Age, Sex, Hypertension and HDL-C Alter Serum BACE1 Activity in Cognitively Normal Subjects: Implications for Alzheimer's Disease.

BACKGROUND: Increasing evidence indicates that ß-secretase 1 (BACE1) activity and concentration in blood are candidate biomarkers for Alzheimer's disease (AD). Investigating potential demographic, biological, and clinical determinants of BACE1 in the blood matrix is the critical step to validate and qualify BACE1 bio-indicators for different contexts-of-use (CoU), such as risk assessment, early detection, diagnosis, prognosis, management of AD, and outcome of amyloid pathway targeted drugs. OBJECTIVES: To evaluate the influence of age, sex, HDL-cholesterol and comorbidities (cardiovascular diseases, hypertension, diabetes) on circulating BACE-1 activity. DESIGN: prospective analysis of serum samples, clinical, biological, and demographic variables. SETTING: Three cohorts: 1) Memory Clinic of the Department of Internal Medicine, S. Anna University Hospital, Ferrara (Italy); 2) outpatients attending the Menopause and Osteoporosis Centre (MOC) of the University of Ferrara (Ferrara, Italy); 3) Prevention Center of the University of Ferrara. PARTICIPANTS: 504 cognitively healthy individuals (median age: 62 years, interquartile range: 51-73) and 175 patients with AD (78 years, 74-82). MEASUREMENTS: serum BACE1 (sBACE1), age, sex, HDL-cholesterol, major comorbidities. RESULTS: Age was the strongest independent predictor of sBACE1 variance (ß=0.425, p<0.0001), followed by sex (ß=0.180, p<0.0001), high density lipoprotein-cholesterol (HDL-C) (ß=-0.168, p<0.0001) and hypertension (ß=0.111, p<0.05) (overall model, R2: 0.232). The probability of having elevated sBACE1 activity increased after 70 years of age, with women being more susceptible to higher sBACE1 activity than men. CONCLUSIONS: We provide evidence about potential clinical and biological determinants of sBACE1 activity with a strong association among biomarker, female sex, and older age.

Heart rate reduction with ivabradine in the early phase of atherosclerosis is protective in the endothelium of ApoE-deficient mice.

Ivabradine, a heart rate reducing agent, protects the vascular system by unidentified mechanisms. We sought to determine the effects of the treatment with ivabradine, started before plaque formation, on early transcriptional changes and endothelium lesions in regions of aorta subjected to disturbed blood flow. Six week-old apolipoprotein E-deficient (ApoE-/-) mice, fed a low-fat diet, were treated with ivabradine to determine the effect on transcriptional changes (2-and 4-week treatment) and on lesions formation (19-week treatment) in the endothelium of the aortic arch. Microarrays analysis (60k probes) of endothelium-enriched RNA was carried out to detect changes in gene expression induced by treatment. Endothelium damage was assessed by en-face immunofluorescence staining for vascular endothelial (VE) cadherin. According to microarray analysis, 930 transcripts were affected by the treatment. We found downregulation of pro-apoptotic and pro-inflammatory genes, the majority of which are nuclear factor-κB (NF-κB)-and/or angiotensin II-regulated genes, and upregulation of anti-inflammatory genes. Many shear stress-responsive genes were affected by the treatment and the MAPK, Notch signalling and sterol metabolic processes were among the most significantly affected pathways. Consistently, we observed increased levels of Hes5, a Notch target gene, together with a reduction of endothelium damage, in the lower aortic arch of treated- compared with untreated- mice. We concluded that an early treatment with ivabradine protected the endothelium of the aortic arch of ApoE-/- mice. Activation of the Notch signalling could be part of the mechanism underlying this protection.