Search

The search for strategies for strengthening the synaptic efficiency in Aβ25-35-treated slices is a challenge for the compensation of amyloidosis-related pathologies. Here, we used the recording of field excitatory postsynaptic potentials (fEPSPs), nitric oxide (NO) imaging, measurements of serine/threonine protein phosphatase (STPP) activity, and the detection of the functional mitochondrial parameters in suspension of brain mitochondria to study the Aβ25-35-associated signaling in the hippocampus. Aβ25-35 aggregates shifted the kinase–phosphatase balance during the long-term potentiation (LTP) induction in the enhancement of STPP activity. The PP1/PP2A inhibitor, okadaic acid, but not the PP2B blocker, cyclosporin A, prevented Aβ25-35-dependent LTP suppression for both simultaneous and delayed enzyme blockade protocols. STPP activity in the Aβ25-35-treated slices was upregulated, which is reverted relative to the control values in the presence of PP1/PP2A but not in the presence of the PP2B blocker. A selective inhibitor of stress-induced PP1α, sephin1, but not of the PP2A blocker, cantharidin, is crucial for Aβ25-35-mediated LTP suppression prevention. A mitochondrial Na+/Ca2+ exchanger (mNCX) blocker, CGP37157, also attenuated the Aβ25-35-induced LTP decline. Aβ25-35 aggregates did not change the mitochondrial transmembrane potential or reactive oxygen species (ROS) production but affected the ion transport and Ca2+-dependent swelling of organelles. The staining of hippocampal slices with NO-sensitive fluorescence dye, DAF-FM, showed stimulation of the NO production in the Aβ25-35-pretreated slices at the dendrite-containing regions of CA1 and CA3, in the dentate gyrus (DG), and in the CA1/DG somata. NO scavenger, PTIO, or nNOS blockade by selective inhibitor 3Br-7NI partly restored the Aβ25-35-induced LTP decline. Thus, hippocampal NO production could be another marker for the impairment of synaptic plasticity in amyloidosis-related states, and kinase–phosphatase balance management could be a promising strategy for the compensation of Aβ25-35-driven deteriorations.

A number of studies performed on rodents suggest that insulin-like growth factor 2 (IGF-2) or its analogs may possibly be used for treating some conditions like Alzheimer’s disease, Huntington’s disease, autistic spectrum disorders or aging-related cognitive impairment. Still, for translational research a comparative knowledge about the function of IGF-2 and related molecules in model organisms (rats and mice) and humans is necessary. There is a number of important differences in IGF-2 signaling between species. In the present review we emphasize species-specific patterns of IGF-2 expression in rodents, humans and some other mammals, using, among other sources, publicly available transcriptomic data. We provide a detailed description of Igf2 mRNA expression regulation and pre-pro-IGF-2 protein processing in different species. We also summarize the function of IGF-binding proteins. We describe three different receptors able to bind IGF-2 and discuss the role of IGF-2 signaling in learning and memory, as well as in neuroprotection. We hope that comprehensive understanding of similarities and differences in IGF-2 signaling between model organisms and humans will be useful for development of more effective medicines targeting IGF-2 receptors.

Compared to other types of cells, neurons express the largest number of diverse mRNAs, including neuron-specific ones. This mRNA diversity is required for neuronal function, memory storage, maintenance and retrieval. Regulation of translation in neurons is very complicated and involves various proteins. Some proteins, implementing translational control in other cell types, are used by neurons for synaptic plasticity. In this review, we discuss the neuron-specific activity of four kinases: protein kinase R (PKR), PKR-like endoplasmic reticulum kinase (PERK), general control nonderepressible 2 kinase (GCN2), and heme-reguated eIF2α kinase (HRI), the substrate for which is α-subunit of eukaryotic initiation factor 2 (eIF2α). Phosphorylation of eIF2α is necessary for the cell during stress conditions, such as lack of amino acids, energy stress or viral infection. We propose that, during memory formation, neurons use some mechanisms similar to those involved in the cellular stress. The four eIF2α kinases regulate translation of certain mRNAs containing upstream open reading frames (uORFs). These mRNAs encode proteins involved in the processes of long-term potentiation (LTP) or long-term depression (LTD). The review examines some neuronal proteins for which translation regulation by eIF2 was suggested and checked experimentally. Of such proteins, we pay close attention to protein kinase Mζ, which is involved in memory storage and regulated at the translational level.

Protein kinase M&zeta, is considered important for memory formation and maintenance in different species, including invertebrates. PKM&zeta, participates in multiple molecular pathways in neurons, regulating translation initiation rate, AMPA receptors turnover, synaptic scaffolding assembly, and other processes. Here, for the first time, we established the sequence of mRNA encoding PKM&zeta, homolog in land snail Helix lucorum. We annotated important features of this mRNA: domains, putative capping sites, translation starts, and splicing sites. We discovered that this mRNA has at least two isoforms, and one of them lacks sequence encoding C1 domain. C1 deletion may be unique for snail because it has not been previously found in other species. We performed behavioral experiments with snails, measured expression levels of identified isoforms, and confirmed that their expression correlates with one type of learning.