Biomedical subjects

A Ducatenzeiler

Publications and source records attributed to A Ducatenzeiler.

4 recordsLinked to original sources

PubMed2005

Endogenous beta-amyloid peptide synthesis modulates cAMP response element-regulated gene expression in PC12 cells.

Extracellular-regulated kinases play a fundamental role in several neuroplasticity processes. In order to test whether endogenous beta-amyloid peptides play a role in the activation of extracellular-regulated kinase, we investigated the Rap1-extracellular-regulated kinase pathway in PC12 cells expressing human beta-amyloid precursor protein containing familial Alzheimer's disease mutations. In PC12 cells transfected with mutant human beta-amyloid precursor proteins that lead to higher levels of endogenous beta-amyloid, we observed an up-regulation of phospho-extracellular-regulated kinase and higher levels of activity-induced cAMP response element-directed gene expression. These results suggest that moderate levels of endogenous beta-amyloid peptides stimulate cAMP response element-directed gene expression. This stimulation was via a Rap1/MEK/extracellular-regulated kinase signaling pathway, as it was blocked by inhibition of Rap1 and MEK activities, and it requires beta-amyloid precursor protein cleavage at the gamma-site as it was abolished by a gamma-secretase inhibitor. Interestingly, in agreement with the previous observations, micromolar levels of extracellular fibrillar beta-amyloid blocked the cAMP response element-regulated gene expression stimulated by potassium and forskolin. This indicates that beta-amyloid can provoke different responses on cAMP response element-directed gene expression, such that low beta-amyloid levels may play a physiological role favoring synaptic plasticity under normal conditions while it would inhibit this mechanism under pathological conditions.

Alzheimer Disease↗

PubMed2004

Altered mitogen-activated protein kinase signaling, tau hyperphosphorylation and mild spatial learning dysfunction in transgenic rats expressing the beta-amyloid peptide intracellularly in hippocampal and cortical neurons.

The pathological significance of intracellular Abeta accumulation in vivo is not yet fully understood. To address this, we have studied transgenic rats expressing Alzheimer's-related transgenes that accumulate Abeta intraneuronally in the cerebral and hippocampal cortices but do not develop extracellular amyloid plaques. In these rats, the presence of intraneuronal Abeta is sufficient to provoke up-regulation of the phosphorylated form of extracellular-regulated kinase (ERK) 2 and its enzymatic activity in the hippocampus while no changes were observed in the activity or phosphorylation status of other putative tau kinases such as p38, glycogen synthase kinase 3, and cycline-dependent kinase 5. The increase in active phospho-ERK2 was accompanied by increased levels of tau phosphorylation at S396 and S404 ERK2 sites and a decrease in the phosphorylation of the CREB kinase p90RSK. In a water maze paradigm, male transgenic rats displayed a mild spatial learning deficit relative to control littermates. Our results suggest that in the absence of plaques, intraneuronal accumulation of Abeta peptide correlates with the initial steps in the tau-phosphorylation cascade, alterations in ERK2 signaling and impairment of higher CNS functions in male rats.

Amyloid beta-Peptides↗

PubMed2000

Abeta immunoreactive material is present in several intracellular compartments in transfected, neuronally differentiated, P19 cells expressing the human amyloid beta-protein precursor.

Processing of the amyloid beta-protein precursor is believed to play a critical role in the development of Alzheimer's disease neuropathology. The localization of the human Abeta epitope within mature neuroectodermally differentiated embryonal carcinoma (P19) cells, stably transfected with the cDNA coding for a wild form human amyloid beta-protein precursor (AbetaPP 751) was investigated. For this, we applied high resolution electron microscopy and immunocytochemistry with a newly developed, highly specfic monoclonal antibody (McSA1). We observed immunoreactive signals in a number of subcellular organelles such as early endosomes, the trans-Golgi network and in the dilated rough endoplasmic reticulum, but not in lysosomes. Occasionally Abeta immunoreactivity was associated with microtubules and filaments, with the outer mitochondrial membrane, and with the nuclear envelope. These observations expand on current data regarding intracellular trafficking of AbetaPP fragments and provoke further questions regarding the role of intracellular Abeta peptides in basal conditions and pathological states.

Journal Article↗

PubMed1988

Human gamma interferon induction by staphylococcal protein A: effector cells, kinetics and the effect of prostaglandin, indomethacin, ibuprofen and aspirin.

Soluble staphylococcal protein A (SpA) induces the synthesis of gamma-interferon (gamma-IFN) by human peripheral blood lymphocytes (PBL). To investigate the kinetics of this gamma-IFN induction and the effector cells involved, we used a highly purified SpA preparation, PBL from healthy volunteers, and a CPE-inhibition gamma-IFN assay with Sindbis virus in human fibroblasts. The production of SpA-induced gamma-IFN (SpA-gamma-IFN) peaked 48 h after the addition of SpA to cultures of PBL and decreased after 72 h. Subpopulations of PBL were purified by depletion using specific monoclonal antibodies and complement; CD4+ or OKT4+ (T4: helper/inducer) cells were able to produce SpA-gamma-IFN in the absence of CD8+ or OKT8+ (T8: suppressor/cytotoxic) or B-cells. PBL pre-incubated with SpA for more than 72 h inhibited gamma-IFN production by autologous fresh PBL; this inhibition segregated with the T8 subpopulation and was not due to cytotoxicity. SpA-gamma-IFN titers increased markedly when CD3+ or OKT3+ (T3) or T4 cells were incubated with a small number (2-10%) of adherent monocytes, whereas larger numbers (greater than 20%) decreased the yield of SpA-gamma-IFN. This decreased yield was probably mediated by prostaglandin E2 (PGE2) of monocyte origin: the presence of PGE2 was demonstrable in these cultures by radioimmunoassay, and the addition of indomethacin reversed the inhibitory effect of large numbers of monocytes; further, treatment of T-cells with exogenous PGE2 also led to an inhibition of SpA-gamma-IFN. Ibuprofen and aspirin also had an effect comparable to indomethacin on SpA-gamma-IFN production. These observations indicate that the production of SpA-gamma-IFN is by T4 lymphocytes, is enhanced by limited numbers of accessory cells (monocytes), and is also regulated by T8 cells via monocyte PGE2.

Aspirin↗