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Background: Default mode network (DMN) dysfunction is well established in Alzheimer’s disease (AD) and documented in both preclinical stages and at-risk subjects, thus representing a potential disease target. Multi-sessions of repetitive transcranial magnetic stimulation (rTMS) seem capable of modulating DMN dynamics and memory in healthy individuals and AD patients; however, the potential of this approach in at-risk subjects has yet to be tested. Objective: This study will test the effect of rTMS on the DMN in healthy older individuals carrying the strongest genetic risk factor for AD, the Apolipoprotein E (APOE) ɛ4 allele. Methods: We will recruit 64 older participants without cognitive deficits, 32 APOE ɛ4 allele carriers and 32 non-carriers as a reference group. Participants will undergo four rTMS sessions of active (high frequency) or sham DMN stimulation. Multimodal imaging exam (including structural, resting-state, and task functional MRI, and diffusion tensor imaging), TMS with concurrent electroencephalography (TMS-EEG), and cognitive assessment will be performed at baseline and after the stimulation sessions. Results: We will assess changes in DMN connectivity with resting-state functional MRI and TMS-EEG, as well as changes in memory performance in APOE ɛ4 carriers. We will also investigate the mechanisms underlying DMN modulation through the assessment of correlations with measures of neuronal activity, excitability, and structural connectivity with multimodal imaging. Conclusion: The results of this study will inform on the physiological and cognitive outcomes of DMN stimulation in subjects at risk for AD and on the possible mechanisms. These results may outline the design of future non-pharmacological preventive interventions for AD.

Objective To gain insight into the regulation of cardiac apoptosis we studied the dose-response and time-course effects of angiotensin II (Ang II) infusion on ventricular cardiomyocyte apoptosis and on the expression of Bax and Bcl-2 genes and proteins. Study design and methods In the dose-response study, Ang II was infused subcutaneously at doses of 100, 200, 400, 800 and 1200 ng/kg per min for 14 days. In the time-course study, rats infused with Ang II at doses of 200 and 400 ng/kg per min were followed for 7 and 14 days. The cardiomyocyte apoptotic density was assessed by DNA end labelling (terminal deoxynucleotide nick-end labelling; TUNEL). Gene and protein expression of Bcl-2 and Bax were evaluated by reverse transcriptase-polymerase chain reaction and by Western blots. Results Systolic blood pressure and left ventricular mass were increased in a dose-dependent manner in Ang II-infused rats. A statistically significant increase in the rate of cardiac apoptosis and pro-apoptotic changes of Bcl-2 and Bax gene and protein expression was observed when high doses of Ang II (800-1200 ng/kg per min) were infused. A positive correlation of apoptotic density with Bax and a negative correlation with Bcl-2 and Bcl-2/Bax ratio were found. Cardiac apoptosis was greatly influenced by the timing of Ang II infusion. Losartan-treated Ang II-infused rats exhibited normalized systolic blood pressure, left ventricular weight, apoptosis, and Bax and Bcl-2 levels. Conclusions Our results are consistent with the pathophysiological role of Ang II in induction of cardiac apoptosis, and explain the cardioprotective effect of Ang II receptor antagonists.

The mechanisms underlying the increased cardiovascular risk after menopause are poorly understood. Estrogens modulate the cardiac renin-angiotensin system (RAS) and influence cardiac adaptation to afterload. To investigate whether the loss of the natural inhibition of the RAS by estrogen may be linked to an increase of cardiac apoptosis, we studied 17β-estradiol (E2) and/or angiotensin-converting enzyme (ACE) inhibitor treatment effects on cardiomyocyte survival in ovariectomized spontaneously hypertensive rats (SHRs).Five groups of female SHRs were evaluated for 8 weeks. One group served as nonovariectomized control; the other four groups underwent bilateral ovariectomy and were randomized to receive 60-day-release pellets containing placebo or 0.5 mg of E2, the ACE inhibitor ramipril at the dosage of 2.5 mg/kg per day, or the combination of the two treatments.Ovariectomy increased cardiomyocyte apoptosis and induced proapoptotic changes of Bcl-2 and Bax genes and proteins. These modifications were associated with an upregulation of ACE and angiotensin II type 1 (AT1) receptor genes. Ramipril was as effective as E2 in preventing cardiac apoptosis and in restoring cardiac brain natriuretic peptide in association with reduced cardiac ACE and AT1 receptor gene expression. In contrast to the ramipril treatment, the favorable effect of E2 on cardiac apoptosis occurred independently from changes in SBP. No synergistic effect was observed when the two treatments were combined.These data show that ovariectomy stimulates myocardium apoptosis by a mechanism involving Bax and Bcl-2 genes. The antiapoptotic effect of E2 and ACE inhibitor treatment was linked to a downregulation of cardiac RAS.

Objective The renin-angiotensin-aldosterone system (RAAS) plays an important role in the control of renal function both in physiological and pathological conditions. The aim of the present study was to evaluate the relation between four genetic polymorphisms of the RAAS and renal insufficiency in a population of patients with essential hypertension living in north-east Italy. Design and methods Eighty-six hypertensive patients with renal insufficiency and 172 hypertensive patients without renal damage matched for age and hypertension duration to within 2 years were evaluated. Genotyping for insertion/ deletion of angiotensin-converting enzyme (ACE I/D), angiotensinogen (AGT) M235T, angiotensin II type 1 receptor (AT 1 R) A1166C and aldosterone synthase (CYP11 B2) -344C/T polymorphisms were performed using polymerase chain reaction, with further restriction analysis when required. Results Each of the genetic polymorphisms of the RAAS genes was associated with renal failure; the adjusted odds ratios were 1.47 and 1.89 for ACE D allele, assuming a co dominant and a recessive mode of inheritance, respectively; 1.51 for AGT T235 allele assuming a co dominant, and 1.98 assuming a recessive, pattern of inheritance; 1.79 for AT 1 R C1166 allele considering a dominant pattern; and 3.89 for CYP11B2 -344C allele as a recessive effect. However, CYP11B2 genotypes were not in Hardy-Weinberg equilibrium among controls. The associations AGT TT-AT 1 R AC and CYP11B2 CC-ACE DD showed a possible positive interaction in the development of renal insufficiency among hypertensive subjects. The association AGT MM-AT 1 R AA and AGT MM-AT 1 R AA-CYP11B2 TT or TC combinations were associated with a reduced risk for renal failure. Conclusions Our findings suggest that in patients with essential hypertension an unfavorable genetic pattern of RAAS may contribute to the increased risk for the development of renal failure.

The regulation of adrenergic receptors during hypoxia is complex, and the results of published reports have not been consistent. In the present study blood cell adrenoceptor characteristics at sea level (SL) before and after prolonged exposure to high altitude (HA) were measured in seven trained young male lowlanders. Sympathoadrenal activity and clinical haemodynamic parameters were also evaluated before departure (SLB), after 1 week (HA1) and 4 weeks (HA4) at HA and 1 week after return to sea level (SLA). As compared to pre-departure sea level values, urinary norepinephrine excretion increased significantly during altitude exposure [SLB: 10.26 (3.04) microg x 3 h(-1); HA1: 23.2 (4.19) microg x 3 h(-1); HA4: 20.3 (8.68) microg x 3 h(-1)] and fell to pre-ascent values 1 week after return to sea level [SLA: 9 (2.91) microg x 3 h(-1)]. In contrast, mean urinary epinephrine levels did not increase over time at HA. Both systolic and diastolic blood pressures, as well as heart rate, were increased during HA exposure. The circadian blood pressure and heart rate rhythms were preserved during all phases of altitude exposure. Mean maximal binding (Bmax) of the alpha2-adrenoceptor antagonist [3H]rauwolscine to platelet membranes was significantly reduced (P < 0.001) after exposure to chronic hypoxia [SLB: 172.6 (48.5) fmol x mg(-1) protein versus SLA: 136.8 (56.1) fmol x mg(-1) protein] without change in the dissociation constant (K(D)). Neither the lymphomonocyte beta2-adrenoceptor Bmax [SLB: 38.5 (13.6) fmol x mg(-1) protein, versus SLA: 32.4 (12.1) fmol mg(-1) protein] nor the K(D) for [3H]dihydroalprenolol was affected by chronic hypoxia. Cyclic AMP (adenosine 3',5'-cyclic monophoshate) generation in lymphomonocytes by maximal isoproterenol stimulation was not modified after prolonged HA exposure. In conclusion, the down-regulation of alpha2-adrenoceptors appears to be an important component of the adrenergic system response to HA exposure.