Dehydroepiandrosterone 7-hydroxylase CYP7B: predominant expression in primate hippocampus and reduced expression in Alzheimer's disease.

Neurosteroids such as dehydroepiandrosterone (DHEA), pregnenolone and 17beta-estradiol are synthesized by cytochrome P450s from endogenous cholesterol. We previously reported a new cytochrome P450 enzyme, CYP7B, highly expressed in rat and mouse brain that metabolizes DHEA and related steroids by hydroxylation at the 7alpha position. Such 7-hydroxylation can enhance DHEA bioactivity in vivo. Here we show that the reaction is conserved across mammalian species: in addition to mouse and rat, DHEA hydroxylation activity was present in brain extracts from sheep, marmoset and human. Northern blotting using a human CYP7B complementary deoxyribonucleic acid (cDNA) probe confirmed the presence of CYP7B mRNA in marmoset and human hippocampus; CYP7B mRNA was present in marmoset cerebellum and brainstem, with lower levels in hypothalamus and cortex. In situ hybridization to human brain revealed higher levels of CYP7B mRNA in the hippocampus than in cerebellum, cortex, or other brain regions. We also measured CYP7B expression in Alzheimer's disease (AD). CYP7B mRNA was significantly decreased (approximately 50% decline; P<0.05) in dentate neurons from AD subjects compared with controls. A decline in CYP7B activity may contribute the loss of effects of DHEA with ageing and perhaps to the pathophysiology of AD.

Increased glucocorticoid production and altered cortisol metabolism in women with mild to moderate Alzheimer's disease.

BACKGROUND: Abnormalities at several levels of the hypothalamic-pituitary-adrenal axis, which may promote glucocorticoid dependent neurodegeneration, have been reported in patients with Alzheimer's disease. In this study we have explored the possibility that peripheral cortisol metabolism is enhanced and glucocorticoid production is increased compensatory in patients with mild to moderate Alzheimer's disease. METHODS: Urinary excretion of cortisol and its principal conjugated metabolites was studied in ten women with mild to moderate Alzheimer's disease, seven healthy elderly women and seven young women. RESULTS: There was an age-related fall in glucocorticoid production (median, 2009 [range 1828--4201] vs. 9315 [range 3613--16,244] microg/24 hours in elderly vs. young control subjects). A-ring metabolism (i.e., the irreversible inactivation of cortisol by 5 alpha- and 5 beta-reductases) was reduced in old age. However, patients with Alzheimer's disease showed persistence of cortisol metabolite excretion. Glucocorticoid production was significantly increased in patients with Alzheimer's disease versus healthy elderly control subjects (median, 7269 [range 6005-15,335] vs. 2009 [range 1828--4201] microg/24 hours), and patients with Alzheimer's disease had increased A-ring reduction of cortisol. CONCLUSIONS: An increased glucocorticoid production is an early feature of Alzheimer's disease and may be secondary to enhanced metabolic clearance of cortisol by A-ring reduction.

Environmental enrichment selectively increases 5-HT1A receptor mRNA expression and binding in the rat hippocampus.

Environmental enrichment augments neuronal plasticity and cognitive function and possible mediators of these changes are of considerable interest. In this study, male rats were exposed to environmental enrichment or single housing for 30 days. Rats from the enriched group had significantly higher 5-HT1A receptor mRNA expression in the dorsal hippocampus (62%, 59% and 44% increase in the CA1, CA2 and CA3 subfields, respectively). This was associated with significantly higher [3H]8-OH-DPAT binding in the inferior part of CA1. No changes were seen for 5-HT2A or 5-HT2C receptor mRNAs. The neuronal plasticity detected after environmental change may be mediated, in part, through 5-HT1A receptors.

Adrenal responsivity in normal aging and mild to moderate Alzheimer's disease.

BACKGROUND: Enhanced levels of cortisol have been found in moderate to severe Alzheimer's disease (AD) and in major depression, while recent studies have suggested decreased levels of serum dehydroepiandrosterone sulfate (DHAS) in patients with dementia. In this study the responsivity of the adrenal cortex to stimulation with a new low dose adrenocorticotropin (ACTH) test was investigated in patients with AD and in normal aging. METHODS: Thirteen patients with mild to moderate AD, 12 healthy old controls, and 15 young controls (78.0 +/- 8.4, 76.7 +/- 7.0, and 28.3 +/- 4.1 years old, mean: +/- SD, respectively) received an intravenous bolus injection of 1 microgram ACTH. Serum cortisol and androgen levels were analyzed before and 5, 10, 20, 25, 30, 35, 40, 60, 90, 120, 180, and 240 minutes after injection. RESULTS: The cortisol responsivity did not differ between the three groups. An enhanced release of androgens was present in patients with AD. AD per se had an independent influence on androstenedione levels after ACTH stimulation after adjustments for age and gender in a general linear regression model. CONCLUSIONS: In contrast to major depression, increased cortisol release to ACTH stimulation does not seem to be a feature of AD. Abnormal androgen levels after ACTH stimulation are characteristic features of mild to moderate Alzheimer's disease.

A low dose ACTH test to assess the function of the hypothalamic-pituitary-adrenal axis.

OBJECTIVE: The insulin tolerance test (ITT) has long been used to assess the hypothalamic-pituitary-adrenal axis, but may be hazardous. The standard synthetic ACTH (Synacthen) test has been advocated as a substitute but is sometimes insensitive. In this study the ITT has been compared to a low dose ACTH stimulation test (1 microg) and the standard ACTH stimulation test (250 microg). SUBJECTS: Twenty-seven subjects were studied, 24 with verified or suspected hypothalamic-pituitary disorders and three on long-term glucocorticoid therapy. DESIGN: Insulin tolerance, low dose ACTH and standard ACTH tests were performed in all patients. The ITT was performed less than 48 hours after the ACTH tests. Synacthen was administered as an intravenous bolus. MEASUREMENTS: Serum cortisol values were determined by radioimmunoassay. The peak cortisol value during ITT was compared to the cortisol levels during the ACTH tests. RESULTS: There was a highly significant correlation between peak cortisol values during ITT and cortisol levels after 20-60 minutes in the low dose ACTH test (r(s) = 0.91-0.93; P < 0.0001) and after 30 and 60 minutes in the standard ACTH test (r(s) = 0.85 and 0.89 respectively; P < 0.0001). Four patients showed discrepancies between the three tests. CONCLUSIONS: The 1-microg ACTH test follows the ITT more closely and may be more sensitive than the standard ACTH test in detecting more subtle insufficiency of the hypothalamic-pituitary-adrenal axis. The standard ACTH test and the insulin tolerance test may thus be replaced by the 1-microg ACTH test in screening for secondary cortisol insufficiency. We recommend that serum cortisol is measured before and 30 and 40 minutes after the ACTH injection.

Peak torque and OBLA running capacity in male orienteers.

The isokinetic (30, 60, 120 and 180 degrees s-1) peak torque of m. quadriceps femoris and m. triceps surae, and the running velocity at the onset of blood lactate accumulation (VOBLA) were determined at three different occasions (November, April and September) during a year in 15 male élite orienteers. The amount and type of training for each individual was also registered. At the first test (November) there was no significant intra-individual correlation between peak torque of m. quadriceps and m. triceps surae. A negative correlation was found between VOBLA and peak torque of m. quadriceps at the lower velocities of angular motion, but not at the higher. The peak torque of m. triceps surae increased during the training period and decreased during the competition period back to the original level. Over the whole year the peak torque of m. quadriceps increased while no changes could be demonstrated within the two periods of the study. The running velocity at the onset of blood lactate accumulation increased during both training and competition periods. The changes in VOBLA were negatively associated with the changes in peak torque of m. quadriceps at 180 degrees s-1 during the training period. During the competition period the changes in VOBLA were, for the majority of the orienteers, negatively correlated to the ratio of quality:quantity running, i.e. to a high content of forest running.

Fatigue and endurance of lower extremity muscles in relation to running velocity at OBLA in male orienteers.

At three occasions during a year, the ratio of contractional work (output)/integrated electromyographic activity (input), that is, CW/iEMG, was measured during repetitive maximum isokinetic manoeuvres for m. quadriceps and m. triceps surae in male elite orienteers. Running velocity at the onset of blood lactate accumulation (VOBLA), which was considered as a measure of running performance, and maximal oxygen uptake (VO2max) were analysed at each test. Type and amount of training were continuously registered. For m. quadriceps there was a decline in CW/iEMG during the first 30 manoeuvres, followed by an unchanged plateau level. In contrast, m. triceps surae showed a plateau level of virtually unaltered CW/iEMG ratio from the start to the end of the experiment. The differences might be explained by structural causes, but also by local muscle adaptation to training. The plateau level of CW/iEMG of m. quadriceps was positively correlated to VO2max. An increase in the plateau level of CW/iEMG was found for both tested muscle groups after the winter training period (mainly low intensity road running) when both VOBLA and VO2OBLA increased. During the competition period (mainly high intensity forest running), the whole group increased while some orienteers lowered their VOBLA. During this period, no changes in the plateau level of CW/iEMG of any muscle group or in VO2OBLA occurred. The changes in the plateau level of CW/iEMG might express local muscle adaptations to changes in running technique and aerobic/anaerobic demands during low intensity road running versus high intensity forest running.