Vascular β-amyloid and early astrocyte alterations impair cerebrovascular function and cerebral metabolism in transgenic arcAβ mice

Cerebrovascular lesions related to congophilic amyloid angiopathy (CAA) often accompany deposition of β-amyloid (Aβ) in Alzheimer’s disease (AD), leading to disturbed cerebral blood flow and cognitive dysfunction, posing the question how cerebrovascular pathology contributes to the pathology of AD. To address this question, we characterised the morphology, biochemistry and functionality of brain blood vessels in transgenic arctic β-amyloid (arcAβ) mice expressing human amyloid precursor protein (APP) with both the familial AD-causing Swedish and Arctic mutations; these mice are characterised by strong CAA pathology. Mice were analysed at early, mid and late-stage pathology. Expression of the glucose transporter GLUT1 at the blood–brain barrier (BBB) was significantly decreased and paralleled by impaired in vivo blood-to-brain glucose transport and reduced cerebral lactate release during neuronal activation from mid-stage pathology onwards. Reductions in astrocytic GLUT1 and lactate transporters, as well as retraction of astrocyte endfeet and swelling consistent with neurovascular uncoupling, preceded wide-spread β-amyloid plaque pathology. We show that CAA at later disease stages is accompanied by severe morphological alterations of brain blood vessels including stenoses, BBB leakages and the loss of vascular smooth muscle cells (SMCs). Together, our data establish that cerebrovascular and astrocytic pathology are paralleled by impaired cerebral metabolism in arcAβ mice, and that astrocyte alterations occur already at premature stages of pathology, suggesting that astrocyte dysfunction can contribute to early behavioural and cognitive impairments seen in these mice

Insulin regulates solublke amyloid precursor protein release via phosphatidyl inositol 3 kinase-dependent pathway

Several lines of biochemical evidence correlate the presence of energy metabolic defects with the functional alterations associated with brain aging and with the pathogenesis of neurodegenerative disorders such as Alzheimer's disease. Within this context we tested the ability of insulin to regulate the amyloid precursor protein (APP) processing in SH-SY5Y neuroblastoma cells. Our findings show that insulin promotes APP metabolism by a glucose-independent mechanism, We demonstrate ai novel intracellular pathway that increases the rate of secretion of soluble APP through the activity of phosphatidyl-inositol 3 kinase (PI3-K). This pathway, downstream of insulin receptor tyrosine kinase activity, does not involve either the activation of protein kinase C or the mitogen-activated protein kinase (MAP-K) pathway. Because of the physiological role of PI3-K in the translocation of glucose transporter-containing vesicles, we speculate that PI3-K involvement in APP metabolism may act at the level of vesicular trafficking

Exercise-induced microalbuminuria in patients with active acromegaly: acute effects of slow-release lanreotide, a long-acting somatostatin analog

Recent clinical studies have demonstrated an increase of urinary albumin excretion (UAE) at rest in acromegalic patients and, on the other hand, a reduced UAE in patients with growth hormone (GH) deficiency. Physical exercise is known to induce abnormal UAE in patients with diabetes, probably unmasking early glomerular alterations. The effect of exercise on UAE in acromegaly is not known. Moreover, the effect of acute but sustained GH inhibition in acromegaly on UAE at rest and after exercise has never been studied. The aim of our study was to evaluate the acute short-term effects of slow-release lanreotide (SR-L), a long-acting somatostatin analog, on UAE and α1-microglobulinuria (A-1-M), a marker of renal tubular damage, at rest and after exercise in 7 normotensive patients with active acromegaly and normal renal function (4 males and 3 females; mean age, 53 ± 3.1 years; body mass index [BMI], 27.3 ± 1.1 kg/m2) at baseline and 7 and 14 days after SR-L injection (30 mg). Two of the acromegalic patients were microalbuminuric at rest, and in other 3 cases, UAE was in the borderline range (10 to 20 μg/min). At baseline in the acromegalic subjects, we found a significant increase in UAE at rest with respect to 7 normal subjects considered as a control group. GH and insulin-like growth factor-1 (IGF-1) were also reduced compared with baseline 7 and 14 days after SR-L injection (GH, 13.4 ± 7.3 and 13.61 ± 7 v 18.5 ± 9.3 μg/L, P < .05; IGF-1, 230 ± 53 and 255 ± 54 v 275 ± 64 μg/L). Concomitantly, we observed a significant decrease of UAE at rest and after exercise and 7 and 14 days after SR-L injection as compared with baseline values (27.3 ± 20.5 and 18.2 ± 13.7 v 35.3 ± 12.8 μg/min, P < .05; exercise, 48.5 ± 24.1 and 18.6 ± 6.8 v 68.3 ± 39.7 μg/min, P < .05). A-1-M always remained in the normal range (<12 mg/L) both at rest and after exercise. We can thus conclude that in acromegaly, submaximal exercise induces abnormal increases in microalbuminuria. We hypothesize that this phenomenon may be due to the functional glomeruler involvement. SR-L can significantly reduce UAE at rest and after exercise in the short-term in acromegaly, probably via a decrease in circulating GH levels. Copyright (C) 2000 by W.B. Saunders Company

Effects of vitamin A administration on serum thyrotropin concentrations in healthy human subjects.

Retinoids play an important role in the regulation of normal growth and development. Their biological action is mediated by a nuclear receptor that belongs to the steroid/thyroid hormone receptors superfamily. Retinoic acid has been shown to inhibit the secretion and synthesis of thyrotropin (TSH); however, little is known on the effects of retinoids on TSH secretion in normal human subjects. In the present study, we evaluated serum TSH concentration following both vitamin A (vit A) and the combined vit A and triiodothyronine (T-3) administration. Basal and thyrotropin-releasing hormone (TRI-1)-stimulated TSH serum concentrations were measured in healthy young subjects in the following experimental conditions: (1) after 10 days of treatment with vit A orally administered as retinol at a dose of 50,000 IU/d; (2) after 10 days of oral placebo (PL) treatment; (3) after 1 hour from the administration of 40 mg T-3 at the end of 10 days of PL treatment; and (4) after 1 hour from the administration of 40 mg T-3 at the end of 10 days of vit A treatment. Serum TSH concentrations were also measured during vitA administration in healthy elderly subjects according to the following protocol: (1) after 10 days of treatment with PL; and (2) after 10 days of treatment with vit A at the same dose used for young subjects. In young subjects, basal serum TSH levels were found to be similar in the 4 different treatment conditions. In the same group of subjects, each of the 4 experimental conditions induced an increase in serum TSH, which rose from basal values of 1.80 +/- 0.31 to a peak of 11.92 +/- 1.75 muIU/mL (P <.001) during the PL treatment, from basal values of 1.81 +/- 0.22 to a peak of 10.81 +/- 1.00 muIU/mL (P <.001) during vit A treatment, from basal values of 1.72 +/- 0.28 to a peak of 9.92 +/- 1.10 muIU/mL (P <.001) during PL + T-3 treatment, and from basal values of 1.79 +/- 0.30 to a peak of 9.51 +/- 1.12 muIU/mL (P <.001) during vit A + T-3 treatment. The 2-way repeated measure analysis of variance revealed no significant differences among treatments. In old subjects, basal serum TSH levels were similar in the 2 experimental conditions and were not different from those observed in young subjects. In these subjects, serum TSH levels increased significantly in response to the TRH stimulus from basal values of 2.16 +/- 0.3 to a peak of 10.27 +/- 0.55 muIU/mL (P <.001) during PL treatment and from basal values of 2.10 +/- 0.51 to a peak of 7.82 +/- 1.4 muIU/mL (P <.001) during vit A treatment. No significant effects of treatment were found in this group of subjects on TRH-induced TSH levels; however, TSH responses were somewhat lower during vit A treatment with a difference close to statistical significance. These results suggest that TSH secretion is poorly affected by vit A administration in healthy human subjects; the data also indicate that any cooperation between T-3 and vit A is unlikely to occur in the regulation of TSH secretion. Copyright 2002, Elsevier Science (USA). All rights reserved

Evaluation of the circadian profile of peripheral plasma galanin concentrations in normal subjects

Galanin administration can influence pituitary function principally resulting in an increase in GH secretion. However, the role of circulating GAL levels in human endocrine function is still unknown. In the present study we simultaneously measured the circadian profiles of GAL, ACTH and GH in peripheral blood of ten adult subjects. Plasma samples were collected through an intravenous catheter at 0800, 1200, 1600, 2000, 2200, 2400, 0200, 0400 hours. The results were statistically evaluated by the cosinor analysis technique. A significant circadian rhythm of both plasma ACTH (p < 0.001) and GH levels (p < 0.03) was found with acrophases occurring at 0753 hrs and 0131 hrs for ACTH and GH, respectively. On the contrary, no significant rhythm was found in plasma GAL levels, indicating that no correlations exist between GAL and either GH or ACTH circadian profiles. Furthermore, the simultaneous assay of both GAL and GH plasma levels during a nocturnal frequent sampling performed in four volunteers showed the presence of peaks in GAL levels which, however, were not concomitant to the peaks in GH levels. These data demonstrate the lack of rhythmicity in the circadian profile of plasma GAL levels in healthy human subjects. The role of GAL in human endocrine function remains unknown and these results suggest that, in spite of the well documented increase in plasma GH concentrations following the intravenous administration of GAL, physiologically circulating levels of GAL are likely not involved in the regulation of GH secretion

No effect of atypical antipsychotic drugs on weight gain and risk of developing type II diabetes or lipid abnormalities among nursing home elderly patients with Alzheimer’s disease.

AIM: Weight gain and the risk of developing alterations in lipid and glucose metabolism are possible side effects of atypical antipsychotic therapy in young and adult patients. The objective of this study was to examine whether elderly patients with Alzheimer's disease (AD) gain weight or develop disturbances in lipid and glucose metabolism while being treated with atypical antipsychotic drugs. METHODS: This retrospective study identified 36 out of 99 patients (mean age: 75.4+/-7.1, 27 female, 9 males) who were taking risperidone (N=9, mean dosage: 1.42+/-0.49 mg/day), olanzapine (N=17: 4.42+/-1.10 mg/day), and quetiapine (N=10: 75+/-27 mg/day) over a 12 months period. Anthropometric parameters, mini nutritional assessment (MNA), total, HDL and LDL cholesterol, triglycerides, glycaemia were assessed at baseline (T0) and 12 (T1) months. RESULTS: Body weight (BMI=23+/-5 vs 23+/-5), MNA score (21+/-4 vs 21+/-4), blood glucose (5.7+/-2 vs 4.9+/-0.9 mmol/L) or total cholesterol (4.9+/-1.1 vs 4.3+/-0.7 mmol/L), HDL cholesterol (1.3+/-0.3 vs 1.1+/-0.3 mmol/L), LDL cholesterol (3.3+/-0.7 vs 3 +/- 0.4 mmol/L), triglycerides (1.1+/-0 vs 1+/-0.3 mmol/L) did not reveal treatment-induced changes in the patients evaluated (T0 vs T1). CONCLUSION: These results suggest that the treatment with low-dose of atypical antipsychotic drugs is not associated with weight gain or increase the risk of developing type II diabetes or abnormalities of lipid metabolism among elderly patients with AD, who were residing in long-term nursing home

Lipoprotein(a), apolipoprotein(a) polymorphism and coronary atherosclerosis severity in type 2 diabetic patients.

(0) Save to: more options Lipoprotein(a), apolipoprotein(a) polymorphism and coronary atherosclerosis severity in type 2 diabetic patients Author(s): Gazzaruso, C (Gazzaruso, C); Bruno, R (Bruno, R); Pujia, A (Pujia, A); De Amici, E (De Amici, E); Fratino, P (Fratino, P); Solerte, SB (Solerte, SB); Garzaniti, A (Garzaniti, A) Source: INTERNATIONAL JOURNAL OF CARDIOLOGY Volume: 108 Issue: 3 Pages: 354-358 DOI: 10.1016/j.ijcard.2005.05.022 Published: APR 14 2006 Times Cited: 8 (from Web of Science) Cited References: 27 [ view related records ] Citation Map Abstract: Background: Few and conflicting data are available in the literature on the association between Lp(a) levels and the severity of coronary artery disease (CAD) in diabetic patients. In addition, no studies took into account the role of apo(a) polymorphism. The purpose of the present study was to analyse the association of the degree of coronary atherosclerosis with Lp(a) levels and apo(a) polymorphism in a large group of type 2 diabetic patients. Methods: The study population consisted of 227 consecutive type 2 diabetic patients undergoing a routine coronary angiography to evaluate chest pain or suspected CAD. The patients were subdivided into four subgroups according to the number of coronary arteries diseased: normal arteries (n = 26), mono-vessel disease (n = 67), bi-vessel disease (n = 54) and multi-vessel disease (n = 80). Results: Lp(a) levels (normal arteries: 14.6 +/- 19.6 mg/dl; mono-vessel disease: 19.0 +/- 16.4 mg/dl; bi-vessel disease: 19.3 +/- 15.1 mg/dl; multi-vessel disease: 26.5 +/- 16.8 mg/dl; p < 0.001) and the percentages of patients with at least one isoform of low molecular weight (normal arteries: 23.1%; mono-vessel disease: 38.8%; bi-vessel disease: 75.9%; multi-vessel disease: 81.2%; p < 0.001) were significantly correlated with increasing number of coronary vessels diseased. Multiple logistic regression analysis showed that both Lp(a) levels (OR: 1.31; 95% CI: 1.02-4.11) and apo(a) polymorphism (OR: 3.43; 95% CI: 1.67-7.05) were independent predictors of CAD severity. Conclusions: Our data suggest that Lp(a) levels and apo(a) polymorphism may be reliable predictors of CAD severity in type 2 diabetic patients