Search

Background Inflammation promotes amyloidogenesis in animals and markers of inflammation are associated with β-amyloid (Aβ) in humans. Hence, we sought to examine the cross-sectional associations between chronically elevated plasma C reactive protein (CRP) and cortical Aβ in 259 non-demented elderly individuals reporting subjective memory complaints from the Multidomain Alzheimer Preventive Trial (MAPT). Methods Cortical-to-cerebellar standard uptake value ratios were obtained using [ 18 F] florbetapir positron emission tomography (PET). CRP was measured in plasma using immunoturbidity. Chronically raised CRP was defined as having 2 consecutively high CRP readings (>3 mg/l ≤ 10 mg/l) between study baseline and the 1 year visit (visits were performed at baseline, 6 months, 1 year and then annually). Associations were explored using adjusted multiple linear regression. Results Chronically raised CRP was found to be inversely associated with cortical Aβ (B-coefficient: −0.054, SE: 0.026, p = 0.040) and this association seemed to be specific to apolipoprotein E (Apo E) ε4 carriers (B-coefficient: −0.130, SE: 0.058, p = 0.027). CRP as an isolated reading measured closest to PET scan was also inversely associated with cortical Aβ when CRP was treated as a dichotomized variable (high CRP > 3 mg/l ≤ 10 mg/l, B-coefficient: −0.048, SE: 0.023, p = 0.043). Conclusions Our preliminary findings suggest that inflammation might be beneficial in the early stages of Alzheimer's disease as the immune systems attempts to combat Aβ pathology particularly in ApoE ε4 carriers. Investigating the temporal relationships between cerebral Aβ and a panel of inflammatory markers would provide further evidence as to whether chronic inflammation might modulate amyloidogenesis in vivo. [ABSTRACT FROM AUTHOR]

P53 is a tumour suppressor protein thought to be primarily involved in cancer biology, but recent evidence suggests it may also coordinate novel functions in the CNS, including mediation of pathways underlying neurodegenerative disease. In microglia, the resident immune cells of the brain, p53 activity can promote an activation-induced pro-inflammatory phenotype Jayadev et al. (2011) [1] , as well as neurodegeneration Davenport et al. (2010) [2] . Synapse degeneration is one of the earliest pathological events in many chronic neurodegenerative diseases Conforti et al. (2007) and Clare et al. (2010) [3,4] and may be influenced by early microglial responses. Here we examined synaptic properties of neurons following modulation of p53 activity in rat microglia exposed to inflammatory stimuli. A significant reduction in the expression of the neuronal synaptic markers synaptophysin and drebrin, occurred following microglial activation and was seen prior to any visible signs of neuronal cell death, including neuronal cleaved caspase-3 activation. This synaptic marker loss together with microglial secretion of the inflammatory cytokines tumour necrosis factor α (TNF-α) and interleukin 1-β (IL-1β) was abolished by the removal of microglia or inhibition of microglial p53 activation. These results suggest that transcriptional-dependent p53 activities in microglia may drive a non-cell autonomous process of synaptic degeneration in neurons during neuroinflammatory degenerative diseases. [ABSTRACT FROM AUTHOR]

Abstract: p53 and tau are both associated with neurodegenerative disorders. Here, we show by Western blotting that p53 is upregulated approximately 2-fold in the superior temporal gyrus of Alzheimer''s patients compared to healthy elderly control subjects. Moreover, p53 was found to induce phosphorylation of human 2N4R tau at the tau-1/AT8 epitope in HEK293a cells. Confocal microscopy revealed that tau and p53 were spatially separated intracellularly. Tau was found in the cytoskeletal compartment, whilst p53 was located in the nucleus, indicating that the effects of p53 on tau phosphorylation are indirect. Collectively, these findings have ramifications for neuronal death associated with Alzheimer''s disease and other tauopathies. [Copyright &y& Elsevier]

Abstract: Notch signalling affects most aspects of development, not least the determination of neural stem cell fate. Here, we describe the presence of the Notch-1 intracellular domain (N1ICD) in sub-nuclear bodies in SH-SY5Y neuroblastomas and in primary rat cortical neurons as well as several other mammalian cell lines. We also demonstrate that these N1ICD-positive sub-nuclear bodies are distinct from premyelocytic leukaemia (PML) and SC35 bodies. Furthermore, using Notch deletion constructs we determined that a region C-terminal of amino acid 2094 is involved in targeting the N1ICD into sub-nuclear bodies. These findings have ramifications for nuclear architecture and gene transcription. [Copyright &y& Elsevier]

Abstract: Chromogranin A (CgA) is associated with microglial activation cascades implicated in neurodegeneration in Alzheimer''s, Pick''s and Parkinson''s diseases. In primary rat microglia, CgA-mediated inducible nitric oxide (iNOS) expression, nitric oxide (NO) production, mitochondrial depolarisation and apoptosis were inhibited by PP2 (Src kinase inhibitor). CgA-mediated iNOS expression and NO production were also inhibited by U0126 (MEK inhibitor), but mitochondrial depolarisation and apoptosis were not. PP2 inhibited ERK phosphorylation; therefore, Src mediates CgA-induced ERK phosphorylation leading to iNOS expression and NO production. Glutamate release induced by CgA was independent of both pathways. These findings provide insights into the way microglia are activated by CgA and the microglial signalling mechanisms associated with neurological disorders such as Alzheimer''s disease. [Copyright &y& Elsevier]

Abstract: p73 and tau both play roles in neurodevelopment and neurodegeneration. In this pilot study we show by Western blotting that TAp73α induces phosphorylation of human 2N4R tau at threonine-205 and at the PHF-1 epitope (serine366/serine404) in HEK293a cells. Neither the dominant negative isoform, ΔNp73, nor a transcriptionally inactive mutant TAp73αR292H altered tau phosphorylation indicating that tau phosphorylation is dependent on the transcriptional activity of TAp73α. Consistent with this, confocal microscopy revealed that tau and TAp73α were spatially separated within the cell; tau being located in the cytoskeletal compartment whilst TAp73α was found in the nucleus. These findings have ramifications for microtubule dynamics associated with axonal growth during development and for neuronal death associated with Alzheimer''s disease and other tauopathies. [Copyright &y& Elsevier]

Members of the cyclic-AMP response-element binding protein (CREB) transcription factor family regulate the expression of genes needed for long-term memory formation. Loss of Notch impairs long-term, but not short-term, memory in flies and mammals. We investigated if the Notch-1 (N1) exerts an effect on CREB-dependent gene transcription. We observed that N1 inhibits CREB mediated activation of cyclic-AMP response element (CRE) containing promoters in a γ-secretase-dependent manner. We went on to find that the γ-cleaved N1 intracellular domain (N1ICD) sequesters nuclear CREB1α, inhibits cAMP/PKA-mediated neurite outgrowth and represses the expression of specific CREB regulated genes associated with learning and memory in primary cortical neurons. Similar transcriptional effects were observed with the N2ICD, N3ICD and N4ICDs. Together, these observations indicate that the effects of Notch on learning and memory are, at least in part, via an effect on CREB-regulated gene expression. [ABSTRACT FROM AUTHOR]