo

11:00 - 11:30
Coffee Break
11:30 - 13:00
Workshop* - Day 1

Reverse virtual screening identification of flavonoids´ targets involved in neuroprotection
Diego Carvalho | J. Andrés Abin-Carriquiry

13:00 - 14:30
Lunch Break
14:30 - 17:30
Workshop* - Day 1

Practical activities: Demonstration of neuronal cultures in microfluidic chambers Immunocytochemistry
Federico Dajas-Bailador | Florencia Arredondo

9:00 - 11:00
Workshop* - Day 2

Preclinical models of neurodegeneration Parkinson´s Disease
Giselle Prunell
Stroke
Felicia Rivera

11:00 - 11:30
Coffee Break
11:30 - 13:00
Workshop* - Day 2

Flavonoids as nutraceuticals with neuroprotective effects: Structure-activity studies
Carolina Echeverry

9:00 - 9:30
Symposium Registration
9:30 - 9:40
Opening
J. ANDRÉS ABIN
9:40 - 11:00
Neuroprotection by flavonoids
FEDERICO DAJAS
Structural Bioinformatics applied to the study of molecular targets of bioactive compounds involved in neuroprotection
MARGOT PAULINO
11:00 - 11:30
Coffee Break
11:30 - 13:00
Modulation of wallerian degeneration by resveratrol
ALDO CALIARI
Targeting AbA cells for the treatment of ALS progression in a rat model
SILVIA OLIVERA
13:00 - 14:30
Lunch Break
14:30 - 16:00
Resveratrol in Alzheimer´s Disease: Clinical evidences
ANDRÉS DAMIAN
ILSI Europe Nutrition for the Aging Brain: Towards Evidence for an Optimal Diet
ROBERT WILLIAMS
16:00 - 16:30
Coffee Break
16:30 - 17:30
Dr. F. Dajas tribute ceremony
17:30 - 18:30
Tea Reception
9:00 - 11:00
Dietary (-)-Epicatechin as a Multi-Modal Risk Reduction Intervention for Dementia?
ROBERT WILLIAMS
Triple-Transgenic Model of Alzheimer Disease
SILVIA HERNÁNDEZ - EDUARDO SAVIO
Evaluation of the effect of resveratrol in Alzheimer 's Disease By longitudinal microPET/CT studies with 11C-PIB
LAURA REYES
11:00 - 11:30
Coffee Break
11:30 - 13:00
Modulation of cellular defenses as a putative mechanism involved in quercetin neuroprotection
FLORENCIA ARREDONDO
Understanding neuron connectivity in health and disease: search for neuroprotective targets
FEDERICO DAJAS-BAILADOR
13:00 - 14:30
Lunch Break
14:30 - 16:00
Sandpit
16:00 - 16:30
Coffee Break
16:30 - 17:30
Establishment of NP&B Network
17:30 - 18:30
Closing Symposium
9:30 - 11:00
Workshop - Day 3

Practical activities: Neuronal cultures in microfluidic chambers Epifluorescense microscopy
Federico Dajas-Bailador | Florencia Arredondo | Robert Williams

11:00 - 11:30
Coffee Break
11:30 - 13:00
Workshop - Day 3

Preclinical models of neurodegeneration (cont.) Alzheimer´s Disease
Robert Williams

* The topics of the Workshop will include:
- In vivo and in vitro models of neurodegeneration.
- Flavonoids as nutraceuticals in neuroprotection.
- In silico modeling for flavonoid target prediction.
- Microfluidic culture techniques.
- Immunocytochemistry and epifluorescense microscopy.

Coffee break, lunch break and reception meals of 4th and 5th april will be covered for all the registered attendees

speakers
  • Juan Andrés Abin-Carriquiry IIBCE
  • Federico Dajas IIBCE
  • Robert Williams University of Bath
  • Aldo Calliari IIBCE
Abstract coming soon
Neuroprotection by flavonoids

Federico Dajas
fdajas@gmail.com
IIBCE, Montevideo, Uruguay

Flavonoids, molecules present in beverages, food and plants have been demonstrated to have a role in the prevention of neurodegenerative and cerebrovascular diseases.
In neuronal culture, they increase survival against oxidative insults. Antioxidation appears to be a necessary but not sufficient condition for its neuroprotective action and modulation of intracellular signalling and transcription factors, increasing the expression of antioxidant and pro survival proteins and modulating inflammation, appears as important for neuronal protection.
Flavonoids also regulate the activity of kinases, changing the phosphorylation state of target molecules, resulting in modulation of cellular function and gene expression. In vivo, some studies show neuroprotection requiring sometimes a drug delivery system or chronic treatments to show neuroprotective effects.
Available studies show that in normal or low oxidative conditions, chronic treatments with flavonoids contribute to re-establish the redox regulation of proteins, transcription factors and survival signalling cascades that promote survival.
Evidence points to flavonoids as preventive molecules for neuropathology when administered in natural matrices such as vegetables and food. They use as lead compounds in their free form in acute treatments requires new pharmaceutical formulations and/or structural changes to improve brain bioavailability.
ILSI Europe Nutrition for the Aging Brain: Towards Evidence for an Optimal Diet.

Robert Williams
R.J.Williams@bath.ac.uk
University of Bath, UK

As global populations get older the challenges of promoting healthy brain aging across the lifespan increase and there is a need to maintain cognitive performance and combat age-associated neurodegenerative disease such as dementia. To date, the majority of drug treatments developed for neurodegenerative disorders are unable to delay the onset or prevent the progression of disease. Consequently, there is an urgent need to address these challenges by developing alternative strategies, such as the potential use of nutritional interventions which could be exploited to impact during the long prodromal phases of neurodegenerative disease. Accumulating pre-clinical and epidemiological research has suggested a beneficial impact of various aspects of nutrition on cognition in older people although outcomes from clinical trials have been largely disappointing. The International Life Sciences Institute’s European Branch (ILSI Europe) led by the Nutrition and Mental Performance Task Force are assessing the available data with a view to proposing an optimal diet to promote healthy brain ageing. Despite some good progress more research is still needed to determine the underlying mechanisms and nutrient doses for optimal brain maintenance. The most recent scientific advances specific to how diet, and in particular nutrients and non-nutrient dietary factors as well as individual and environmental differences may affect cognitive aging, is likely to prove critical. ILSI Europe are considering several key points related to mechanisms contributing to brain aging, pathological conditions affecting brain function, brain biomarkers and special dietary requirements and interventions that could promote healthy cognitive aging. Such approaches are likely to provide the much needed evidence to develop research portfolios that will inform new product development and associated health claims.

References: http://www.ilsi.org/Europe/Pages/TF_NutritionandMental.aspx

Dietary (-)-Epicatechin as a Multi-Modal Risk Reduction Intervention for Dementia?

Accumulating evidence suggests that certain dietary flavonoids might delay the onset and/or slow the progression of Alzheimer’s Disease (AD) but the precise identity of the bioactive form(s) involved is unknown and critical information about bioavailability and metabolism has hindered progress in the field. Despite significant advances in our understanding of the biology of flavonoids they are still mistakenly regarded by many as acting simply as antioxidants yet flavonoids are equally likely to combat neuronal dysfunction and toxicity by recruiting anti-apoptotic pro-survival signalling pathways, increasing antioxidant gene expression, and reducing the emergence of Aβ or tau pathology (Williams et al., 2004; Williams and Spencer, 2012). There is however, a lack of consensus as to the precise identities of the flavonoids capable of exerting these effects, partly because flavonoids have poor bioavailability and are extensively metabolised in vivo but also because many in vitro studies use concentrations that are at least 100 times higher than those found following dietary administration. We have started to address these limitations by adopting unbiased in vitro screening strategies using flavonoids at concentrations that are potentially achievable in humans to mimic more closely what occurs in vivo as a first step towards identifying possible dietary interventions for AD. Using a novel APP-GAL4 gene reporter assay in primary rodent neurones to screen modulators of amyloid precursor protein (APP) processing we identified a number of flavonoids that potently inhibited βγ-secretase activity (Cox et al., 2015). Most notably, the flavanols (−)-epicatechin and epigallocatechin reduced βγ-secretase activity and Ab production at nanomolar concentrations and reductions in Ab pathology were also observed following oral administration of (-)-epicatechin to APP-PS1 mutant mice. (-)-Epicatechin also enhanced Nrf2-mediated anti-oxidant response element mediated transcription in astrocytes and promoted PI3-kinase dependent signalling in neurones suggesting a breadth of bioactivity that could be beneficial in AD. (−)-Epicatechin is readily absorbed and circulates primarily as glucuronidated, sulfated, and O-methylated forms in human plasma, thus the observed bioactivity is most likely to reside in an (−)-epicatechin metabolite. Our working hypothesis therefore, is that dietary (−)-epicatechin, acting as prodrug, or alternatively a synthetic (−)-epicatechin analogue based on a metabolite, has the potential to be developed into a prophylactic dietary supplement for AD.

References:
Williams RJ, Spencer JP, Rice-Evans C. (2004) Flavonoids: antioxidants or signalling molecules? Free Radical Biology and Medicine. 36:838-49.
Williams RJ, Spencer JP (2012) Flavonoids, cognition, and dementia: actions, mechanisms, and potential therapeutic utility for Alzheimer disease. Free Radical Biology and Medicine. 52:35-45.
Cox CJ, Choudhry F, (2015) Dietary (−)-epicatechin as a potent inhibitor of βγ-secretase amyloid precursor protein processing. Neurobiology of Aging 36:178-87.
Abstract coming soon
  • Silvia Olivera IIBCE
  • Margot Paulino Facultad de Química, UdelaR
  • Andrés Damián CUDIM
  • Florencia Arredondo IIBCE
Abstract coming soon
Abstract coming soon
Abstract coming soon
Abstract coming soon
  • Federico Dajas-Bailador University of Nottingham
  • Laura Reyes CUDIM
  • Eduardo Savio CUDIM
Understanding neuron connectivity in health and disease: search for neuroprotective targets

Federico Dajas-Bailador
F.Dajas-Bailador@nottingham.ac.uk
University of Nottingham, UK

The capacity of neurons to polarize by developing a long axon and multiple dendrites defines their function and underlies the flow of information in the nervous system. In essence, the formation and growth of an axon comprises a series of concerted events controlled by intrinsic molecular mechanisms and extracellular cues, which lead to changes in cytoskeleton dynamics. As a whole, the process of neuronal polarization provides not only a model for the understanding of neuron development, but also for the identification of signalling processes able to promote neuronal survival after injury or disease.

The highly polarized morphology of neurons makes them very sensitive to localized environmental cues, including neurotransmitter release, differential gradients of soluble signals and changes in the extracellular matrix. For this reason, the different physiology and function of somata, axons and dendrites need to be addressed in conditions that allow for microenvironmental control. The manipulation of fluids in channels with dimensions of micrometers (microfluidics) has emerged as a distinct new field. It allows bio-analytical studies on axon development, ligand-receptor interactions and the identification of pathophysiological and therapeutic mechanisms. We have implemented microfluidic devices for the compartmentalization of axonal vs somatic domains in my lab, and we are using them for studying the molecular and cellular mechanisms that can locally influence axonal plasticity, degeneration and its response to injury.
Evaluation of the effect of resveratrol in Alzheimer 's Disease by longitudinal micro PET/CT studies with 11C-PIB

Ana Laura Reyes Veiga
laura.reyes@cudim.org
Uruguayan Centre of Molecular Imaging (CUDIM), Montevideo, Uruguay

Alzheimer's disease (AD) is a degenerative brain disorder characterized by the presence of two neuropathological hallmarks: amyloid plaques and neurofibrillary tangles.

Resveratrol is a polyphenol present in grapes and other nutrients available as nutraceutical. Many in vitro studies have indicated that it has an antioxidant effect preventing the formation of toxic beta-amyloid oligomers.

PIB is a PET radiopharmaceutical that binds to fibrillary beta-amyloid and is used clinically for the diagnosis of AD as well as in other amyloidosis.

The aim of this study is to evaluate the effect of resveratrol on amyloid depositions in a transgenic (Tg) mouse model of AD.

Two groups of Tg females mice (n=4) were used, one under treatment with resveratrol and another as sham control. The treatment started when the mice were 10 weeks old with an oral administration of (1.5-2.0) mg/day of resveratrol. Both groups were followed by PET/CT studies with PIB (Triumph® camera) at 3, 6, 9 and 15 months old.

In the treated six months old Tg mice a significant difference in PIB uptake in the hippocampus, cortex and midbrain was observed. After nine months, the significant difference was also found even in the hypothalamus and the amygdala. However, at fifteen months significant differences are the same as at the age of six months.

These preliminary results support our hypothesis that resveratrol could bind to amyloid; blocking PIB and/or delaying amyloid depositions in Tg mice. These findings must be confirmed by anatomopathology and behavioural studies, which are in process.
Triple-Transgenic Model of Alzheimer’s Disease (AD)

Silvia Hernández – Eduardo Savio
silvia.hernandez@cudim.orgeduardo.savio@cudim.org
Uruguayan Centre of Molecular Imaging (CUDIM), Montevideo, Uruguay.

A”transgenic model” (B6;129-Psen1tm1Mpm Tg(APPSwe,tauP301L)1Lfa/J) has had its genome altered through the use of genetic engineering techniques. A mouse is a suitable model because: i) the high genetic homology between human and mouse genomic sequence, ii) ease of control reproduction, iii) the availability of reagents, iv) the possibility of obtaining homozygous strains, v) humanized mouse alternative.

Predisposition for development of AD or early onset of the disease has been related to the presence of genes APOE, PSEN1/2, APP. This model has a similar evolution as AD in patients: i) exhibits plaque and tangle associated with synaptic dysfunction, ii) the Aß deposit is age dependent and specific brain´s region, iii) the cognitive deficits are related of intraneuronal Aß (Oddo, S. et al., 2003). PS1: PS1M1 46V Knockin mice were generated as a hybrid 129/C57BL6 background (Guo et al., 1999). Loss of presenilin function could promote neurodegeneration and amyloid accumulation via two distinct pathways, according to Jie Shen and Raymond Kelleher. [Xia et al., Neuron, 2015.] Single-cell embryos from mice bearing the presenilin knockin mutation were co-injected with two independent mutant human transgenes.

The following image shows phenotype timeline of the disease:

Abstract coming soon
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