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1

The role of cyclin-dependent kinase 5 in regulating early inflammatory signaling in the mouse brain during amyloid beta toxicity

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Czapski G. A., Wilkaniec A., Gassowska-Dobrowolska M., Adamczyk A.
Acta Neurobiologiae Experimentalis
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2017
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tom 77
|
nr Suppl.1
INTRODUCTION: Cyclin-dependent kinase 5 (Cdk5) belongs to the family of serine/threonine kinases and plays a fundamental role in brain development and functioning, but its deregulated activity has also been implicated in various neurodegenerative disorders, including Alzheimer’s disease (AD). Moreover, our recent study demonstrated the involvement of Cdk5 in regulating inflammatory processes in the brain during peripheral activation of immune system. However, the relationship between AD, Cdk5 and neuroinflammation is poorly understood. AIM(S): The aim of this study was to investigate the involvement of Cdk5 in regulating neuroinflammation in mouse model of amyloid beta (Aβ) toxicity METHOD(S): Here, we used the experimental model, based on single intracerebroventricular injection of Aβ1‑42 oligomers, enabling the production of Alzheimer-like behavioral abnormalities and resembling some molecular events occurring during early stage of AD. The brain tissue was analyzed up to 35 days post-injection. The role of Cdk5 in inflammatory process activation was evaluated using the pharmacological Cdk5 inhibitor roscovitine. RESULTS: Our results demonstrated that injection of Aβ1‑42 oligomers induces long‑lasting activation of microglia and astrocytes in hippocampus. Analysis of mRNA level for inflammation‑related genes (e.g. Tnf‑α, IL‑1β, IL‑6) showed rapid rise as early as 3 h after injection of Aβ1‑42. Notably, injection of scrambled Aβ1‑42 had no effect on expression of inflammatory mediators. Furthermore, Aβ1‑42 promotes p25 generation, indicative of increased Cdk5 activity. Importantly, inhibition of Cdk5 with roscovitine significantly reduced gene expression and/or protein level of Tnf‑α, IL‑1β, IL‑6, IL‑10 and Nos2. CONCLUSIONS: Our data indicated that Cdk5 plays an important role in Aβ toxicity via controlling brain inflammatory processes. These findings provide important new insights into the molecular mechanisms linking neuroinflammation with the pathogenesis of Alzheimer’s disease. FINANCIAL SUPPORT: This study was supported by The NCN Grant 2011/03/B/NZ3/04549.
2

Alteration of mTOR signalling pathway in rats prenatally exposed to valproic acid

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Adamczyk A., Cieslik M., Gassowska-Dobrowolska M., Jesko H., Filipkowski R. K., Boguszewski P. M.
Acta Neurobiologiae Experimentalis
|
2017
|
tom 77
|
nr Suppl.1
INTRODUCTION: Autism is a neurodevelopmental disorder characterised by impaired social interaction, deficits in communication and stereotyped behaviours with synaptic dysfunction suggested as the major causative factor. However, the molecular mechanisms of synapses impairment remain unclear. The most recent studies point to mTOR, a regulator of protein synthesis at spines, as a potential molecular basis of autism. AIM(S): Here, we investigated whether the Akt/mTOR pathway is damaged in rats prenatally exposed to valproic acid (VPA), an animal model exhibiting autistic-like behaviour. METHOD(S): Pregnant Wistar rats were injected i.p. with a single dose of 400 mg/kg VPA on embryonic day 12.5. Autism‑like behaviours were verified by measuring ultrasonic vocalizations and elevated plus maze test. Gene expression and protein levels were analysed using real-time PCR and western blot methods, respectively. RESULTS: Our behavioural investigations have shown impaired communication and increased anxiety in VPA group. Along with the behavioural changes we observed alteration of mTOR signalling in the cerebral cortex, hippocampus and cerebellum of autistic model rats. Enhancement of phospho-mTOR protein level was the most pronounced in the hippocampus, where the phosphorylation of mTOR targets was observed: increased p-4E-BP1, and reduced phospho-p70S6K. These changes were accompanied by an increase in p-Akt protein level. Activation of mTOR in the cerebellum caused an increase of p-4E-BP1, but not of p70S6K. The mild but significant rise in phosphorylated mTOR in the cerebral cortex did not lead to any changes in p70 or 4E-BP1 phosphorylation. Synaptosomes isolated from VPA subjects revealed significant abnormalities in their ultrastructure including unidentified electron-dense matrix material as well as fragile and malformed the post-synaptic densities. CONCLUSIONS: These results suggested that altered signalling via Akt/mTOR/p70S6K/p-4E-BP1 may result in disturbed spine protein synthesis and thereby lead to synaptic dysfunction. FINANCIAL SUPPORT: Supported from MMRC statutory theme 8.
3

Maternal immune activation alters synaptic protein expression and causes social interaction impairment in rat offspring

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Cieslik M., Gassowska-Dobrowolska M., Jesko H., Boguszewski P. M., Filipkowski R. K., Adamczyk A.
Acta Neurobiologiae Experimentalis
|
2017
|
tom 77
|
nr Suppl.1
INTRODUCTION: Emerging epidemiology data indicate that maternal immune activation (MIA) resulting from inflammatory stimuli such as bacterial infections during pregnancy may constitute a risk factor for multiple neurodevelopmental diseases including autism spectrum disorders (ASD). Genetic and environmental variation, inflammation during early development, and their interaction can influence synaptic dysfunction in ASD. However, the molecular links between infection-induced fetal development alterations and the risk of ASD are still unclear. AIM(S): The aim of this study was to investigate the effect of MIA on the expression and protein level of key synaptic proteins along with the autism-associated behavior in male rat offspring. METHOD(S): Pregnant Wistar rat dams were injected intraperitoneally (i.p.) at gestational day 9.5 with 0.1 mg/kg lipopolysaccharide (LPS), which induces immune response similar to that against gram-negative bacteria. RESULTS: Our data shown impaired social interaction, tested by the play behaviors (Tickling test on post-natal day PND 45–50). However, we did not observe any changes in ultrasonic vocalization (9–11 PND) and bedding preference (PND 15) in MIA offspring. Along with the social interaction changes, MIA has induced presynaptic protein alterations in adolescent rat offspring. These alterations included decreased level of synaptobrevin and syntaxin-1, the key components of SNARE complex, as well as higher level of synapsin. Together with changes in presynaptic proteins, MIA induced reduction in PSD-95 and down-regulation of SHANK family proteins. Moreover, alteration in the protein level of phospho-Akt, and 4E-BP1 was found in MIA subjects. CONCLUSIONS: It is possible that variations of Akt/ mTOR pathway are responsible for aberrant synthesis of key synaptic proteins. The altered synthesis of these proteins would generate changes in synaptic structure and function, contributing to ASD-like behaviors. FINANCIAL SUPPORT: Supported by the statutory theme 8.
4

Prenatal exposure to valproic acid leads to behavioral alterations and defects of synaptic proteins in the hippocampus of adolescent rats

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Adamczyk A., Gassowska-Dobrowolska M., Cieslik M., Czapski G. A., Jesko H., Gewartowska M., Frontczak-Baniewicz M.
Acta Neurobiologiae Experimentalis
|
2019
|
tom 79
|
nr Suppl.1
Autism spectrum disorders (ASDs) are among the most common neurodevelopmental diseases characterized by impairment in communication and social interaction along with stereotyped or repetitive behaviors. Multiple studies have highlighted the involvement of synaptic proteins in the pathogenesis of ASDs. AIM(S): The aim of this study was to investigate the effect of fetal exposure to valproic acid (VPA) – a rodent model of environmentally triggered autism – on behavioral phenotype as well as gene expression of autism-associated synaptic proteins and synapse morphology in the hippocampus of adolescent rats. METHOD(S): Pregnant Wistar rats received a single intraperitoneal injection of VPA (450 mg/kg b.w.) on gestational day 12.5. Ultrasonic vocalization was analyzed in all infant rats at postnatal day (PND) 11 and anxiety‑related behavior in adolescent male offspring. At PND 52, male offspring were decapitated and the hippocampi were isolated. Transmission electron microscopy (TEM), qPCR, and immunoblotting were used to analyze synaptic structure and protein expression. RESULTS: VPA administration during pregnancy disturbed communication in neonatal rats and led to anxiety-like and repetitive behavior in adolescent animals. TEM showed synaptic pathology including nerve endings swelling, blurred and thickened synaptic cleft structure, and disruption of synaptic membranes. Ultrastructural changes were accompanied by increased expression of proteins involved in synaptic vesicle recycling and neurotransmitter release (Synaptobrevin, Synaptophysin, Synapsin‑1) and reduction in presynaptic membrane protein SNAP25 and the postsynaptic density scaffold PSD95. Changes also occurred in the expression of Shank family proteins and neuroligin 3. CONCLUSIONS: Deregulated expression of synaptic proteins could be involved in ASDs via alterations of synaptic structure/function, subsequently contributing to behavioral abnormalities. FINANCIAL SUPPORT: Supported by NSC grant 2017/25/B/NZ4/01969.
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