Changes of renin-angiotensin system-related aminopeptidases in early stage Alzheimer's disease

Abstract

Activities of aminopeptidases A, B, and N (ApA, ApB & ApN) and insulin-regulated aminopeptidase (IRAP) have been seen to be decreased amongst patients with Alzheimer's disease (AD). All of these enzymes are involved with the brain renin-angiotensin system which is believed to be involved with learning and memory. This study aimed to explore the time course and the mechanisms underlying these changes. Serum samples were collected from 45 AD patients at the start of the study, and again 13 months later (n=37). The control group was 22 healthy, older, adults. Enzyme activity was determined at two substrate concentrations to allow Michaelis-Menten analysis of the enzyme activity. The results indicated that there was decreased activity of ApA, ApB and ApN amongst AD patients but no difference in serum IRAP activity. There were no associations between enzyme activity and age, gender nor scores on psychomotor tests. Consideration of the data for the two time points for AD patients showed that the changes in ApB occurred at an early stage of the disease and persisted, whilst those of ApA and ApN only became apparent at later stages of the disease. Although differences in MichaelisMenten parameters were not statistically significant, consideration of the values suggested that the decrease in ApB activity may be a result of changes in enzyme protein conformation, whilst that of ApN may be a consequence of decreased enzyme expression. Importantly, the different time courses of the effects and the differential changes in enzyme affinity and expression indicated that the observed changes with progression of AD were not a 'class effect' for serum aminopeptidases but were idiosyncratic for the individual enzymes.

Angiotensin-III is Increased in Alzheimer’s Disease in Association with Amyloid-β and Tau Pathology

“…These findings in brain tissue are in contrast to previous studies showing a gender-specific reduction (lower in males) in plasma and serum AP-A activity in AD [32,33]; whether this is due to differences between the brain and periphery (as we have also observed for ACE-1 activity in brain tissue [8,9,35]) remains unknown. Our immunohistochemical studies revealed that AP-A was mostly localised within microglia surrounding Aβ plaques in AD suggesting that there may be upregulation of a specific pool of AP-A in conjunction with an immune response associated with AD pathology.…”

“…A reduction in AP-N activity could however potentially mediate reduced conversion of Ang-III to Ang-IV resulting in elevated Ang-III level, which would not only impact on disease pathology but could also influence downstream signalling pathways involved in cognition -Ang-IV mediated inhibition of its receptor IRAP is heavily implicated in learning and memory processes [30,31]. Serum and plasma AP-N activities are also reduced in AD [32,33]. Together, our data indicate that Ang-III may be increased in AD as a result of dysregulation of the APA/Ang-III/APN/Ang-IV/AT4R pathway and could contribute not only to disease pathology but also to memory impairment.…”

“…Longitudinal studies, such as those described by Gard et al [32] who measured changes in serum aminopeptidases activity in healthy and mild-moderate AD at various stages of disease, will be useful in determining whether changes within these RAS pathways contribute to the early pathological changes in AD. …”

“…This APA/Ang-III/APN/Ang-IV/AT4R pathway remains poorly characterised within the brain and its potential role in AD is poorly understood. Recent studies indicate that serum and plasma AP-A and AP-N activities are reduced in early AD [32,33].…”

Comparison of protease and aminopeptidase activities in meconium: A pilot study

“…Aminopeptidase N serves a role in signal transduction, inflammation, immunological responses, matrix degradation, chemokines and cytokines processing (28). Aminopeptidases are an important subgroup of peptidases which serve a key role in a variety of processes, such as regulation of hormone levels, protein maturation, inactivation of proteins and protein digestion (25)(26)(27)(28)(29). Further research is required to determine the activity of each of the aminopeptidases identified in meconium in the present study, and to measure their activities in the maternal serum and/or amniotic fluid.…”