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Stress, depending on its level and quality, may cause adaptive and maladaptive alterations in brain functioning. As one of its multiple effects, elevated blood cortisol levels decrease the synthesis of the neuroprotective BDNF, thus leading to hippocampal atrophy and synapse loss, and rendering it a possible cause for the Alzheimer's disease (AD) related neuropathological and cognitive changes. As a result of the stress response, intraneuronal alterations--also affecting the metabolism of beta-actin--can develop. These have a role in the regulation of memory formation (LTP), but in pathological conditions (AD) they could lead to the accumulation of Hirano bodies (actin-cofilin rods). According to the dementia treatment guidelines, the behavioural and psychological symptoms of AD can be treated with certain antipsychotics. Therefore, the aim of our study was to examine the effects of sertindole (currently not used in the standard management of AD) on the transcription of some AD associated genes (amyloid precursor protein [APP], mitogen activated protein kinase-1 [MAPK-1], beta-actin) in the brain of rats exposed to chronic immobilization stress (CIS). Male Wistar rats were exposed to CIS for three weeks. The four groups were: control (n = 16), CIS (n = 10), 10 mg/kg sertindole (n = 5) and 10 mg/kg sertindole + CIS (n = 4). Following transcardial perfusion, the relative levels of hippocampal and cortical mRNA of the previously mentioned genes were measured with real-time PCR. CIS induced hippocampal beta-actin (p < 0.01), MAPK-1 and APP (p < 0.05) mRNA overexpression. The simultaneous administration of sertindole suppressed this increase in beta-actin, MAPK-1 and APP expression (p < 0.05). Ours is the first report about CIS induced beta-actin gene overexpression. This finding, in accordance with the similar results in APP and MAPK-1 expression, underlines the significance of cytoskeletal alterations in AD pathogenesis. The gene expression reducing effect of sertindole suggests that antipsychotic drugs may have a neuroprotective effect.

Preclinical and clinical studies demonstrate that stress may be implicated in the risk of neurodegenerative diseases such as Alzheimer's disease (AD). Our study aimed to investigate the effects of acute and chronic immobilization stress (IS) on the gene transcriptions of beta-actin, amyloid precursor protein (APP) and mitogen activated protein kinase-1 (MAPK-1), proteins related to synaptic plasticity and neuronal degeneration. Male Wistar rats were exposed to IS for five hours daily for 3 days (acute stress) or through 7-14-21 days (chronic stress). At the end of exposure periods, total RNA was purified from the cortex and hippocampus. The amounts of beta-actin, APP and MAPK-1 mRNA were determined with real time PCR method. Our results indicate that the mRNA expression of beta-actin and APP followed a U-shaped time-response curve. Both acute and chronic IS caused a significant increase in beta-actin and MAPK-1 mRNA expression. Significant APP mRNA elevation was observed only by the 3rd week after RS. Our findings demonstrate that both acute and chronic IS lead to gene transcriptional changes of beta-actin, APP and MAPK-1. These proteins maintain the normal function of the cytoskeleton and the synaptic plasticity. The above changes may lead to cognitive deterioration, and the development of AD.

Damage to and functional alteration of structures responsible for synaptic plasticity correlate with memory loss and cognitive decline in Alzheimer's disease. The results of recent research in the pathomechanism of Alzheimer's disease emphasize the significance of cytoskeletal changes. The changes in actin dynamics and its regulation by actin-binding proteins have been proven in Alzheimer's disease, which may have a key role in the conformation and alteration of synapses and dendritic spines. The most important proteins in the regulation of actin dynamics are ADF/cofilin, kinases and drebrin. In this review, we summarize the physiological functions and complex regulation of these cytoskeletal proteins and their alterations in Alzheimer's disease. Additionally, the effects of some psychopharmacons on the actin cytoskeleton and cytoskeletal changes induced by stress are also summarized.

Alzheimer's disease (AD) is the most frequent form of neurodegenerative dementias. The aetiology and the exact pathomechanism of AD is not known, but stress has been considered recently in the aetiology. Beside the abnormal metabolism of the amyloid protein precursor (APP), the hyperactivity of the mitogen-activated protein kinase 1 (MAPK1) involved in the hyperphosphorylation of the tau proteins, which are considered the major component of neurofibrillary tangles, in addition to β-actin, being involved in synaptogenesis and neuronal plasticity, are all considered important contributors to the development of AD specific neuropathological changes. The chief aim of our present investigation was to examine the effect of stress on the expression of APP, MAPK1 and β-actin mRNAs in the rat hippocampus and cortex. The effect of 9-hydroxy-risperidone (9OHRIS) on the transcription of these genes was also examined. Adult, male Wistar rats were exposed to chronic immobilization stress for 3 weeks. The 9OHRIS (4 mg/bwkg) was administred by gastric tube. Four groups were formed depending on the treatment: (1) control, (2) stress, (3) 9OHRIS, (4) stress and parallel 9OHRIS treatment (n=5-6). The expression of APP, MAPK1, β-actin mRNAs from the perfused brain samples was measured with real-time PCR technique. The β-actin mRNA was significantly overexpressed in the hippocampus after 3 weeks of stress treatment. On the other hand, the stress induced hippocampal β-actin mRNA overexpression was repressed by the 9OHRIS treatment. There were no changes in the cortical or hippocampal expression of APP and MAPK1 mRNAs after neither the stress nor the 9OHRIS treatments. These results emphasize the importance of the stress induced β-actin expression in rat hippocampus. The stress induced alterations in the β-actin RNA expression could be associated with neuronal plasticity and adaptional processes, which could be modified by the 9OHRIS treatment. Our findings indicate that a second generation antipsychotic drug could have a beneficial effect in the pathomechanism of stress and this may have relevance in the treatment of such devastating conditions like AD and psychotic disorders.

Depression is a frequent prodromal symptom of Alzheimer's disease (AD). Stress factors play an important role in the etiopathology of both diseases, since increased corticosteroid levels caused by chronic stress indirectly induce neuronal damage. The aim of our experiments was to evaluate the changes induced by stress in the transcription of amyloid precursor protein (APP), mitogen activated protein kinase-1 (MAPK-1) and beta-actin, of which the latest plays a leading role in synaptic plasticity. Additionally we intended to examine how duloxetine - a serotonin-norepinephrin reuptake inhibitor type antidepressant - would modify the stress-induced changes. Wistar rats were exposed to immobilization stress for five hours daily through 21 days, while part of the animals received 45 mg/bwkg of duloxetine. At the end of the third week total RNA was purified from the cortex and hippocampus. The amount of beta-actin, APP and MAPK-1 mRNA was determined by real time PCR method. On protein level, semiquantitative measurement was performed by Western blot. The expression of beta-actin mRNA in the animals exposed to stress was four times as intense as in the control group. The increase in the beta-actin mRNA levels was repressed by the duloxetine treatment. In the case of APP and MAPK-1 no changes were detected. According to the Western blot results, the antidepressant treatment slightly, the drug along with the stress treatment strongly decreased the amount of the beta-actin protein. Our findings indicate that antidepressant treatment with duloxetine could play a protective role against the chronic stress-induced changes in the nervous system, such as disorders of synaptic plasticity, and the consequent cognitive dysfunctions in case of both affective disorders and AD.