ALZOBIN

In recent decades, increased life expectancy and a sedentary lifestyle have resulted in an aging and obese society. This fact translates into a higher incidence of diabetes, cardiovascular and/or neurodegenerative diseases that cause millions of deaths each year and significantly increase the associated healthcare costs. On the other hand, aging, and related neurological disorders, are complex phenomena characterized by a chronic inflammatory state of low Degree (a process that also occurs in obesity) known as inflammaging. Alzheimer's disease (AD) is the neurological disorder with the highest incidence in Spain, with a prevalence of 5-10% among people over 65 years of age. The main risk factor for AD is advanced age but recently it has been identified that obesity is another transcendental risk factor for the development of this pathology. Although the exact mechanism by which obesity facilitates the development of AD is not known, it has been suggested that an altered secretion of proinflammatory adipokines could induce neuroinflammation, altering cognitive function.

However, to date there are no effective pharmacological treatments for either of these two diseases. The main goal of this project is to characterize whether p27-Cdk2 axis proteins can become a new therapeutic target for the treatment of obesity and AD risk.

Our hypothesis is based on the fact that, at the molecular level, several programs of study have defined essential pathophysiological functions of different components of the cell cycle machinery in AD and obesity. Thus, p27 inhibits Cdk2 and Cdk5, kinases involved in the phosphorylation of Tau, one of the main histopathological markers of AD. In addition, the role of the p27-Cdk2 axis in neurogenesis has been demonstrated and, on the other hand, p27 knockout mice show higher levels of proinflammatory cytokines, which would point to its role in the inflammaging process. Furthermore, preliminary programs of study and programs of study in silico our group suggest a variation of different axis proteins in relation to aging, AD severity Degree and obesity in brain and adipose tissue samples. However, to date, no study has analyzed the possible link between the p27-Cdk2 axis and these diseases.

To this end, the levels of p27, Cdk2, cyclin A/E (in human adipose tissue and brain samples) will be analysed and whether they are modulated by ageing, AD or obesity and the correlation of these changes with neuropathological, cognitive or inflammatory markers. The effects of the absence of p27 (p27 KO mice), during the ageing process and the susceptibility to develop obesity with a high-fat per diem expenses will also be studied in animal models. On the other hand, the possible therapeutic effects of the administration of Bortezomib (a drug used in the treatment of haematological pathologies that, among other actions, increases p27 levels) will be evaluated in animals with accelerated senescence (SAMP8), fed with a control or high-fat per diem expenses , analysing the susceptibility to prevent / reverse the cognitive deficits associated with senescence and obesity induced by per diem expenses.

The results of this project will be of great relevance as they respond to the important social, medical and economic challenge of having an increasingly aging, obese population with a higher prevalence of cognitive impairment, and the need to find effective interventions and/or therapies for healthier aging.