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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]

The amyloid cascade hypothesis assumes that the development of Alzheimer's disease (AD) is driven by a self-perpetuating cycle, in which β-amyloid (Aβ) accumulation leads to Tau pathology and neuronal damages. A particular mutation (A673T) of the amyloid precursor protein (APP) was identified among Icelandic population. It provides a protective effect against Alzheimer- and age-related cognitive decline. This APP mutation leads to the reduced production of Aβ with A2T (position in peptide sequence) change (Aβ ice ). In addition, Aβ ice has the capacity to form protective heterodimers in association with wild-type Aβ. Despite the emerging interest in Aβ ice during the last decade, the impact of Aβ ice on events associated with the amyloid cascade has never been reported. First, the effects of Aβ ice were evaluated in vitro by electrophysiology on hippocampal slices and by studying synapse morphology in cortical neurons. We showed that Aβ ice protects against endogenous Aβ-mediated synaptotoxicity. Second, as several studies have outlined that a single intracerebral administration of Aβ can worsen Aβ deposition and cognitive functions several months after the inoculation, we evaluated in vivo the long-term effects of a single inoculation of Aβ ice or Aβ-wild-type (Aβ wt ) in the hippocampus of transgenic mice (APP swe /PS1 dE9 ) over-expressing Aβ 1-42 peptide. Interestingly, we found that the single intra-hippocampal inoculation of Aβ ice to mice rescued synaptic density and spatial memory losses four months post-inoculation, compared with Aβ wt inoculation. Although Aβ load was not modulated by Aβ ice infusion, the amount of Tau-positive neuritic plaques was significantly reduced. Finally, a lower phagocytosis by microglia of post-synaptic compounds was detected in Aβ ice -inoculated animals, which can partly explain the increased density of synapses in the Aβ ice animals. Thus, a single event as Aβ ice inoculation can improve the fate of AD-associated pathology and phenotype in mice several months after the event. These results open unexpected fields to develop innovative therapeutic strategies against AD., (© 2024. The Author(s).)