Abstract
Hormonal deficit in post-menopausal women has been proposed to be one risk factor in Alzheimer's disease (AD) since two thirds of AD patients are women. However, large treatment trials showed negative effects of long-term treatment with oestrogens in older women. Thus, oestrogen treatment after menopause is still under debate, and several hypotheses trying to explain the failure in outcome are under discussion. Concurrently, it was shown that amyloid-beta (Aβ) peptide, the main constituent of senile plaques, as well as abnormally hyperphosphorylated tau protein, the main component of neurofibrillary tangles, can modulate the level of neurosteroids which notably represent neuroactive steroids synthetized within the nervous system, independently of peripheral endocrine glands. In this review, we summarize the role of neurosteroids especially that of oestrogen in AD and discuss their potentially neuroprotective effects with specific regard to the role of oestrogens on the maintenance and function of mitochondria, important organelles which are highly vulnerable to Aβ- and tau-induced toxicity. We also discuss the role of Aβ-binding alcohol dehydrogenase (ABAD), a mitochondrial enzyme able to bind Aβ peptide thereby modifying mitochondrial function as well as oestradiol levels suggesting possible modes of interaction between the three, and the potential therapeutic implication of inhibiting Aβ–ABAD interaction.
Highlights
Steroid hormones are molecules, mainly produced by endocrine glands such as the adrenal gland, gonads and placenta, involved in the control of many physiological processes mainly in the periphery, from reproductive behaviour to stress response
Cell death was observed after inhibition of aromatase by treatment with letrozole, suggesting that endogenous oestradiol formation plays a critical role in cell survival
We recently summarized evidence from ageing and Alzheimer models showing that the harmful trio “ageing, amyloid-β peptide (Aβ) and tau protein” triggers mitochondrial dysfunction through a number of pathways, such as impairment of oxidative phosphorylation, elevation of reactive oxygen species production and interaction with mitochondrial proteins, contributing to the development and progression of the disease [13, 49]
Summary
Mainly produced by endocrine glands such as the adrenal gland, gonads and placenta, involved in the control of many physiological processes mainly in the periphery, from reproductive behaviour to stress response. Another study using radioimmunoassay for steroid quantification demonstrated a decrease in oestrogen level in postmortem brain from female AD patients aged 80 years and older but no significant difference in the 60–79-year age range compared to non-demented women [17]. A decrease of PROG and 17-hydroxyprogesterone production was observed in cells expressing human wild-type APP (wtAPP), whereas 3α-androstanediol and oestradiol levels were increased.
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