Local metabolic response to physio-pathological demands: The pentose phosphate pathway

Résumé On a constaté dans le métabolisme de glucose une augmentation de l'utilisation de la voie oxydative directe dans la paroi de l'estomac durant la digestion, et dans celle des vaisseaux sanguins pendant inflammation, réparation et reconstruction. Les resultats ont été analysés en fonction de leur intérêt pour les problèmes cliniques.

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Investigation was conducted during tenure of Special Research Fellowship (No. 11091), U.S. Public Health Service.     

Effects of chlorpromazine on neural tissue in culture

Résumé L'activité acétylcholinesterasique de fragments de moelle d'embryon de poulet de 9 jours augmente lorsqu'ils sont maintenus en culture organotypique, après addition de Chlorpromazine au milieu standard deEagle.     

Influence of prenatal X-radiation on brain lipid and cerebroside content in developing rats

Résumé Lorsque des rats sont irradiés par des rayons X au 14e jour de la gestation, le contenu en cérébrosides du cortex cérébral et du diencéphale est plus élevé que chez les témoins. Or il est bien connu que ce traitement entraîne d'une part une prolifération gliale et d'autre part une augmentation de la sensibilité du système nerveux central à une stimulation électrique. La possibilité d'une relation entre ces phénomènes est discutée.

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USPHS HD-101 fellow.     

Effects of estradiol and cortisol on neural tissue in culture

Résumé L'activité acétylcholinestérasique et la teneur globale en protéines de fragments de cervelet et de moelle d'embryon de poulet de 16 jours diminue lorsqu'ils sont maintenus en culture organotypique dans le milieu standard deEagle. Après addition de cortisol ou d'oestradiol au milieu, les caractéristiques des tissus ne sont pas alterées par la mise en culture.

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This work was partially supported by contract AT (11-1), Project 82, between U.S. Atomic Energy Commission and University of California, Berkeley.     

Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-β

Extracellular plaques of amyloid-β and intraneuronal neurofibrillary tangles made from tau are the histopathological signatures of Alzheimer's disease. Plaques comprise amyloid-β fibrils that assemble from monomeric and oligomeric intermediates, and are prognostic indicators of Alzheimer's disease. Despite the importance of plaques to Alzheimer's disease, oligomers are considered to be the principal toxic forms of amyloid-β. Interestingly, many adverse responses to amyloid-β, such as cytotoxicity, microtubule loss, impaired memory and learning, and neuritic degeneration, are greatly amplified by tau expression. Amino-terminally truncated, pyroglutamylated (pE) forms of amyloid-β are strongly associated with Alzheimer's disease, are more toxic than amyloid-β, residues 1-42 (Aβ(1-42)) and Aβ(1-40), and have been proposed as initiators of Alzheimer's disease pathogenesis. Here we report a mechanism by which pE-Aβ may trigger Alzheimer's disease. Aβ(3(pE)-42) co-oligomerizes with excess Aβ(1-42) to form metastable low-n oligomers (LNOs) that are structurally distinct and far more cytotoxic to cultured neurons than comparable LNOs made from Aβ(1-42) alone. Tau is required for cytotoxicity, and LNOs comprising 5% Aβ(3(pE)-42) plus 95% Aβ(1-42) (5% pE-Aβ) seed new cytotoxic LNOs through multiple serial dilutions into Aβ(1-42) monomers in the absence of additional Aβ(3(pE)-42). LNOs isolated from human Alzheimer's disease brain contained Aβ(3(pE)-42), and enhanced Aβ(3(pE)-42) formation in mice triggered neuron loss and gliosis at 3 months, but not in a tau-null background. We conclude that Aβ(3(pE)-42) confers tau-dependent neuronal death and causes template-induced misfolding of Aβ(1-42) into structurally distinct LNOs that propagate by a prion-like mechanism. Our results raise the possibility that Aβ(3(pE)-42) acts similarly at a primary step in Alzheimer's disease pathogenesis.     

Gas chromatographic-mass spectrometric identification of epinine in rat superior cervical ganglia and formation in vivo

Summary Epinine was identified in rat superior cervical ganglia by a gas chromatographic-mass spectrometric method. The deuterated methyl group of i.v. administered labeled methionine was incorporated into epinine at a slow rate, although epinephrine-CD₃ was rapidly formed. These results indicated that epinine found in the ganglia is not a precursor of epinephrine.Acknowledgments. We wish to thank Dr Magda Claeys for helpful discussions.     

Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10% of cases are familial (FALS), typically with a dominant inheritance mode. Despite numerous advances in recent years, nearly 50% of FALS cases have unknown genetic aetiology. Here we show that mutations within the profilin 1 (PFN1) gene can cause FALS. PFN1 is crucial for the conversion of monomeric (G)-actin to filamentous (F)-actin. Exome sequencing of two large ALS families showed different mutations within the PFN1 gene. Further sequence analysis identified 4 mutations in 7 out of 274 FALS cases. Cells expressing PFN1 mutants contain ubiquitinated, insoluble aggregates that in many cases contain the ALS-associated protein TDP-43. PFN1 mutants also display decreased bound actin levels and can inhibit axon outgrowth. Furthermore, primary motor neurons expressing mutant PFN1 display smaller growth cones with a reduced F/G-actin ratio. These observations further document that cytoskeletal pathway alterations contribute to ALS pathogenesis.