Apolipoprotein E epsilon 4 is associated with an increased vulnerability to cell death in Alzheimer's disease.

The presumption to suffer from Alzheimer's disease (AD) accelerates with aging. One important risk factor seems to be the isoform epsilon 4 of the apolipoprotein E gene (Apo epsilon 4), which increases the risk to develop AD at an earlier age. Furthermore, convincing evidence is provided that apoptotic cell death mechanisms play an important role in neuronal cell death in AD. In the present study, we investigated whether abnormalities in apoptosis and caspase-3 activity can be found at the level of lymphocytes and a T cell subtype, CD4 T cells, from AD patients compared to aged sex- and ApoE genotype-matched non-demented controls. Under different experimental conditions (at baseline or after in vitro incubation in the presence of proapoptotic stimuli) increased levels of apoptosis and enhanced caspase-3 activity were detected in lymphocytes from AD patients. This difference was most pronounced in the CD4(+) T cell subtype. Notably, we found a significant increase of apoptotic cells and caspase-3 activity in lymphocytes from AD patients bearing one or two alleles of the ApoE4 compared to non-E4 carriers. Again, these effects were strongest in CD4(+) T cells. Circulating amyloid-beta (A beta) levels did not differ between AD patients bearing ApoE4 and non-ApoE4 and age-matched controls. Therefore, it is likely that circulating A beta is not responsible for the observed effects, which might rather reflect an ongoing systemic response in AD, e.g. an increase in CD95 expression.

Enhanced ROS-generation in lymphocytes from Alzheimer's patients.

INTRODUCTION: Reactive oxygen species (ROS) have been implicated in neurodegeneration and seem to be involved in the physiology and pathophysiology of several diseases, including normal aging and Alzheimer's disease (AD). Enhanced ROS production in aging or AD is not restricted to the brain, but can also been seen in several peripheral tissues. The objective of the present study was to evaluate whether the mechanisms involved in the generation of oxidative stress in normal senescence and Alzheimer's disease are identical or not. METHODS: We analysed intracellular basal levels of ROS in lymphocytes from AD patients and healthy young and aged not-demented subjects as well as ROS levels following stimulation with d-ribose and staurosporine in all three groups. ROS levels were measured by flow cytometry using the intracellular fluorescence dye dihydrorhodamine123 (DHR123). RESULTS: Our study shows that AD lymphocytes have increased basal levels of ROS, low susceptibility to ROS stimulation by 2-deoxy- D-ribose (dRib) and an increased response to staurosporine when compared with age-matched controls. DISCUSSION: The data suggest that the defect(s) responsible for enhanced ROS production in AD may involve different or additional biological pathways than those involved in enhanced ROS generation during aging.

Subclinical hyperthyroidism in dementia and correlation of the metabolic index in FDG-PET.

AIM: Thyroid hormone status and thyroid antibodies were evaluated in patients suffering from dementia for further study of an association of hyperthyroidism with AD and vascular dementia (VD), respectively. PATIENTS: In 77 patients with dementia, and 42 controls, thyrotropin (TSH) and thyroid antibodies were correlated with the different types of dementia and the metabolic index (MI) based on imaging with F-18-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET). RESULTS: Twenty-two of all patients with dementia (29%) had borderline (TSH 0.3-0.5 mU/l) or decreased TSH levels (TSH < 0.3 mU/L). TSH values were significantly lower in patients suffering from AD (median: 1.1 mU/l) and VD (0.5 mU/l) than in the control group (1.5 mU/l) (p < 0.01). Decreased or borderline TSH levels were present in 52% of the patients with VD, but in only 10% of the controls, and in 23% of the patients with AD. Antibodies to thyroid peroxidase were positive in 16% of all patients with dementia. The MI in patients suffering from AD with borderline TSH levels was 0.81 (0.70, 0.94). In contrast, patients suffering from AD with normal TSH values showed a slightly higher MI of 0.84 (0.76, 0.89) (p = n.s.). CONCLUSION: Decreased or borderline TSH values are associated with an increased probability of having dementia, especially VD.

[Etiology and pathogenesis of Alzheimer dementia]. / Atiologie und Pathogenese der Alzheimer-Demenz.

Alzheimer's disease (AD) is the most common cause of primary dementia, characterized by a progressive process of pathophysiological restructuring of the brain over decades. The hallmark of Alzheimer's disease is the extracellular accumulation and deposition of insoluble amyloid, to be found in the parenchyma in the form of amyloid plaques and in meningeal and cerebral vessels as a congophile angiopathy. Equally conspicuous is the intraneuronal occurrence of neurofibrillary tangles, consisting mainly of hyperphosphorylated tau-protein. Amyloid plaques and neurofibrillary tangles are characteristic, but not specific to Alzheimer's disease. Similar changes can be found in healthy ageing processes and in various other neurodegenerative diseases. It is common to differentiate between an early-onset, familial Alzheimer's disease with an established genetic etiology, representing only about 5% of all cases, and the more typical late-onset, sporadic Alzheimer's disease with an age of onset above 65 years and no clear pattern of inheritance. Although there seems to be a large heterogeneity in the etiology of Alzheimer's disease, the amyloid-cascade-hypothesis has taken a central position as a model for the general etiopathogenesis. The regulation of amyloid plaques underlies a diversity of cellular and molecular factors. In addition to ageing, apolipoprotein E 4 is a firmly established risk factor. Disturbance in the cerebral glucose metabolism, especially in the hippocampal regions, is a further proposed factor in the pathogenesis of Alzheimer's disease. The wide-spread loss of cortical cholinergic neurotransmission associated with the cognitive deficits is of importance to the comprehension of the symptoms and the present pharmacotherapy of Alzheimer's disease.

[Therapy of Alzheimer dementia. Current status and prospects]. / Therapie der Alzheimer-Demenz. Aktueller Stand und Perspektiven.

In recent years, considerable progress has been made both in the diagnosis and treatment of dementia. Drugs have been developed which enhance cognitive performance in a large percentage of those afflicted, delay impairment of the ability to cope with the tasks of daily life, and avoid premature admission to a nursing home. In the practical medical care setting, however, these advantages are being utilized to only a limited extent, and this despite the fact that numerous therapeutic options are now available for the treatment of AD. New therapeutic approaches are aimed at inhibiting the pathological cleavage and extracellular and intracellular deposition of amyloid, preventing the toxic effects of amyloid accumulation around the neurons, and re-establishing intracellular transport deranged by the aggregation of neurofibrils. A further approach is the use of combinations of available substances with differing, possibly synergic, effects. Over and beyond this, treatment of AD in the "presymptomatic stage", or in the stage of only mild cognitive disturbance, is currently the subject of clinical trials.

No short-term effects of high-frequency electromagnetic fields on the mammalian pineal gland.

There is ample experimental evidence that changes of earth-strength static magnetic fields, pulsed magnetic fields, or alternating electric fields (60 Hz) depress the nocturnally enhanced melatonin synthesis of the pineal gland of certain mammals. No data on the effects of high-frequency electromagnetic fields on melatonin synthesis is available. In the present study, exposure to 900 MHz electromagnetic fields [0.1 to 0.6 mW/cm2, approximately 0.06 to 0.36 W/kg specific absorption rate (SAR) in rats and 0.04 W/kg in Djungarian hamsters; both continuous and/or pulsed at 217 Hz, for 15 min to 6 h] at day or night had no notable short-term effect on pineal melatonin synthesis in male and female Sprague-Dawley rats and Djungarian hamsters. Pineal synaptic ribbon profile numbers (studied in rats only) were likewise not affected. The 900 MHz electromagnetic fields, unpulsed or pulsed at 217 Hz, as applied in the present study, have no short-term effect on the mammalian pineal gland.