Ether stress‐induced Alzheimer‐like tau phosphorylation in the normal mouse brain

Ikeda, Y.; Ishiguro, Koichi; Fujita, Shinobu C.

doi:10.1016/j.febslet.2007.01.064

Cited by 51 publications

(43 citation statements)

References 49 publications

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“…Recently, it became known that different forms of acute stress can induce the transient phosphorylation of tau protein (Feng et al 2005;Ikeda et al 2007;Rissman 2009;Sotiropoulos et al 2011). Our data presented above are in agreement with results published by these authors.…”

Section: Discussionsupporting

confidence: 93%

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Tau Protein Phosphorylation in Diverse Brain Areas of Normal and CRH Deficient Mice: Up-Regulation by Stress

et al. 2012

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Tau protein misfolding is a pathological mechanism, which plays a critical role in the etiopathogenesis of neurodegeneration. However, it is not entirely known what kind of stimuli can induce the misfolding. It is believed that physical and emotional stresses belong to such risk factors. Although the influence of stress on the onset and progression of Alzheimer's disease (AD) has already been proposed, the molecular links between stresses and AD are still unknown. We have therefore focused our attention on determination of the influence of acute immobilization stress (IMO) in normal mice and mice deficient in corticotropin-releasing hormone (CRH). Specifically, we have analyzed levels of hyperphosphorylated tau proteins, bearing the AD-specific phospho-epitopes (AT-8, pT181, and PHF-1), which are implicated in the pathogenesis of AD. We found that IMO induces transient hyperphosphorylation of tau proteins regardless of continuation of the stimulus. Concerning tau modifications, detailed analysis of the mouse brain revealed that neurons in different brain regions including frontal cortex, temporal cortex, hippocampal C1 and CA3 regions, dentate gyrus as well as nucleus basalis Meynert, and several brainstem nuclei such as locus coeruleus but also raphe nucleus and substantia nigra respond similarly to IMO. The strongest tau protein phosphorylation was observed after 30 min of IMO stress. Stress lasting for 120 min led either to the disappearance of tau hyperphosphorylation or to the induction of a second wave of hyperphosphorylation. Noteworthy is the magnitude of pathological phosphorylation of tau protein in CRH and glucocorticoids deficient mice, being much lower in comparison to that observed in wild-type animals, which suggests a critical role of CRH in the pathogenesis of AD. Thus, our results indicate that hyperphosphorylation of tau protein induced by stress may represent the pathogenic event upstream of tau protein misfolding, which leads to progression or eventually initiation of neurodegeneration. The data show that CRH plays an important role in stress induced hyperphosphorylation of tau protein, which might be either a direct effect of CRH innervations in the brain or an effect mediated via the hypothalamo-pituitary-adrenal axis.

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Section: Discussionsupporting

confidence: 93%

“…Most of the papers dealing with the effect of stress on tau protein phosphorylation published to date are focused on the analysis of the prefrontal cortex and hippocampus (Feng et al 2005;Rissman et al 2007;Ikeda et al 2007). Little is known about the pathological tau phosphorylation in other brain areas.…”

Section: Discussionmentioning

confidence: 99%

Tau Protein Phosphorylation in Diverse Brain Areas of Normal and CRH Deficient Mice: Up-Regulation by Stress

et al. 2012

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“…An increase in tau phosphorylation level at Ser202/Thr205 (AT8 site) was observed in the hippocampus of Tg2576 mice treated with saline. Phosphotau is an integral component of the NFT deposits that disrupt neuronal function, and it is possible that dysregulation of tau phosphorylation in the hippocampus can be translated into a memory impairment in the development of synaptic dysfunction such as AD (Arendt et al, 2003;Ikeda et al, 2007). Here, we found that phospho-tau levels did not differ between the transgenic 4-PBA-treated mice and the non-transgenic mice.…”

Section: Discussionmentioning

confidence: 53%

Phenylbutyrate Ameliorates Cognitive Deficit and Reduces Tau Pathology in an Alzheimer's Disease Mouse Model

Ricobaraza

Cuadrado‐Tejedor

Pérez-Mediavilla

et al. 2009

Neuropsychopharmacol

365

265

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Chromatin modification through histone acetylation is a molecular pathway involved in the regulation of transcription underlying memory storage. Sodium 4-phenylbutyrate (4-PBA) is a well-known histone deacetylase inhibitor, which increases gene transcription of a number of genes, and also exerts neuroprotective effects. In this study, we report that administration of 4-PBA reversed spatial learning and memory deficits in an established mouse model of Alzheimer's disease (AD) without altering b-amyloid burden. We also observed that the phosphorylated form of tau was decreased in the AD mouse brain after 4-PBA treatment, an effect probably due to an increase in the inactive form of the glycogen synthase kinase 3b (GSK3b). Interestingly, we found a dramatic decrease in brain histone acetylation in the transgenic mice that may reflect an indirect transcriptional repression underlying memory impairment. The administration of 4-PBA restored brain histone acetylation levels and, as a most likely consequence, activated the transcription of synaptic plasticity markers such as the GluR1 subunit of the AMPA receptor, PSD95, and microtubule-associated protein-2. The results suggest that 4-PBA, a drug already approved for clinical use, may provide a novel approach for the treatment of AD.

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“…In contrast to our previous study where a high CORT level was found upon chronic isolation [31] , in this study we found low levels of CORT in the blood serum of chronically stressed animals relative to the control. This discrepancy is likely due to the exclusion of ether anesthesia prior to sacrifice [32][33][34] . The current finding of low CORT in isolated animals is similar to the results of other authors showing HPA axis hypoactivity in stress conditions caused by isolation on either young animals or animals subjected to social isolation for shorter periods of time [35,36] .…”

Section: Discussionmentioning

confidence: 99%

Stress Type Dependence of Expression and Cytoplasmic-Nuclear Partitioning of Glucocorticoid Receptor, Hsp90 and Hsp70 in Wistar Rat Brain

Djordjević¹,

Adžić²,

Djordjević³

et al. 2009

Neuropsychobiology

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Chronic exposure to stress is associated with different behavioral and neurological syndromes including impaired excitability of nerve cells in hippocampus (HIPPO) and prefrontal cortex (PFC), regions of the brain that are important for adaptation. The successful adaptation to stress involves negative feedback at the level of the hypothalamic-pituitary-adrenal (HPA) axis provided by the glucocorticoid receptor (GR), which is a steroid-dependent transcription factor found in a heterocomplex with heat shock proteins Hsp90 and Hsp70. In Wistar rats, chronic social isolation leads to a significant decrease in serum corticosterone (CORT), probably due to alterations in the GR signaling pathway. We exploited this type of stress, alone or in combination with acute immobilization, to define changes in the expression level and compartmental distribution of GR, Hsp90 and Hsp70 in HIPPO and PFC. The results indicated that in acute and combined stress, when CORT was increased, GR was translocated to the nucleus in both brain structures. Under chronic stress, when CORT was below the control level, GR was retained in the cytoplasm of PFC, and evenly distributed between compartments in HIPPO. Simultaneously, heat shock proteins partitioning in HIPPO seemed to be mainly stress type-independent, while that of PFC was dependent on stress type. Thus, the stress type-specific responses of GR and heat shock proteins were mainly detected in PFC rather than in HIPPO of Wistar rats. The observed alterations in protein expression and cytoplasmic-nuclear partitioning of the GR, Hsp90 and Hsp70 proteins may be related to maladaptive response of the HPA axis under chronic stress.

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Ether stress‐induced Alzheimer‐like tau phosphorylation in the normal mouse brain

Cited by 51 publications

References 49 publications

Tau Protein Phosphorylation in Diverse Brain Areas of Normal and CRH Deficient Mice: Up-Regulation by Stress

Tau Protein Phosphorylation in Diverse Brain Areas of Normal and CRH Deficient Mice: Up-Regulation by Stress

Phenylbutyrate Ameliorates Cognitive Deficit and Reduces Tau Pathology in an Alzheimer's Disease Mouse Model

Stress Type Dependence of Expression and Cytoplasmic-Nuclear Partitioning of Glucocorticoid Receptor, Hsp90 and Hsp70 in Wistar Rat Brain

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