17β-Hydroxysteroid dehydrogenases and neurosteroid metabolism in the central nervous system.

17β-Hydroxysteroid dehydrogenases are indispensable for downstream enzyme steps of the neurosteroidogenesis. Neurosteroids are synthesized de novo in neurons and glia from cholesterol transported into mitochondria, or by conversion from proneurosteroids, e. g. dehydroepiandrosterone (DHEA) and pregnenolone, through the same metabolic pathway as revealed in the de novo neurosteroidogenesis. Hormonal steroids generated from endocrine glands are transported into brain from the circulation to exert neuronal activity via genomic pathway, whereas neurosteroids produced in brain cells without genomic targets identified could bind to cell surface targets, e.g., GABAA or NMDA receptors and elicit antidepressant, anxiolytic, anticonvulsant and anesthetic effects by regulating neuroexcitability. In a broad sense, neurosteroids include hormonal steroids in brain, and they are irrespective of origin playing important roles in brain development including neuroprotection, neurogenesis and neural plasticity. They are also a critical element in cognitive and memory functions. Mitochondrial 17β-HSD10, encoded by the HSD17B10 gene mapping to Xp11.2, is found in various brain regions, essential for the maintenance of neurosteroid homeostasis. Mutations identified in this gene resulted in two distinct brain diseases, namely HSD10 deficiency and MRXS10, of which clinical presentations and pathogenetic mechanisms are quite different. Since elevated levels of 17β-HSD10 was found in brains of Alzheimer's disease patients and AD mouse model, it may also act as an adverse factor in the AD pathogenesis due to an imbalance of neurosteroid metabolism.