The mosaic of brain glial hyperactivity during normal ageing and its attenuation by food restriction.

Food restriction of adult rodents increases lifespan, with commensurate attenuation of age-related pathological lesions in many organs, as well as attenuation of normal ageing changes that are distinct from gross lesions. Previous work showed that chronic food restriction attenuated age-associated astrocyte and microglial hyperactivity in the hippocampal hilus, as measured by expression of glial fibrillary acidic protein and major histocompatibility complex II antigen (OX6). Here, we examined other markers of astrocyte and microglial activation in gray and white matter regions of ad libitum-fed (Brown Norway x Fischer 344) F1 male rats aged three and 24 months and chronic food-restricted rats aged 24 months. In situ hybridization and immunohistochemical techniques evaluated glial expression of glial fibrillary acidic protein, apolipoprotein E, apolipoprotein J (clusterin), heme oxygenase-1, complement 3 receptor (OX42), OX6 and transforming growth factor-beta1. All markers were elevated in the corpus callosum during ageing and were attenuated by food restriction, but other regions showed marked dissociation of the extent and direction of changes. Astrocytic activation, as measured with glial fibrillary acidic protein expression (coding and intron-containing RNA, immunoreactivity), increased with age in the corpus callosum, basal ganglia and hippocampus. Generally, food restriction attenuated the age-related increase in glial fibrillary acidic protein messenger RNA and immunoreactivity. Food restriction also reduced the age-related increase in apolipoprotein J and E messenger RNA and heme oxygenase-1 immunoreactivity in the basal ganglia and corpus callosum. However, astrocytes in the hilus of the hippocampus showed an age-related decrease in apolipoprotein J and E messenger RNA, which was further intensified by food restriction. The age-associated microglial activation measured by OX6 and OX42 immunoreactivity was reduced by food restriction in most subregions. The localized subsets of glial age changes and effects of food restriction comprise a mosaic of ageing consistent with the regional heterogeneity of ageing changes reported by others. In particular, age has a differential effect on astrocytic and microglial hyperactivity in gray versus white matter areas. The evident mosaic of glial ageing and responses to food restriction suggests that multiple mechanisms are at work during ageing.

Longitudinal study of inflammatory factors in serum, cerebrospinal fluid, and brain tissue in Alzheimer disease: interleukin-1beta, interleukin-6, interleukin-1 receptor antagonist, tumor necrosis factor-alpha, the soluble tumor necrosis factor receptors I and II, and alpha1-antichymotrypsin.

There is evidence consistent with the hypothesis that inflammatory and immune mechanisms are involved in the pathogenesis of Alzheimer disease (AD). We have investigated whether the levels of inflammatory associated proteins in serum or lumbar cerebrospinal fluid (CSF) reflect the progressive cognitive decline and brain atrophy of AD-patients. Levels of interleukin-1beta(IL-1beta), IL-1 receptor antagonist (IL-1ra), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), the soluble TNF receptors type I and II (sTNFR I and II), and the acute phase protein alpha1-antichymotrypsin (x1-ACT) were determined in paired serum and CSF samples taken yearly over a period of 2-5 years from pathologically confirmed AD patients (n = 8) and normal controls or non-AD subjects with other CNS pathology (n = 9). No significant differences were found between AD subjects and controls in the mean levels of the above mediators. There was also no correlation in either subject group between the levels of these inflammatory mediators in serum or CSF, and the change in cognitive status or the progression of the atrophy of the medial temporal lobe measured by X-ray computed tomography (CT). The concentrations of IL-1beta, IL-6, and TNF-alpha were determined in brain tissue specimens of five to nine different brain regions in six of the AD patients and four of the non-AD subjects. The levels of IL-1beta and IL-6 in the various brain regions were not significantly different in the AD and the non-AD group. However, in AD patients the level of TNF-alpha was significantly lower in the frontal cortex (32%, p = 0.024), the superior temporal gyrus (57%, p = 0.021), and the entorhinal cortex (49%, p = 0.009) compared with non-AD subjects. Low levels of TNF-alpha in the brain areas that showed neuropathology in AD may indicate a dysregulation of the inflammatory process in AD. Despite this finding, this study does not support the use of measurements of any of the inflammatory mediators investigated here as a diagnostic parameter for AD, due the large overlap in the levels of these factors between AD patients and other subjects, and the poor relation to clinical signs of AD.

Mannan-binding lectin in human serum, cerebrospinal fluid and brain tissue and its role in Alzheimer's disease.

Mannan-Binding lectin (MBL) is a serum lectin which can activate the classical complement pathway. Complement proteins of the classical pathway have been found in the brains of patients with Alzheimer's disease (AD) in association with AD brain pathology. To investigate the role for MBL in AD we have looked for its presence in the brain by immunohistochemistry and determined the levels of MBL in paired samples of cerebrospinal fluid and serum from AD patients and controls. MBL was detected in association with blood vessels in the brain tissue of both AD patients and control subjects. There was no apparent difference in the distribution of MBL in the brain tissue between the two groups. The mean concentration of MBL in the CSF was 44% lower in AD patients than in controls (AD 154 +/- 35 pg/ml, n = 19; non-AD 276 +/- 50 pg/ml, n = 15, p < 0.05). The levels of MBL in serum were not significantly different in the two groups. Thus, this study shows that MBL is associated with blood vessels in the brains of both AD and control subjects. Moreover, CSF levels of MBL appear to be lower in AD patients than in control subjects which may indicate a higher degree of MBL consumption connected with complement activation in the AD patients.