Lizabeth Jane Davis

Increased plasma levels of interleukin-1, interleukin-6 and α-1-antichymotrypsin in patients with Alzheimer's disease: peripheral inflammation or signals from the brain?

Plasma concentrations of interleukin-1beta (IL-1beta), interleukin-6 (IL-6), C reactive protein (CRP) and alpha-1-antichymotrypsin (ACT) in 145 patients with probable Alzheimers disease (AD) and 51 non-demented controls were measured. To investigate the cellular activation of peripheral immune system, plasma levels of neopterin were also investigated. Plasma levels of IL-1 were detectable in 17 patients with AD (13%) and only in one control (2%) and average levels of IL-1 were higher in AD patients than in controls (p < 0.001). IL-6 plasma levels were detectable in a higher proportion of AD and controls (53% and 27%, respectively), and were increased in patients with AD (p < 0.001). Plasma levels of ACT were increased in patients with AD (p < 0.001) and CRP levels were in the normal range. Plasma levels of neopterin were slightly lower in AD patients than in controls, but differences were not statistically significant. No significant correlation was observed between IL-1 and IL-6 levels or neopterin and cytokine levels in plasma from AD patients. Plasma levels of ACT negatively correlated with cognitive performances, as assessed by the mini mental state examination (MMSE; R = -0.26, p < 0.02) and positively correlated with the global deterioration state (GDS) of AD patients (R = 0.30, p < 0.007). Present findings suggested that detectable levels of circulating cytokines and increased ACT might not be derived by activation of peripheral immune system of AD patients. Detection of these molecules might be used for monitoring the progression of brain inflammation associated with AD.

Lectins and superantigens: Membrane interactions of these compounds with T lymphocytes affect immune responses

1. Lectins and superantigens belong to two different families of macromolecules which are able to interact with cells of the immune system. 2. The principal mechanisms by which they modulate immune responses are presented in this review. 3. Possible similarities shared by these proteins and their common mechanisms of action upon immunocytes will be presented along with a brief discussion regarding the role of these molecules in physiological immune responses and human diseases.

Acute Phase Reactant α1antichymotrypsin Is Increased in Cerebrospinal Fluid and Serum of Patients with Probable Alzheimer Disease

Levels of α1-antichymotrypsin (α1-ACT) in cerebrospinal fluid (CSF) and serum from patients with probable Alzheimer disease (AD) of both early (e-AD) and late (1-AD) onset assessed by a competitive enzyme-linked immunosorbent assay were higher than those found in controls or in patients with vascular dementia (VD). A negative correlation between CSF levels of α1-ACT and the stage of the disease was present in patients with both e-AD and 1-AD. No difference in α1-macroglobulin levels in CSF and serum from patients with e-AD, 1-AD, VD, and nondemented controls was found. Serum concentrations of α1-antitrypsin from 1-AD subjects were within the normal range. Thus, increased levels of α1-ACT in CSF and serum were specifically associated with AD, and the detection of this serpin in CSF may be useful in monitoring the progression of the disease.

Effect of age and extent of dietary restriction on hepatic microsomal lipid peroxidation potential in mice

Lipid peroxidation potential in hepatic microsomes from young and old mice following two different caloric restriction regimens was measured by a colorimetric thiobarbituric acid method under conditions where Fe2+ autoxidation and free oxygen radical production were undetectable. Peroxidation was highest in the young (3.5-month-old) slightly restricted group (caloric intake 75% of ad libitum mice) but very low in young severely restricted (caloric intake 50% of ad libitum mice) and in both old (27-month-old) slightly and severely restricted groups. Very old (45-month-old) severely restricted animals had intermediate lipid peroxidation potentials. Fatty acid composition of liver homogenates was also determined. Significant differences between groups were found for only three fatty acids. Linoleic acid (18:2(n-6)) decreased in aged slightly restricted animals while it remained stable in severely restricted animals during aging. Dihomo-gamma-linolenic acid (20:3(n-6)) was higher in very old restricted animals than in old slightly restricted animals. Docosahexaenoic acid (22:6(n-3)) decreased in old slightly restricted animals. These results indicated that the effect of diets on hepatic fatty acid composition and the potential for microsomal lipid peroxidation in mice was dependent on the degree of caloric restriction and age.

Alpha-1-antichymotrypsin and oxidative stress in the peripheral blood from patients with probable Alzheimer disease: a short-term longitudinal study

To evaluate the stability and reproducibility of selected peripheral oxidative stress markers and their possible relation to cognitive performance, three different blood samples were taken at 7- to 10-day intervals from 11 patients with probable Alzheimer disease (AD) and 11 nondemented controls. Blood samples were also collected once from 6 patients with vascular dementia (VD). Alpha-1-antichymotrypsin (ACT), C-reactive protein (CRP), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), lactoferrin (LTF), and total lipid peroxidation (LPO) were then measured. Blood levels of ACT and GSH-Px were increased in AD patients but not in patients with VD. Levels of LTF, CRP, and LPO were comparable between AD patients and controls. Erythrocyte SOD activity was increased in AD patients. Blood levels of ACT negatively correlated with LPO levels and positively correlated with scores of the Global Deterioration Scale of AD patients. ACT might be implicated in controlling oxidative damage of blood lipids and their turnover during the progression of AD.

Kinetics of the glycation of bovine serum albumin by mannose and fucose in vitro

Glycation of bovine serum albumin was measured for mannose and fucose at 37 degrees C. Mannose as well as fucose demonstrated an initial rapid increase in rate of formation of total adducts followed by a slower secondary reaction. The equilibrium constant for Schiff base formation was almost two times larger for mannose than fucose, although the Schiff base formed by fucose rearranged 1.5 times faster than that for mannose. Both sugars showed parallel lines for the formation of total and acid stable products after three hours. Discussion integrates new mechanistic data with previously suggested mechanisms.

Impaired peripheral zinc metabolism in patients with senile dementia of probable Alzheimer’s type as shown by low plasma concentrations of thymulin

Plasma concentrations of a zinc carrier peptide, namely thymulin, were measured according to a bioassay in young donors, healthy elderly, and patients with senile dementia of Alzheimer’s type (SDAT). Thymulin is a hormone released by thymic epithelial cells and its biological activity on cells of immune system is dependent on the presence of one molecule of zinc bound to the peptide. Plasma from different subjects were fractionated by gel filtration to yield protein-bound thymulin and free thymulin. The biological activity of the peptide was then assessed in the two different fractions. The activity of protein-bound thymulin was higher in young donors than in elderly of SDAT patients, being the lowest in SDAT. Addition of zinc ions to plasma fractions increased the thymulin activity of samples from elderly and SDAT patients to levels observed in young donors. Thymulin activity in free thymulin fractions was lower in the elderly than in the young and was practically undetectable in SDAT patients. The addition of zinc ions normalized the activity of thymulin in these fractions from both the elderly and SDAT patients. These findings confirm the presence of an altered zinc status in the elderly and suggest that an impaired zinc metabolism may be present in SDAT patients.

Increased chemiluminescence response of neutrophils from the peripheral blood of patients with senile dementia of the Alzheimer's type

The metabolic activity of circulating neutrophils from patients with senile dementia of the Alzheimers type (SDAT) was investigated by a chemiluminescence assay and compared with that of old and young healthy controls. Neutrophils from demented patients showed a higher and faster chemiluminescence emission than those of controls when activated in vitro by autologous or heterologous sera. Granulocytes from patients with Parkinsons disease did not show an increased chemiluminescence activity. Moreover, serum from patients with SDAT depressed the chemiluminescence emission of granulocytes from young donors. Serum levels of alpha 1-antichymotrypsin (alpha 1-ACT) were also determined and were found to be higher in demented subjects than in old and young controls. These data suggest that peripheral and systemic indexes of inflammation are present in the disease and might be associated with mental deterioration.

Influence of Age and Health on Immune Functions and Trace Elements

Apparently healthy elderly donors were screened according to a simple protocol that included clinical examination and the determination of hematological and biochemical values. This screening was performed to detect subclinical alterations which might interfere with immune responses and trace element status. The elderly were divided into two groups. The first group consisted of 22 (age 76 +/- 1 years) positively selected elderly (PSE), i.e. healthy subjects with no hematological and laboratory alterations, the second one comprised 13 (age 75 +/- 1 years) negatively selected elderly (NSE). Data were then compared with those obtained from 40 (age 35 +/- 2 years) healthy young controls. In both groups of elderly donors, plasma zinc levels were normal, while plasma copper concentrations were increased. Intracellular values of zinc and copper in mono- and polymorphonuclear cells from both groups of elderly were within reference limits. After in vitro activation, granulocyte chemiluminescence activity was impaired only in NSE. A decrement in the number of circulating CD3 lymphocytes and an increase in CD8d, CD57 cells were found in PSE, while NSE showed an increased number of CD3,DR cells and CD8d, CD57, CD8b,CD57 and CD16,CD56 positive cells. Our results indicate that only plasma copper levels were affected by age, whereas subclinical alterations in hematological or biochemical values appear to impair immune responses in the elderly.

Cerebrospinal fluid of patients with senile dementia of Alzheimer's type shows an increased inhibition of alpha-chymotrypsin.

Summary The inhibition of α-chymotrypsin induced by cerebrospinal fluid from patients with senile dementia of Alzheimers type, vascular dementia, and nondemented controls was investigated. We optimized the sensitivity of the assay so that the inhibition of α-chymotrypsin could be measured in all samples. The competitive inhibition was proportional to the amount of cerebrospinal fluid (CSF) added to the reaction mixture. After correction for protein concentration, the inhibition was higher with CSF from patients with senile dementia of Alzheimers type than with those from patients with vascular dementia or controls. Inhibitory activity appeared to be specific for α-chymotrypsin because no inhibition for papain was found. Moreover, the depletion of α1-antichymotrypsin from CSF by immunoadsorption revealed that this serpin was responsible for the disappearance of the inhibitory activity. Our findings suggested that the increased α-chymotrypsin inhibitory activity might represent an in vivo functional index of an abnormal protease metabolism in patients with Alzheimers disease.