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M Goedert

Publications and source records attributed to M Goedert.

211 records · Page 12Linked to original sources
PubMedDate not supplied

Molecular dissection of the paired helical filament.

Abundant neurofibrillary tangles, neuropil threads and plaque neurites constitute the neurofibrillary pathology of Alzheimer's disease. They form in the nerve cells that undergo degeneration in the disease where their regional distribution correlates with the degree of dementia. Each lesion contains the paired helical filament (PHF) as its major fibrous component. Recent work has shown that PHFs are composed of the microtubule-associated protein tau in a hyperphosphorylated state. PHF-tau is hyperphosphorylated on six adult brain tau isoforms. As a consequence, tau is unable to bind to microtubules and is believed to self-assemble into the PHF. Current evidence suggests that protein kinases or protein phosphatases with a specificity for serine/threonine-proline residues play an important role in the hyperphosphorylation of tau. Candidate protein kinases include mitogen-activated protein kinase, glycogen synthase kinase-3 and cyclin-dependent kinase 5, whereas the trimeric form of protein phosphatase 2A is a candidate phosphatase.

Aged↗
PubMedDate not supplied

Expression of APP in transgenic mice: a comparison of neuron-specific promoters.

The beta-amyloid precursor protein (APP) carries mutations in codons 717 or 670/671, which cosegregate with familial forms of Alzheimer's disease (AD). As an initial step to study the related pathogenetic mechanisms in vivo we have generated transgenic mice expressing APP with these mutations. Several neuron-specific promoters were used to drive expression of human APP cDNAs. Only the Thy-1 promoter yielded transgene expression levels comparable to or above the endogenous mouse levels. Deletion of a 121 bp sequence from the 3' untranslated region of APP appeared to increase mRNA levels. Transgene mRNA was found throughout the brain with highest levels in hippocampus and cerebral cortex. Accordingly, human APP was detected in these regions by Western blotting. Protein levels paralleled mRNA levels reaching or exceeding the amount of endogenous APP. Variable reactivity of human APP in cell bodies was shown by immunocytochemistry. Although our initial histological examinations did not reveal any alterations characteristic of AD, further studied will be required.

Aging↗
PubMedDate not supplied

Synergistic activation of SAPK1/JNK1 by two MAP kinase kinases in vitro.

Mitogen-activated protein kinases (MAPKs) mediate many of the cellular effects of growth factors, cytokines and stress stimuli. Their activation requires the phosphorylation of a threonine and a tyrosine residue located in a Thr-X-Tyr motif (where X is any amino acid) [1]. This phosphorylation is catalysed by MAPK kinases (MKKs), which are all thought to be 'dual specificity' enzymes that phosphorylate both the threonine and the tyrosine residue of the Thr-X-Tyr motif [2]. Here, we report that the MAPK family member known as stress-activated protein kinase-1c (SAPK1c, also known as JNK1) [3] is activated synergistically in vitro by MKK4 ([4] [5] [6]; also called SKK1 and JNKK1) and MKK7 ([7] [8] [9]; also called SKK4 and JNKK2). We found that MKK4 had a preference for the tyrosine residue, and MKK7 for the threonine residue, within the Thr-X-Tyr motif. These observations suggest that the full activation of SAPK1c in vivo may sometimes require phosphorylation by two different MKKs, providing the potential for integrating the effects of different extracellular signals. They also raise the possibility that other MAPK family members may be activated by two or more MKKs and that some MKKs may have gone undetected because they phosphorylate the tyrosine residue only, and therefore do not induce any activation unless the threonine has first been phosphorylated by another MKK.

Amino Acid Sequence↗
PubMedDate not supplied

Role of endogenous substance P in stress-induced activation of mesocortical dopamine neurones.

The dopamine (DA) innervation to the forebrain arises from subpopulations of midbrain DA neurones broadly classified as nigrostriatal, mesolimbic and mesocortical. Significant differences in the autoregulatory mechanisms and neuronal inputs of these DA pathways may account for their differences in physiological and pharmacological responsiveness. For example, footshock stress can activate rat mesocortical DA cells but does not alter nigrostriatal DA turnover, while also decreasing substance P (SP) concentrations in the midbrain interpeduncular nucleus and in the adjacent ventral tegmental area (VTA), but not in the substantia nigra (SN). This suggested that the activation of the SP input to the VTA may mediate activation of certain DA systems by footshock stress; behavioural studies also had suggested an excitatory effect of SP on DA cells in the VTA. SP antagonists now available are neurotoxic and of questionable efficacy, we therefore used monoclonal antibody against SP. Antibody microinjected into the VTA prevented normal footshock-induced activation of mesocortical DA neurones, suggesting mediation by SP input to the VTA. The in vivo application of antibodies may prove valuable in studies of neuropeptides in the central nervous system (CNS).

3,4-Dihydroxyphenylacetic Acid↗
PubMedDate not supplied

Inverse relationship between neurotensin receptors and neurotensin-like immunoreactivity in cat striatum.

The adult corpus striatum in mammals is divided into distinct histochemical compartments. If the cat caudate nucleus is stained for acetylcholinesterase a number of macroscopically visible zones appear that have lower acetylcholinesterase activity than the surrounding tissue. These patches, called 'striosomes', correspond to regions of high [Met]-enkephalin-like immunoreactivity and dense opiate receptor binding and are related to the uneven distribution of striatal efferent neurones and cortical afferent terminations. One of the highest concentrations of neurotensin-like immunoreactivity is in the striatum and the immunoreactive material co-elutes with synthetic neurotensin on gel chromatography. Recently, we have found that neurotensin-like immunoreactivity in the cat caudate nucleus coincides with the striosomes. We have now localized neurotensin receptors in the cat caudate nucleus by autoradiography and found low density in the neurotensin-rich striosomes and a high density in the neurotensin-poor surrounding tissue.

Acetylcholinesterase↗
PubMedDate not supplied

Correlation between inositol phospholipid hydrolysis and substance P receptors in rat CNS.

The undecapeptide substance P is a neurotransmitter candidate in the mammalian central and peripheral nervous system. Although the distribution of substance P-like immunoreactivity within the central nervous system (CNS) is well established, the recent identification and autoradiographic localization of specific substance P-binding sites has revealed numerous areas of mismatch between peptide levels and numbers of such sites. Previous studies have shown that substance P stimulates the hydrolysis of inositol phospholipids in peripheral tissues and in the hypothalamus, probably through stimulation of a polyphosphoinositide-specific phospholipase C (refs 9-11). Inositol phospholipid hydrolysis has been implicated in the mobilization of cytosolic calcium following receptor activation in several neurotransmitter and hormonal systems. We have therefore investigated the distribution of 3H-labelled substance P binding sites within various rat brain regions and correlated this with the rate of substance P-induced hydrolysis of inositol phospholipids in the same areas of the CNS. We found that the rate of inositol phospholipid hydrolysis was proportional to the number of binding sites specific for 3H-substance P, suggesting that binding sites revealed by 3H-substance P autoradiography correspond to functional substance P receptors.

Animals↗
PubMedDate not supplied

Evidence for neurotensin as a non-adrenergic, non-cholinergic neurotransmitter in guinea pig ileum.

Neurotensin is a 13-amino acid peptide that is widely distributed in central and peripheral tissues of various mammalian species. In peripheral tissues, the highest concentration of neurotensin-like immunoreactivity is found in the ileum, where it is present in endocrine-like cells and nerve fibres. The longitudinal smooth muscle layer of the guinea pig ileum, where neurotensin has both a direct relaxant and an indirect contractile action, has been used extensively as a biological assay system for neurotensin. We report here that the majority of specific 3H-neurotensin binding sites is present in the guinea pig ileum circular smooth muscle layer, which is known to be innervated by a large proportion of the ileal non-adrenergic inhibitory nerves. Neurotensin produces a dose-dependent, tetrodotoxin-resistant relaxation, whereas the relaxation produced by field stimulation of the inhibitory nerves is frequency-dependent and tetrodotoxin-sensitive. The calcium-dependent potassium channel blocker apamin inhibits both the neurotensin- and nerve stimulation-induced muscle relaxation. Incubation of the circular smooth muscle preparation with a neurotensin antiserum substantially inhibited the nerve stimulation-induced relaxation, indicating a direct relationship between the effects of neurotensin and of nerve stimulation.

Animals↗
PubMedDate not supplied

Phosphorylation of tau by cyclic-AMP-dependent protein kinase.

Alzheimer's disease paired helical filaments contain abnormally phosphorylated tau (PHF-tau) which has reduced electrophoretic mobility on sodium dodecyl sulphate polyacrylamide electrophoresis. We have investigated the effects of cyclic-AMP-dependent protein kinase (PKA) on recombinant human tau isoforms and two recombinant tau fragments. PKA phosphorylated tau and reduced its electrophoretic mobility, phosphorylation towards the C-terminus of tau having a major influence on this property. Substitution of serine396 (phosphorylated in PHF-tau) or serine416 (phosphorylated by calcium/calmodulin kinase II) by alanine demonstrated that these are not major sites for PKA phosphorylation. Although the phosphorylated forms of tau generated by PKA are not identical to those of PHF-tau, PKA may be involved in the generation of PHF-tau in Alzheimer's disease via phosphorylation of additional, as yet unidentified, sites on tau.

Alzheimer Disease↗