The transcription of steroidogenic genes in the human cerebellum and hippocampus: a comparative survey of normal and Alzheimer's tissue

Abstract

Steroid actions on brain tissue have been implicated in processes such as blood pressure regulation and neurodegeneration, including the progression of Alzheimer's disease (AD). mRNAs from all of the genes required for de novo synthesis from cholesterol of aldosterone and corticosterone (equivalent to cortisol in humans) have been identified in rat brain, together with abundant steroid hormone receptors, but the situation in human brain requires clarification. We used real-time RT-PCR to assess whether transcription of 13 steroid-associated genes occurs in human hippocampus and cerebellum, and to identify whether transcription of these genes is significantly altered in cases of AD. Frozen post-mortem samples of hippocampus and cerebellum from patients with AD (nZ7) and age-matched controls free from neurological disease at the time of death (nZ9) were used. We found all of the genes under investigation to be transcribed within normal and AD hippocampus and cerebellum except for CYP11B1 (11b-hydroxylase), CYP11B2 (aldosterone synthase) and CYP17 (17a-hydroxylase). No significant differences in mRNA levels were observed between the AD tissue and the equivalent control tissue, although significant regional differences in gene transcription were observed between hippocampus and cerebellum in AD and control samples. The absence of key mRNAs from human hippocampus and cerebellum rules out the de novo generation of aldosterone, cortisol or the sex steroids within these regions. However, the pattern of gene expression does suggest that the mineralocorticoid 11-deoxycorticosterone can be generated de novo. There is no evidence of a link between AD and altered steroid biosynthesis within human hippocampus and cerebellum.

Aldosterone in the brain

“…At least a marginal level of gene expression for most steroid synthetic enzymes has been detected using RT-PCR amplification of mRNA in tissue from various regions of the brain (67,68,115,116,190). The low-level expression of some of these enzymes may be regulated in the brain with some semblance to their counterparts in the adrenal gland (185,186).…”

“…Third, there are major species differences in aldosterone synthase expression in the brain. One group found evidence for expression in rat, but not mouse, brain (165), and a more recent report failed to identify expression anywhere in the human brain (116). Fourth, and perhaps most importantly, the small amount of aldosterone detected in the brains of adrenal-intact animals rises and falls in direct proportion to plasma aldosterone, and little or no aldosterone can be detected in the brain after adrenalectomy (71,191).…”

Central mineralocorticoid receptors, sympathetic activity, and hypertension

“…However, although mRNA for other corticosteroidogenic genes has been detected in human brain samples, reverse transcription polymerase chain reaction (RT-PCR) studies have not found evidence of aldosterone synthase or 11β-hydroxylase gene transcription in human hippocampus or cerebellum [24,25]. Such differences prompt caution when drawing comparisons between the rat and human systems but do not necessarily mean that central corticosteroid synthesis is irrelevant to the human brain.…”

“…Such differences prompt caution when drawing comparisons between the rat and human systems but do not necessarily mean that central corticosteroid synthesis is irrelevant to the human brain. First, the machinery does exist within the human hippocampus and cerebellum to produce 11-deoxycorticosterone (DOC), a steroid hormone capable of binding MRs, albeit with lower affi nity than aldosterone [25]. Second, rat studies point to another important cortico steroid-producing system within the paraventricular nucleus (PVN), and a corresponding system in this area of the human brain has not been ruled out.…”

Protective effect of estrogens on the brain of rats with essential and endocrine hypertension

“…However, more subtle evidence suggests that deoxycorticosterone (DOC) might play direct roles on the hippocampus. First, DOC can be synthesized de novo in the hippocampus, implying the viability of local steroid effects (24). Second, hippocampal receptors for adrenal steroids are occupied and downregulated by systemic treatment with DOCA (22).…”