Stress influence in neurodegeneration. Unravelling the mechanisms underlying stress response in brain ageing by 11ß-HSD1 inhibition

Abstract

The world is facing an unprecedented situation: soon the number of people over 60 years old will exceed the number of children, and more people at extreme old age than ever before. This is due to medical advances that have increased life expectancy and with it, the number of elderly. The latest data published by the WHO predicts that by 2050 the world’s population aged 60 years and older is expected to nearly double from 12% to 22% achieving a total 2 billion, up from 900 million in 2015. A longer life brings with it opportunities, however, there is little evidence to suggest that older people today are experiencing their later years in better health than their parents. While rates of severe disability have declined over the past 30 years, there has been no significant change in mild to moderate disability over the same period. If this added years are dominated by declines in physical and mental capacity, the implications for older people and for society will be more negative. Therefore, in the last years research has focused on the biology of ageing with the purpose of achieving better understanding of its mechanisms for preventing the onset and progression of age-related conditions.

Besides, modern society is experiencing an increasingly common stressful lifestyle together to increased rates of metabolic stress caused, in part, by high-fat diet consumption. Several pieces of evidence state that environmental factors are essential in determining the development of different diseases as well as compromising healthy ageing. With upcoming age, the capability to fight against harmful stimuli decreases and the organism becomes more vulnerable to infections and disease. In agreement, stressful experiences have been identified as an important risk factor for cognitive impairment. Therefore, it is important to study the molecular mechanisms underpinning the effects of chronic stress on cognition and its relationship with ageing in order to unveil what challenges we might have to cope with as a society in the not-so-far future.

In parallel with ageing, stress and neurodegenerative diseases, such as Alzheimer’s disease (AD), there is impaired glucocorticoid (GC) signalling. Disturbances in the GC-mediated stress response and individual’s adaptive abilities appear to increase the vulnerability of elderly to age-related pathologies. In consequence, the present doctoral dissertation has been focused on the study of the mechanisms involved in age-related neurodegeneration modified by GC excess attenuation through the inhibition of the enzyme 11β-HSD1 in an animal model of accelerated ageing, as well as, their response to chronic mild stress exposure. Last but not least, the present doctoral thesis has been devoted to evaluate the GC-mediated stress response to chronic moderate stressful situations and to metabolic stress underlying neurodegeneration and the potential role of 11β-HSD1 inhibition to restore those detrimental effects induced by stress.

In summary, results obtained pointed out a protective role of the 11β-HSD1 inhibitor tested as improved cognitive and behavioural abilities of aged mice, as well as restored the deleterious effects induced by stressful conditions applied. Additionally, some of the molecular pathways related to ageing and neurodegeneration – particularly, AD neurodegeneration – were altered as a consequence of stress, but most of them were re-established after 11β-HSD1 inhibition, such as proteostasis, oxidative stress, neuroinflammation and epigenetics, among others. Overall, GC excess attenuation may become a potential therapeutic strategy for age-related cognitive decline.