Serum paraoxonase activity changes in patients with Alzheimer's disease and vascular dementia

Abstract

The prevalence of Alzheimer's disease (AD) and vascular dementia (VAD) increases with aging of the population. The role of lipoproteins in the pathogenesis of AD is unclear: apoE(2) offers protection and apoE(3) is neutral, while apoE(4) promotes the development of the disease. Recently, several studies have confirmed the role of oxidative stress in the pathogenesis of AD and VAD. HDL-associated paraoxonase is one of the antioxidative enzymes that may reduce LDL oxidation. In our study, we investigated the lipid parameters of the sera and the serum paraoxonase activity in patients with AD and VAD. Lipid parameters were determined by an autoanalyzer in 30 AD patients, 40 VAD patients and 40 healthy, age-matched control (C) subjects. Paraoxonase activity was measured spectrophotometrically using paraoxon as the substrate. The phenotypic distribution of paraoxonase was determined by the dual substrate method, using paraoxon and phenylacetate as substrates. In our results, we found that most of the patients with AD had the apoE(4) isoform, consistent with other studies. In the VAD and AD patients we found significantly higher total-cholesterol compared to the control group (C: 4.71 +/- 0.89, VAD: 6.3 +/- 0.8, AD: 6.52 +/- 0.7 mmol/l; p < 0.01) and LDL-cholesterol levels (C: 2.6 +/- 0.6, VAD: 3.96 +/- 0.8, AD: 3.84 +/- 0.6 mmol/l; p < 0.001). The HDL-associated antioxidant, paraoxonase activity did not differ significantly in the patient groups, but compared to the healthy control subjects, paraoxonase activity was significantly lower in both of the patient groups (C: 188 +/- 55 U/l; AD: 131 +/- 37, VAD: 151 +/- 50 l; p < 0.05). Our results suggest that the defect in HDL-associated antioxidant capacity plays a role in the pathogenesis of Alzheimer's disease and vascular dementia.

Preferential inhibition of paraoxonase activity of human paraoxonase 1 by negatively charged lipids

“…Despite reports (16,23,(25)(26)(27)(44)(45)(46) on the preferential loss of paraoxon-hydrolyzing activity in serum of persons with oxidative stress-associated pathological signs, there have been no reports concerning causes for the preferential loss of paraoxonase activity. Even the substrate-dependent polymorphism could not account for the preferential reduction of serum paraoxonase activity in cardiovascular disease patients versus controls (21,47).…”

“…The importance of the substrate-specific feature of PON1 may be seen in the substrate-dependent alteration of serum PON1 activity in cardiovascular disease patients; the serum paraoxonase activity decreased significantly ( ‫ف‬ 20%), in contrast to no change of serum arylesterase activity (21)(22)(23). Likewise, such a preferential decrease of paraoxonase activity has been demonstrated in some oxidative stress-associated diseases such as hypercholesterolemia, di-abetes mellitus, or Alzheimer's disease (24)(25)(26). The same phenomenon was also observed with smoking or advancing age, in which oxidative stress was predominant (8,27).…”

“…Recently, there have been reports (35)(36)(37)(38) that the level of negatively charged lipids is enhanced in lipoproteins in the oxidative stress-associated state. In some oxidative stress-related diseases, the preferential reduction of paraoxonase activity has been commonly observed (24)(25)(26). In this regard, it would be interesting to determine how the lipids, especially negatively charged lipids, affect two activities, paraoxonase and arylesterase activities, of PON1 with the aim of finding the causes responsible for the preferential loss of paraoxonase activity.…”

Metabolic Risk Factors of Sporadic Alzheimer's Disease: Implications in the Pathology, Pathogenesis and Treatment

“…One population based study of African Americans has shown that higher serum cholesterol is associated with increased risk of AD in APOE4 negative subjects, but not in those carrying at least one ε4 allele [61]. Many case -control studies have also confirmed that mild hypercholesterolemia accompanies late-onset AD [49,62,63]. However, a 32-year long follow-up study of 1462 women has failed to find an association of mid-life hypercholesterolemia with increasing risk of AD, and even some studies have indicated that a high blood cholesterol especially in latelife is actually protective against AD [64,65,66].…”

The Past and Present of Paraoxonase Enzyme: Its Role in the Cardiovascular System and Some Diseases

“…It was noted in several studies that there was no relation between dementia and PON1 (95)(96)(97)(98). Similarly, PON1 activity was reported to drop in Alzheimer's patients, although the results are contradictory (99)(100)(101). Dantoine et al argued that the 192 PON1 polymorphism might be a critical marker in distinguishing Alzheimer's patients from patients with vascular dementia and healthy individuals (96).…”