It remains to elucidate whether proteolytic

It remains to elucidate whether proteolytic activity is the cause or the consequence of changing levels of peptidergic substrates. In fact, in some cases, the expression of the enzyme does not necessarily parallel with its activity [26], [55], [57] and other factors such as a definite biochemical environment in AZD2932 australia or plasma, established by specific experimental conditions, may be involved [38]. In addition, the co-localization of several neuropeptides in the same synapsis [56] may lead to a competition for the same enzyme and also influence the type of peptide hydrolyzed by a precise enzyme in the established conditions [38]. In this context, it is important to realize a clear divergent profile in some aminopeptidase activities between hypothalamus and plasma, profile that may change under sympathetic blockade. This may determine the response of their endogenous substrates. A bidirectional influence of the sympathetic nervous system on aminopeptidase activities was proposed between hypothalamus and peripheral tissues such as heart and kidney [34] by modulation of the axonal transport, secretion of aminopeptidases into the neuroeffector junction or enzymatic expression on the plasma membrane. The present results showing an inverted response after propranolol treatment between hypothalamus and plasma clearly support such a bidirectional influence between central and circulatory aminopeptidases. In addition, an asymmetry in the peripheral autonomic innervation of the vessels was suggested, resulting in a possible differential secretion of GluAP from the endothelium [2]. Furthermore, propranolol may asymmetrically affect the aminopeptidase activities of the hypothalamus and the innervation of the vessels (unpublished results by I Prieto, AB Segarra, AB Villarejo, M de Gasparo, MM Martínez and M Ramírez-Sánchez). Also, this may influence differently WKY and SHR and, as a consequence, be in part responsible for the changes observed in hypothalamus and plasma and for the differences in the intensity of the effect observed for food intake, water intake and diuresis between WKY and SHR. In addition, a change in the observed interaction between aminopeptidase activities in plasma and cortico-limbic structures in control rats was reported under stress conditions in which there is an activation of the sympathetic system [44]. These results may be important since they reveal the interdependence between hypothalamus and plasma. Therefore, it should be necessary to take into account that systemic treatments to inhibit plasmatic aminopeptidase activities might influence central ones and vice versa [33], [59].
Conflict of interest
Introduction Aminopeptidases are a group of enzymes typically involved in proteolytic processing of precursors to produce biologically active neuropeptides and hormones, or conversely in the processing of biologically active molecules to produce inactive metabolites or metabolites of different activity. In tissues such as the brain, the enzymes are commonly found anchored within the cell membrane, but they may be endocytosed and found within the cytoplasm; free enzyme is also found in blood. The enzymes of current interest are aminopeptidases A, B and N and insulin-regulated aminopeptidase (IRAP), all of which are involved in the synthesis, metabolism or actions of the brain renin-angiotensin system (RAS, see Fig. 1). The brain RAS is known to influence, amongst other things, learning and memory (Gard, 2002, Mechaeil et al., 2011), hence its interest in conditions associated with learning deficits. The literature, reviewed in Gard (2002), reports a complex relationship with angiotensin II seen to both enhance and diminish learning and memory in animal models, depending when the animals were tested after administration of the angiotensin II. Angiotensin IV consistently improves learning and memory in animal models (e.g. Golding et al., 2010) and it is the metabolism of angiotensin II to angiotensin IV that probably underlies the observed beneficial effects of angiotensin II (Braszko et al., 2006). Clinically, drugs which decrease angiotensin II activity such as angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists, are associated with improved cognition (Nelson et al., 2013), but whether this observed effect is associated with increased activity of angiotensin IV remains to be determined. The aim of this study was to explore further the possible association between the cognitive impairment of Alzheimer's disease and angiotensin IV activity through a detailed profile of the activities of enzymes associated with angiotensin synthesis and action.