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Alterations of excitatory synaptic function are the strongest correlate to the pathologic disturbance of cognitive ability observed in the early stages of Alzheimer's disease (AD). This pathologic feature is driven by amyloid-β oligomers (Aβios) and propagates from neuron to neuron. Here, we investigated the mechanism by which Aβios affect the function of synapses and how these alterations propagate to surrounding healthy neurons. We used complementary techniques ranging from electrophysiological recordings and molecular biology to confocal microscopy in primary cortical cultures, and from acute hippocampal and cortical slices from male wild-type and amyloid precursor protein (APP) knock-out (KO) mice to assess the effects of Aβios on glutamatergic transmission, synaptic plasticity, and dendritic spine structure. We showed that extracellular application of Aβios reduced glutamatergic synaptic transmission and long-term potentiation. These alterations were not observed in APP KO neurons, suggesting that APP expression is required. We demonstrated that AβiosβAPP interaction increases the amyloidogenic processing of APP leading to intracellular accumulation of newly produced Aβios. Intracellular AβJos participate in synaptic dysfunctions as shown by pharmacological inhibition of APP processing or by intraneuronal infusion of an antibody raised against Aβios. Furthermore, we provide evidence that following APP processing, extracellular release of Aβios mediates the propagation of the synaptic pathology characterized by a decreased spine density of neighboring healthy neurons in an APP-dependent manner. Together, our data unveil a complementary role for Aβios in AD, while intracellular Aβios alter synaptic function, extracellular Aβios promote a vicious cycle that propagates synaptic pathology from diseased to healthy neurons. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) brain dysfunctions are not exclusively related to amyloid plaques occurrence, but are thought to start much earlier, presumably due to soluble pathological forms of b‐amyloid peptide (Aβ). Indeed Aβ oligomers induce synaptic dysfunctions that cause cognitive decline, exacerbate tau pathology[1] and influence neuronal networks[2]. Although mutation‐induced phenotypes are identified in AD patients, the in vivo effects of different Aβ variants are poorly understood. Here we characterized the effects of different Aβ variants in a transgenic mouse model to provide deeper insight of transconformational processes and the subsequent alterations. Deciphering Ab profiles would help in developing new diagnostic and therapeutic approaches. Method: We developed well‐characterized amyloid variants: Aβ1‐42, Aβ bearing the icelandic mutation (A2T), Aβ bearing the Osaka mutation (E22D[1]) and Aβ bearing the mutation F19S/L34P. First, these variants were overexpressed in cortical neuron cultures. Then, two‐month‐old APP/PS1dE9 mice were inoculated with these variants in the dentate gyrus (n = 5/per group). We assessed Aβ oligomerization profiles, cerebral amyloid load and synaptic health in neuron and mouse (4 months post‐inoculation) models by biochemistry and histology. Result: The different amyloid forms exhibit distinct aggregation profiles and synaptotoxicity in vitro (Figure 1). They did not have the same effect on mouse survival. Osaka‐Aβ induced the highest mortality. Then, we focused on the local reorganization of amyloid. Osaka‐Aβ led to increased 6‐mer and 12‐mer amyloid forms at inoculation site (Figure 2) but also at distance in the cortex. This suggests that Aβ variants differently modulate Aβ metabolism and aggregation. Amyloid plaque assessment showed an Osaka‐Aβ‐induced increase in amyloid load in the hippocampus (Figure 3) and its connected regions. Conclusion: A single inoculation of different Aβ variants in APP/PS1dE9 mice expressing wild‐type Aβ is sufficient to differentially modulate Aβ metabolism, amyloid load and mouse mortality. This suggests that Aβ variants differentially interact with the biochemical/biophysical cerebral environments to differentially induce toxic downstream events that are crucial for better AD physiopathology understanding. References: (1) Delacourte et al., Experimental Gerontology, 2002. (2) Bero et al., Journal of Neuroscience, 2012. (3) Tomiyama et al., Ann Neurol, 2008. [ABSTRACT FROM AUTHOR]

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.