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Amyloid-β (Aβ) drives the synaptic impairment and dendritic spine loss characteristic of Alzheimer's disease (AD), but how Aβ affects the actin cytoskeleton remains unknown and contentious. The actin-binding protein, cofilin-1 (cofl), is a major regulator of actin dynamics in dendritic spines, and is subject to phospho-regulation by multiple pathways, including the Rho-associated protein kinase (ROCK) pathway. While cofl is implicated as a driver of the synaptotoxicity characteristic of the early phases of AD pathophysiology, questions remain about the molecular mechanisms involved. Cofilin-actin rods are observed in neurons exposed to Aβ oligomers (Aβ) and in tissue from AD patients, and others have described an increased cofdin phosphorylation (p-cofl) in AD patients. Here, we report elevated p-cofl of the postsynaptic enriched fraction of synaptosomes from cortical samples of male APPPS1 mice and human AD cases of either sex. In primary cortical neurons, Aβ induced rapid actin stabilization and increased p-cofl in the postsynaptic compartment of excitatory synapses within 30 min. Fluorescence recovery after photobleaching of actin-GFP and calcium imaging in live neurons expressing active or inactive cofl mutants suggest that cofl phosphorylation is necessary and sufficient for Aβ-induced synaptic impairment via actin stabilization before the reported formation of cofilin-actin rods. Moreover, the clinically available and welltolerated ROCK inhibitor, fasudil, prevented Aβ-induced actin stabilization, synaptic impairment, and synaptic loss by blocking cofilin phosphorylation. Aβ also blocked the LTP-induced insertion of the AMPAR subunit, GluAl, at the postsynaptic density, in a fasudilsensitive manner. These data support an important role for ROCKs and cofilin in mediating Aβ-induced synaptic impairment. [ABSTRACT FROM AUTHOR]

Tau is a microtubule-associated protein well known for its stabilization of microtubules in axons. Recently, it has emerged that tau participates in synaptic function as part of the molecular pathway leading to amyloid-beta (Aβ)-driven synaptotoxicity in the context of Alzheimer's disease. Here, we report the implication of tau in the profound functional synaptic modification associated with synaptic plasticity. By exposing murine cultured cortical neurons to a pharmacological synaptic activation, we induced translocation of endogenous tau from the dendritic to the postsynaptic compartment. We observed similar tau translocation to the postsynaptic fraction in acute hippocampal slices subjected to long-term potentiation. When we performed live confocal microscopy on cortical neurons transfected with human-tau-GFP, we visualized an activity-dependent accumulation of tau in the postsynaptic density. Coprecipitation using phalloidin revealed that tau interacts with the most predominant cytoskeletal component present, filamentous actin. Finally, when we exposed cortical cultures to 100 nM human synthetic Aβ oligomers (Aβo's) for 15 min, we induced mislocalization of tau into the spines under resting conditions and abrogated subsequent activity-dependent synaptic tau translocation. These changes in synaptic tau dynamics may rely on a difference between physiological and pathological phosphorylation of tau. Together, these results suggest that intense synaptic activity drives tau to the postsynaptic density of excitatory synapses and that Aβo-driven tau translocation to the spine deserves further investigation as a key event toward synaptotoxicity in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

The pre-T-cell receptor (TCR) delivers essential survival/differentiation signals to the developing thymocytes. Severe combined immunodeficient (SCID) and recombination-activating gene (RAG)-deficient mice are unable to assemble antigen receptor genes, and therefore cannot express a pre-TCR. Consequently, T lymphocyte differentiation is arrested at an early stage in the thymus of these animals, and immature thymocytes are eliminated through apoptotic processes. This maturation arrest can be relieved and thymocyte differentiation rescued after the exposure of these mice to whole-body ?-irradiation. Whereas the promotion of immature thymocyte survival/differentiation was shown to require p53 activity in irradiated SCID mice, it was suggested, on the other hand, that p53 activation prevents immature thymocytes survival/differentiation in irradiated RAG-deficient mice. However, SCID mice have impaired responses to ionizing radiation. In this paper, we analysed p53 requirement in radiation-induced thymocyte differentiation in CD3??5/?5 mice, where pre-TCR deficiency also results in an early block of lymphocyte development. Our results show at the cellular and molecular levels that, in this DNA repair-proficient model, irradiation-induced thymocyte differentiation proceeds either by a p53-dependent or by a p53-independent pathway, which differ in their sensitivity to the radiation dose delivered.Oncogene (2004) 23, 1922-1929. doi:10.1038/sj.onc.1207320 Published online 2 February 2004 [ABSTRACT FROM AUTHOR]

Presents the abstracts of articles presented at the 11th International Congress of Immunology slated in July 2001 in Stockholm, Sweden. Rearrangement of antigen receptor genes; Signalling through B and T cell receptors; Molecular mechanisms of apoptosis; Dendritic cells in antigen presentation and inflammatory disorders.

Presents the author index for the July 2001 issue of the periodical 'Scandinavian Journal of Immunology.' Author names.