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Effect on memory of acute administration of naturally secreted fibrils and synthetic amyloid-beta peptides in an invertebrate model.
No full textAmyloid beta peptide (Abeta) is considered one of the main agents of Alzheimer's disease pathogenesis. Recently, it has been proposed that memory deficits are caused by different stages of Abeta aggregation, particularly by oligomers. In addition, although memory impairment was found after Abeta administration in rodents and chicks, the nature of the memory deficits induced in invertebrates by acute administration of mammalian Abeta peptides is not well understood. Previously, we reported the amnesic effect of acute pre-training administration of naturally formed fibrils (NF) in crab memory. Here we evaluate the effect of NF and synthetic Abeta peptides administration at different times before and after training in this well characterized invertebrate memory model, the context-signal memory of the crab Chasmagnathus. We found a clear amnesic effect at very low doses of naturally Abeta NF only when administered immediately pre- and post-training, but not 24 h and 18 h before or 6h after training. Activation of ERK/MAPK (a protein kinase required for memory formation in this model) 60 min after administration was found. In contrast, neither JNK/SAPK nor NF-kappaB transcription factor were activated. Furthermore, synthetic Abeta1-42 and Abetapy3-42 administration induced amnesia when used after a protocol for fibrillation but not after a protocol for oligomerization. On the contrary, no amnestic effect was found when fibrillated Abeta1-40 and Abetapy11-42 peptides were used. Thus, Abeta1-42 and Abetapy3-42 peptides impaired memory and the effects were only found when highly aggregated peptides, which may include fibrils, protofibrils and oligomers, were administered. These temporally- and signaling-specific effects suggest that Abeta impairs memory by inducing transient physiological, rather than permanent neuropathological, alterations of the brain and this effect is achieved through generalized ERK activation
Phosphorylation by PKA and Cdk5 Mediates the Early Effects of Synapsin III in Neuronal Morphological Maturation.
Full text linkSynapsin III (SynIII) is a neuron-specific phosphoprotein that plays a unique role in neuronal development. SynIII is phosphorylated by cAMP-dependent protein kinase (PKA) at a highly conserved phosphorylation site and by cyclin-dependent kinase-5 (Cdk5) at a newly described site. Although SynIII is known to be involved in axon elongation in vitro, the role of its phosphorylation by PKA and Cdk5 in the modulation of this process is unknown. We expressed either wild-type (WT) or phosphorylation-site mutants of SynIII in primary SynIII knock-out (KO) mouse neurons at early stages of in vitro development. Whereas the neurite elongation phenotype of SynIII KO neurons was fully rescued by the expression of WT SynIII, the expression of nonphosphorylatable and pseudo-phosphorylated PKA mutants was ineffective. Also, the nonphosphorylatable Cdk5 mutant was unable to rescue the neurite elongation phenotype of SynIII KO neurons. By contrast, the pseudo-phosphorylated mutant rescued the delay in neuronal maturation and axonal elongation, revealing a Cdk5-dependent regulation of SynIII function. Interestingly, SynIII KO neurons also exhibited decreased survival that was fully rescued by the expression of WT SynIII, but not by its phosphorylation mutants, and was associated with increased activated caspase3 and altered tropomyosin receptor kinase B isoform expression. These results indicate that PKA and Cdk5 phosphorylation is required for the physiological action of SynIII on axon specification and neurite outgrowth and that the expression of a functional SynIII is crucial for cell survival. Significance statement: Synapsin III is an atypical member of the synapsin family of synaptic vesicle-associated phosphoproteins that is precociously expressed in neurons and is downregulated afterward. Although experimental evidence suggests a specific role for Synapsin III in neuronal development, the molecular mechanisms are still largely unknown. We found that Synapsin III plays a central role in early stages of neuronal development involving neuronal survival, polarization, and neuritic growth and that these effects are dependent on phosphorylation by cAMP-dependent protein kinase and cyclin-dependent protein kinase-5. These results explain the recently described neurodevelopmental defects in the migration and orientation of Synapsin III-depleted cortical neurons and support the potential association of Synapsin III with neurodevelopmental disorders such as schizophrenia
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Protein levels of glycogen synthase 3 kinase are normal in progressive supranuclear palsy.
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