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    • Kuda et al reported that the activity

    2024-03-20

    Kuda et al. (1997) reported that the activity of aminopeptidase A (ApA) but not aminopeptidase B (ApB) nor aminopeptidase N (ApN) was decreased in plasma from patients with Alzheimer's disease (AD). More recently Puertas et al. (2013) reported that the activities of plasma ApA, ApB, ApN and IRAP were decreased in patients with early stage Alzheimer's disease (AD) compared to healthy, age-matched controls. The changes in ApA activity were seen in male patients only and there was no difference in the activity of aspartyl aminopeptidase between patients and controls. In this recent study enzyme activity of ApA, ApB, ApN and IRAP was determined by cleavage of the artificial substrates glutamyl-β-naphthylamide, arginine-β-naphthylamide, alanyl-β-naphthylamide and leucyl-β-naphthylamide respectively, using a single 100μM concentration of substrate. The Kuda study utilised a single 3mM concentration of nitroaniline-based artificial substrates (see later). Whilst use of a single concentration of substrate approximate to that which elicits 50% of the maximal enzyme activity (KM, Michaelis-Menten constant) allows demonstration of reduced enzyme activity, it does not allow interrogation of the possible mechanism underlying the reduction. The aim of this study was to use multiple concentrations of substrate to allow further dissection as to whether the previously-reported reduction in activity was due to a change in enzyme affinity for the substrate (KM) or a change in sphingosine-1-phosphate of the enzyme (Vmax). The current study measured serum activity of ApA, ApB, ApN and IRAP using two concentrations of the artificial substrates l-glutamyl-p-nitroanilide; l-arginine-p-nitroanilide; l-alanine-p-nitroanilide and l-leucine-p-nitroanilide in a healthy control group and in a group of patients with mild to moderate AD who were sampled twice 13months apart in order to assess changes with disease progression.
    Methods
    Results The age range of the patients at recruitment (66–90yrs) was similar to that of the controls (65–90yrs), but as demonstrated in Table 1, the mean age of the control group was significantly younger, by approximately 6years, than that of the patient group (Student's t-test, p<0.002). There was no significant difference in the gender ratio between the patient group and control group (Chi-squared). MMSE scores (derived from the ACE-R) were significantly lower in the patient group than the control group (ANOVA, p<0.001) and there was a significant decline within the patient group over the 13months of the study (Paired t-test, p=0.003). For ACE-R scores, there was a similar significant difference between the control volunteers and the patients (ANOVA, p<0.001) and considering data for those individuals for which ACE-R scores were available at both time points, ACE-R scores declined significantly over the 13months of the study indicated by a mean decrease in score of 3.38 points (paired t-test, p=0.011). In the Trail Making test, there were significant increases in times taken to complete parts A and B of the test over the 13month study period (Paired t-test, p=0.012 and <0.001 respectively). Within the samples obtained from the control individuals, activity of none of the enzymes studied, at a substrate concentration of 3mM, differed between males and females. Importantly, see later, there was no gender difference in total serum protein concentration within the control individuals. Inclusion of data from the patient group to increase the sample size did not reveal any significant gender difference in activity of any of the enzymes. Similarly there were no statistically significant relationships between age and enzyme activity at 3mM substrate for any of the enzymes studied either within the control group (R2=0.005–0.085, Pearson's Product-Moment correlation) or within the combined control and patient groups (R2=0.007–0.025, Pearson's Product-Moment correlation).