The Neurobiotechnology Group of the UJI explores how to curb neuroinflammation and the brain insulin resistance underlying many neurological and psychiatric disorders



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## The Neurobiotechnology Group of the UJI explores how to curb neuroinflammation and the brain insulin resistance underlying many neurological and psychiatric disorders

19/07/2023 |
SCP

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Central and systemic inflammation is increasingly recognised by the international scientific community as a common denominator for neurological and psychiatric disorders. This characteristic is shared by conditions such as the metabolic syndrome that induces insulin resistance, Alzheimer's disease (AD), Parkinson's disease or psychiatric disorders such as depression or attention deficit hyperactivity disorder (ADHD). Yet, the reasons why a neuroinflammatory process leads to specific psychiatric or neurological symptoms remain unknown.

The Universitat Jaume I in Castelló has several teams working on the study of the neuronal factors that influence the development of these diseases, including the [Neurobiotechnology Group](https://www.uji.es/serveis/ocit/base/grupsinvestigacio/detall?codi=268) led by Ana María Sánchez Pérez, of the Department of Medicine in the Faculty of Health Sciences and the Institute of Advanced Materials (INAM). The group is made up of the postdoctoral researcher Sandra Sánchez-Sarasúa (with a *Margarita Salas* contract at the University of Bordeaux) and the doctoral students María Meseguer-Beltrán, Ania Canseco-Rodríguez and Sariah Narcizo-Giraldo. In addition, every year there are students preparing their Master's Thesis, others from the Study & Research programme and some doing external work placements at national and foreign universities, as well as Fulbright scholarship holders.

In its most recent studies, the group has proposed a treatment with a plant hormone, abscisic acid (ABA), to reduce neuroinflammation in animal models of ADHD, a psychiatric neurodevelopmental disorder. Central dopaminergic dysfunction is one of the causes now recognised as a determining factor in ADHD. This deficit leads to impulsivity, hyperactivity, inattention and is often associated with emotion regulation problems, including increased sensitivity to pain. In the study "Targeting Neuroinflammation with Abscisic Acid Reduces Pain Sensitivity in Females and Hyperactivity in Males of an ADHD Mice Model" the group proved that, in a validated preclinical model of ADHD, dopamine deficiency induces neuroinflammation in certain areas of the brain, and showed that reducing dopamine deficiency induces a therapeutic effect without pharmacologically altering dopamine levels.

In addition, differences were found in the manifestation of symptoms depending on gender and age. In this study, females exhibited greater sensitivity to pain and males displayed greater hyperactivity. With ABA administration, these symptoms were significantly reduced and associated with a significant decrease in neuroinflammation in the brain areas involved. This article demonstrates, for the first time (according to data available to the group), that ABA supplementation as a natural anti-inflammatory has therapeutic potential in the management of ADHD, thereby opening new effective non-pharmacological alternatives in the treatment and/or prevention of this syndrome.

Alzheimer's disease is one of the topics constantly being researched by the Neurobiotechnology group, given that in this neurodegenerative disease cerebral insulin resistance and neuroinflammation play a decisive role prior to the deposits of amyloid plaques and neurofibrillary tangles. In the article "Long Non-Coding RNAs, Extracellular Vesicles and Inflammation in Alzheimer's Disease" the authors reviewed studies focusing on the positive relationship between long non-coding RNA (lncRNA) and the underlying neuroinflammation in this disease. The conclusion of the study supports the emerging role of lncRNAs in the identification of biomarkers of Alzheimer's disease to aid diagnosis as well as their role as new therapeutic targets for a better and more effective intervention, including precision medicine.

Another important aspect in this disease is the dysbiosis of the gut microbiota; the group has reviewed the most recent clinical trials on probiotic intervention to prevent its progression in people with mild cognitive impairment. The conclusion from the review is that the use of probiotics may be helpful in individuals with mild cognitive impairment and may delay its progression.

Indeed, early intervention in the case of Alzheimer's remains the most effective way of managing the disease and delays its progression to a considerable extent. In this line, a few years ago the group reported the beneficial impact of early intervention with ABA in a preclinical model of Alzheimer's disease. In humans, the FINGER study showed that a multimodal intervention (exercise, diet and cognitive training) over two years had beneficial and remarkable effects in people with mild cognitive impairment and at risk of developing the disease.

For early intervention it is important to be able to assess the risk of developing the disease long before the first symptoms appear. In this field, Artificial Intelligence (AI) studies are giving rise to new and reliable prediction methods. In the study "Prediction of Alzheimer's disease by a novel image-based representation of gene expression" the Neurobiotechnology group, in collaboration with Dr Habil Kalkan, has developed a reliable AI model capable of detecting the risk of Alzheimer's disease based on gene expression arrays using blood samples. The proposal develops a new method of prediction, consisting in transforming the one-dimensional gene expression information into a discriminative two-dimensional image. The method described in the article provides a high rate of accuracy in predicting the risk of developing the disease early in life and offers the possibility of widespread implementation that favours prevention.

Another line of research the group is working on is the study of brain insulin resistance as a target in the treatment and management of this disease. Insulin and insulin-like growth factor-1 (IGF-1) play a major role in neuronal survival and in brain activity throughout life. The group has also published two articles in recent years demonstrating the importance of the insulin receptor substrate (IRS1) as a key player at the crossroads of synaptic maturation processes during development and in degenerative processes.

Much of this research has been carried out in collaboration with other scientists from the Institute of Neurodegenerative Disorders of the University of Bordeaux (France); Department of Health Sciences of the University West (Sweden); Department of Biology of the University of Naples Federico II (Italy); Department of Computer Engineering of the Gebze Technical University and Department of Physiology of the Istanbul Okan University (Turkey).

**Articles**

Meseguer-Beltrán M, Sánchez-Sarasúa S, Landry M, Kerekes N, Sánchez-Pérez AM. Targeting Neuroinflammation with Abscisic Acid Reduces Pain Sensitivity in Females and Hyperactivity in Males of an ADHD Mice Model. Cells. 2023;12(3):465. <https://doi.org/10.3390/cells12030465>

Canseco-Rodriguez A, Masola V, Aliperti V, Meseguer-Beltran M, Donizetti A, Sanchez-Perez AM. Long Non-Coding RNAs, Extracellular Vesicles and Inflammation in Alzheimer's Disease. Int J Mol Sci. 2022;23(21):13171. <https://doi.org/10.3390/ijms232113171>

Sánchez-de-Lara-Sánchez S, Sánchez-Pérez AM. Probiotics Treatment Can Improve Cognition in Patients with Mild Cognitive Impairment: A Systematic Review. J Alzheimers Dis. 2022;89(4):1173-1191. <https://doi.org/10.3390/foods10071672>

Espinosa-Fernández V, Mañas-Ojeda A, Pacheco-Herrero M, Castro-Salazar E, Ros-Bernal F, Sánchez-Pérez AM. Early intervention with ABA prevents neuroinflammation and memory impairment in a triple transgenic mice model of Alzheimer´s disease. Behav Brain Res. 2019;374:112106. <https://doi.org/10.1016/j.bbr.2019.112106>

Kalkan H, Akkaya UM, Inal-Gültekin G, Sanchez-Perez AM. Prediction of Alzheimer's Disease by a Novel Image-Based Representation of Gene Expression. Genes (Basel). 2022;13(8):1406. 6. [10.3390/genes13081406](https://doi.org/10.3390/genes13081406)

Sánchez-Sarasúa S, Meseguer-Beltrán M, García-Díaz C, Beltrán-Bretones MT, ElMlili N, Sánchez-Pérez AM. IRS1 expression in hippocampus is age-dependent and is required for mature spine maintenance and neuritogenesis. Mol Cell Neurosci. 2022;118:103693. [https://doi.org/10.1016/j.mcn.2021.103693](https://doi.org/10.1016/j.mcn.2021.103693 "Persistent link using digital object identifier")

Sánchez-Sarasúa S, Ribes-Navarro A, Beltrán-Bretones MT, Sánchez-Pérez AM. AAV delivery of shRNA against IRS1 in GABAergic neurons in rat hippocampus impairs spatial memory in females and male rats. Brain Struct Funct. 2021;226(1):163-178. <http://dx.doi.org/10.1007/s00429-020-02155-x>

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