Therapeutic potential of neurosteroids DHEA and DHEAS in mouse models of Alzheimer’s disease

Dementia is a syndrome characterized by the progressive loss of cognitive functions, predominantly affecting older individuals. It is often accompanied by behavioral and psychological symptoms, significantly impacting dementia prognosis and treatment. Alzheimer's disease (AD) is the most common form of dementia, primarily affecting neurons in the cortex and hippocampus. The main pathological features of AD include extracellular accumulations of amyloid beta peptides in amyloid plaques and intracellular accumulations of hyperphosphorylated tau protein in neurofibrillary tangles. Since there is still no effective cure or prevention for AD, this study aims to investigate the therapeutic potential of dehydroepiandrosterone (DHEA) and its sulfated form (DHEAS), abundant neurosteroids in the bloodstream and the brain, whose levels decline with age and in various neuropsychiatic disorders. One potential mechanism for DHEA(S)'s neuroprotective effects could involve brain-derived neurotrophic factor (BDNF) and the PI3K-AKT signaling pathway, modulated by tyrosine kinase receptors for BDNF. In our research, genetic (3xTg-AD mice) and pharmacologically induced (C57BL/6 mice) models of AD were chronically treated with DHEA(S). Following treatment, mice were tested in a battery of cognitive (Morris water maze, Passive avoidance, Novel object recognition, Social discrimination, and Y maze) and behavioral (Open field, Forced swim, and Splash) tests and their hippocampi were isolated for Western blot analysis of proteins involved in the PI3K-AKT signaling pathway. Our results demonstrated a mild beneficial effects of DHEA(S) on cognition and behavior in mice, as well as modulation of the hippocampal protein expression of BCL2 and BAX, the key regulators of apoptosis, via PI3K-AKT signaling pathway.