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DHEA and DHEAS – neuronal guardians against amyloid beta toxicity and ishemic injury

Dementia represents a group of related symptoms associated with ongoing decline of brain functioning, which affects memory, learning, thinking, as well as social abilities, and interferes with daily life of patients. Since it usually affects the elderly, given the rapid population aging, dementia is becoming one of the leading medical, social and economic problems, and finding of effective treatment is urgent. Current therapy represents symptomatic treatment, while many studies of new effective drugs have been unsuccessful so far. Over 100 different diseases may cause dementia, with Alzheimer´s disease (AD) and vascular dementia (VaD) as the most common causes. AD is a progressive and incurable neurodegenerative disease, most often characterized by memory deficits and cognitive decline, although other clinical presentations are increasingly recognized. Neurological techniques demonstrated reduced brain volume and weight and enlargement of lateral brain ventricles and gyrus in AD. Post-mortem studies in the brain of AD patients identified extracellular accumulations of amyloid-beta in senile plaques, as well as intracellular neurofibrillary tangles, generated due to accumulation of hyperphosphorylated tau protein. Both of these hallmark pathologies of AD lead to functional disruption and death of neurons. VaD, the second most common form of dementia, is caused by a reduced blood flow to the various brain regions, depriving them of oxygen and nutrients and causing damage and death of neurons. It could be due to a narrowing/blockage of the small blood vessels in the brain, to a single stroke (ischemic/hemorrhagic), where the blood supply to part of the brain is cut off, or to transient ischemic attacks that cause tiny but widespread brain damage, leading to cognitive problems, characteristic for VaD. Neurosteroids, dehydroepiandrosterone (DHEA) and its sulfated form dehydroepiandrosterone sulfate (DHEAS) are the most abundant circulating steroids present in the human body, which concentrations decrease with age. They are synthesized in the adrenal glands, gonads and de novo in the brain, where their concentrations are 6-8 times higher than in the peripheral blood. In addition to the numerous positive effects on human health, DHEA and DHEAS are potent modulators of neural function, including neurogenesis, neuronal growth and differentiation, as well as neuroprotection. Neuroprotective actions of DHEA and DHEAS were investigated using primary mouse neurons, derived from C57BL/6 mice embryos, which were treated with toxic amyloid beta oligomers, as in vitro model of AD. The oxygen‑glucose deprivation (OGD) was applied by culturing human SH‑SY5Y neuroblastoma cells and primary mouse neurons in glucose- and serum- free medium in a hypoxic chamber, in order to simulate ischemic brain injury. This in vitro model of VaD was used to study neuroprotective effects of DHEA and DHEAS pre- and post-treatment. Our study demonstrated that DHEA and DHEAS exert neuroprotective actions on primary mouse neurons exposed to amyloid beta oligomers (Figure 1), probably via anti-apoptotic mechanisms. Moreover, DHEA and DHEAS protected SH-SY5Y cells and primary mouse neurons when applied both before and after OGD (Figure 2). These findings suggest that these neurosteroids might be considered as guardians of neuronal cells against amyloid beta toxicity and ischemic injury, and could potentially represent novel preventive and/or therapeutic strategies for dementia. Obtained results need to be confirmed and extended by further in vitro research, but also in studies using animal models and human samples.

DHEA/S ; primary mouse neurons ; SH-SY5Y cells ; Alzheimer´s disease ; vascular dementia

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