Mesial temporal astrocyte tau pathology in the MRC-CFAS ageing brain cohort.

BACKGROUND: Glial tau pathology is seen in certain tauopathies and in ageing. We determined its frequency in ageing mesial temporal lobe and its relationship to other tau pathologies in the MRC-CFAS population-representative neuropathology cohort. METHODS: Mesial temporal lobe, including hippocampus, amygdala, entorhinal cortex and white matter, was examined using immunohistochemistry with the AT8 antibody to phospho-tau and RD3 and RD4 antibodies to 3R and 4R tau isoforms. Gallyas silver stain was used to detect fibrillar aggregates. RESULTS: Thorn-shaped astrocytes (TSA), positive with AT8, RD4 and Gallyas, were present in 49% of cases. They were particularly prevalent in subpial, periventricular and white matter perivascular locations and were less frequent in grey matter. Coiled bodies were seen in 18.8%. TSA were not related to Braak neurofibrillary tangle or hippocampal tangle pathology stages. TSA in grey matter were associated with coiled bodies (p = 0.011) and argyrophilic grains (p = 0.048), which were identified in 11.5% of cases. They did not correlate with dementia. CONCLUSIONS: Astrocyte tau pathology is common in the ageing mesial temporal lobe. Its formation is independent of Alzheimer-type pathology. It is a 4R tauopathy, which may form part of a mesial temporal age-related 4R tauopathy that includes oligodendroglial tau and argyrophilic grains.

Population variation in oxidative stress and astrocyte DNA damage in relation to Alzheimer-type pathology in the ageing brain.

AIMS: Increasing evidence suggests a role for oxidative damage to DNA in brain ageing and in neurodegenerative disorders, including Alzheimer's disease. Most studies have focussed on the reduced capacity for DNA repair by neurones, and have not taken into account the effect of oxidative stress on astrocytes, and their contribution to pathology. METHODS: We examined levels of oxidative stress, DNA damage and DNA repair mechanisms in astrocytes in a population-based sample derived from the Medical Research Council Cognitive Function and Ageing Neuropathology Study. RESULTS: We demonstrate wide variation in parameters for oxidative stress and DNA damage in astrocytes in the ageing population. We show that there is a significant reduction (P = 0.002) in the lipid peroxidation marker malondialdehyde with increasing Braak stage in Alzheimer's disease. Furthermore, we demonstrate that expression of the DNA damage-associated molecules H2AX and DNA-dependent protein kinase do not increase with increasing Braak stage, rather there is evidence of a nonsignificant reduction in DNA-dependent protein kinase expression by neurones and astrocytes, and in H2AX by neurones with increasing levels of Alzheimer's type pathology. CONCLUSIONS: These findings suggest that the changes in oxidative stress and the astrocyte DNA damage response are not accounted for as an accumulating effect due to established Alzheimer-type pathology. We hypothesize that astrocyte damage, leading to impaired function, may contribute to the development of ageing brain pathology in some individuals.

Astrocyte phenotype in relation to Alzheimer-type pathology in the ageing brain.

Astrocyte pathology occurs in association with Alzheimer's disease (AD) and in brain ageing, but is poorly characterised. We sought to define the detailed cellular pathology of astrocytes, the extent of population variation and the relationship to Alzheimer-type changes in a population-based cohort. Three staining patterns were associated with GFAP and excitatory amino acid transporter 2 (EAAT2): minimal, moderate or extensive immunoreactivity. GFAP and EAAT2 expression were inversely related (p=0.015), with trends to increased expression of GFAP (p=0.019) and decreased expression of EAAT2 (p=ns) with increasing Braak stage. GFAP and EAAT2 correlated incompletely with beta-amyloid and tau immunoreactivity. However, gliosis increased with increasing burden of neuritic (p=0.011), but not diffuse (p=ns), plaques. Double-staining revealed distinct subsets of astrocytes; GFAP(+)EAAT(-), GFAP(-)EAAT(+), or GFAP(+)EAAT(+). In contrast to the variation in GFAP and EAAT2, levels of EAAT1 and S100B showed consistent staining patterns. Alzheimer-type pathology only partially explains the variation in gliosis and astrocyte functional markers, suggesting that other factors contribute to the population variance in astrocyte pathology.

Hippocampal tau pathology is related to neuroanatomical connections: an ageing population-based study.

Deposits of abnormally phosphorylated tau protein are found in numerous neurodegenerative disorders; the 'tauopathies', which include Alzheimer's and Pick's diseases, but tau pathology is also found in the ageing brain. Variation in tau pathology in brain ageing and its relationship to development of tauopathies and cognitive impairment remains unclear. We aimed to determine the extent and pattern of spread of tau pathology in the hippocampus, a susceptible region important in dementia and milder states of memory impairment, using hippocampal samples from the elderly population-based Medical Research Council Cognitive Function and Ageing Study neuropathology cohort. Tau deposition was assessed in hippocampal anatomical sub-regions using the AT8 antibody to phosphorylated tau and isoform-specific antibodies to 3 and 4-repeat tau (RD3 and RD4). Abeta pathology was also assessed. In this population sample, which includes the full ageing spectrum from individuals with no cognitive impairment to those with dementia satisfying clinico-pathology criteria for Alzheimer's disease, we have demonstrated a high prevalence at death of tau pathology. AT8, Abeta, RD3 and RD4 showed similar regional distribution and increased RD3 was noted in late-stage ghost tangles. Abeta was shown to be a poor explanatory variable for tau pathology. Tau deposition progressed in a hierarchical manner. Hippocampal input regions and projection zones (such as lateral entorhinal cortex, CA1/subiculum border and outer molecular layer of dentate) were initially affected, with anterograde progression though the hippocampal circuitry. Six hippocampal tau anatomical stages were defined, each linking projectionally to their adjacent stages, suggesting spread of tau malfunction through neuroanatomical pathways in hippocampal ageing. These stages were significantly associated with dementia, and may provide a clinically useful tool in the clinico-pathological assessment of dementia and mild cognitive impairment.

A brief history of tau: the evolving view of the microtubule-associated protein tau in neurodegenerative diseases.

The major historical milestones in tau-research are reviewed, with their implications for changing perspectives about the significance of tau-pathology in neurodegeneration. Abnormalities of tau-protein characterize the pathology of numerous neurodegenerative disorders, both sporadic and inherited. Over the years, opinions regarding the significance of tau in disease pathogenesis, particularly in Alzheimer's disease, have fluctuated. Early caution about the role of tau as a significant factor in neurodegenerative disease, especially Alzheimer's disease, has been superseded by acceptance of its key involvement in pathways which led to cell dysfunction and death. The discovery of familial "tauopathies", associated with tau-gene mutations, has confirmed that tau-dysmetabolism can independently lead to neurodegeneration. Debate about the centrality of its role remains, but current evidence makes it difficult to ignore the importance of tau in many neurodegenerative diseases. By examining the evolution of research on tau, related to advances in technology and the emergence of new diseases, the future developments needed to resolve remaining issues in the tau-story may be discerned.