FotoCNPqCristoforo Scavone, Ph.D. – Professor – Pharmacology Department – Institute of Biomedical Sciences – University of São Paulo

Our research employs a multifaceted array of experimental models of aging and age-related neurodegenerative disorders to establish the molecular and biochemical changes that occur during aging and in disorders such as Alzheimer’s and Parkinson’s diseases. An area of focus is to understand adaptive cellular stress responses in neurons and how they can be activated by behavioral and pharmacological interventions to protect the brain against injury and disease.

Data obtained in these experimental models are integrated with data obtained in studies of normal elderly humans and patients with neurodegenerative disorders to arrive at conclusions as to why neuronal dysfunction and degeneration occur in the disorders. Discoveries made in animal models in the laboratory are being translated into preclinical studies and clinical trials in human subjects.

Segundo Elisa Kawamoto, um dos desafios da ciência é descobrir o que há de diferente no cérebro de quem envelhece sadiamente e daquele que desenvolve uma doença degenerativa. Foto: Francisco Emolo

Elisa Kawamoto, Ph.D. – Assistant Professor – Pharmacology Department – Institute of Biomedical Sciences – University of São Paulo

Molecular and Functional Neurobiology Laboratory – Changes in cognitive abilities are a typical feature of the normal aging process and many chronic neurodegenerative disorders, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. Although the etiology is different, a common hallmark amongst all these disorders is neuroinflammation. In the last decade, clinical trials to determine the efficacy of anti-inflammatory drugs in preventing cognitive decline have given contradictory results. Thus, it is necessary to further our knowledge of the complex and still elusive role of the inflammatory process in cognitive dysfunction. It also emphasizes the requirement to identify therapeutic agents with pleiotropic rather than mere anti-inflammatory properties.

Caio Mazuanti, Ph.D., NIH, USA. & Research fellow University of Sao Paulo, Brazil  – Foto: Cecília Bastos/USP.

Studies prove the benefits of “longevity protein” in the brain, which was named Klotho. This protein is antioxidant, anti-inflammatory, and vital for lactate production, one of the neurons’ foods. In Greek mythology, the “Moiras” were three women who made, wove, and cut the threads of men and gods’ lives. One of them, named Klotho, was responsible for weaving this thread. In 1997, Japanese researchers discovered Klotho protein that regulates aging and is associated with longevity. Since then, the protein has been studied by several research groups around the world. At the University of Sao Paulo, some of these studies are done at the Laboratory of Molecular Neuropharmacology of the Institute of Biomedical Sciences, under the leadership of Professor Cristoforo Scavone. The most recent work published by the group brings unprecedented findings that show that klotho stimulates the production of lactate (one of the foods of neurons) and is essential in insulin signaling and exerting an antioxidant and anti-inflammatory action on the central nervous system.

The data are in the article Activity-dependent neuronal Klotho enhances astrocytic aerobic glycolysis published in the Journal of Cerebral Blood Flow and Metabolism (https://doi.org/10.1177/0271678X18762700). The research is the result of the doctoral thesis of the neuroscientist Caio Mazucanti (Ph.D. Pharmacology) conducted under the guidance of Professor Scavone. Mazucanti explains that in human DNA, there is the klotho gene. This gene produces the klotho protein, mainly in the kidneys and brain, and throws it into the bloodstream. In the brain, this occurs in neurons. However, with the aging process, its presence decreases in the body. And that decrease is even more significant when there are neurodegenerative diseases like Alzheimer’s and Parkinson’s.

Cristoforo Scavone, professor do ICB e Marina Cararo , mestranda no laboratório de Neurofarmacologia Molecular.Foto: Cecilia Bastos/USP Imagem

Cristoforo Scavone, Professor – University of Sao Paulo, Brazil & Marina Cararo, Ph.D. student – Rutgers University, USA. Cecilia Bastos/USP

Studies of the same group also found that the drop in klotho protein levels in the body, in conditions such as chronic kidney disease, is related to the appearance of damage to the central nervous system, including cognitive deficit (https://doi.org/10.1371/journal.pone.0125271).

New studies of our laboratory seek to reveal klotho’s physiological actions in the central and peripheral nervous system, aiming to discover potential therapeutic uses. This protein, produced by the body and present in the cell membrane or the circulation, seems to perform physiological functions that can be exploited to prevent or treat specific diseases related to aging.

Na+/K+-ATPase is a transmembrane ion pump that is essential for the maintenance of ion gradients and regulation of multiple cellular functions. Na+/K+-ATPase has been associated with nuclear factor kappa B (NFκB) signalling, a signal associated with lipopolysaccharides (LPSs)-induced immune response in connection with activated Toll-like receptor 4 (TLR4) signalling. However, the contribution of Na+/K+-ATPase to regulating inflammatory responses remains elusive. Recent studies report that mice haploinsufficient for the astrocyte-enriched α2Na+/K+-ATPase isoform (α2+/G301R mice) have a reduced proinflammatory response to LPS, accompanied by a reduced hypothermic reaction compared to wild type litter mates. Following intraperitoneal injection of LPS, gene expressions of Tnf-α, Il-1β, and Il-6 was reduced in the hypothalamus and hippocampus from α2+/G301R mice compared to α2+/+ littermates. The α2+/G301R mice experienced increased expression of the gene encoding an antioxidant enzyme, NRF2, in hippocampal astrocytes. Our findings indicate that α2Na+/K+-ATPase haploinsufficiency negatively modulates LPS-induced immune responses, highlighting a rational pharmacological target for reducing LPS-induced inflammation. (https://doi.org/10.1038/s41598-020-71027-5).

Inverse sex-based expression profiles of PTEN and Klotho in mice.

Sex differences are considered predictive factors in the development of several neurological diseases, which are also known to coincide with impaired phosphoinositide 3-kinase (PI3K)-AKT pathway activity, an essential signaling cascade involved in the control of several cellular functions such as autophagy and apoptosis. Here, under physiological conditions, we show important sex differences in the underlying balancing mechanisms that lead to similar AKT activity levels and autophagy and apoptosis processes in the two sexes. We demonstrate inverse sex-based expression of PTEN and Klotho, two important proteins that are known to negatively regulate the AKT pathway, and inverse sex-dependent levels of mTOR and FoxO3a activity. Taken together, our findings indicate that inverse sex-based regulation may be one of the underlying balancing mechanisms that differ between the sexes and a possible cause of sex-based autophagic and apoptotic responses to triggering situations that can lead to a sex-based predisposition to some neurological diseases. Sci Rep 2020 Nov 19;10(1):20189. Epub 2020 Nov 19.