Abstract
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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Bao X, Lu CM, Liu F, Gu Y, Dalton ND, Zhu BQ, Foster E, Chen J, Karliner JS, Ross J Jr, Simpson PC, Ziegler MG (2007) Epinephrine is required for normal cardiovascular responses to stress in the phenylethanolamine N-methyltransferase knockout mouse. Circulation 116(9):1024–1031
Bissette G (2009) Does Alzheimer’s disease result from attempts at repair or protection after transient stress? J Alzheimers Dis 18:371–380
Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82:239–259
Braak H, Del Tredici K (2011) The pathological process underlying Alzheimer’s disease in individuals under thirty. Acta Neuropathol 121(2):171–181
Feng Q, Cheng B, Yang R, Sun FY, Zhu CQ (2005) Dynamic changes of phosphorylated tau in mouse hippocampus after cold water stress. Neurosci Lett 388(1):13–16
Garcia-Sierra F, Ghoshal N, Quinn B, Berry RW, Binder LI (2003) Conformational changes and truncation of tau protein during tangle evolution in Alzheimer’s disease. J Alzheimers Dis 5:65–77
Grudzien A, Shaw P, Weintraub S, Bigio E, Mash DC, Mesulam MM (2007) Locus coeruleus neurofibrillary degeneration in aging, mild cognitive impairment and early Alzheimer’s disease. Neurobiol Aging 28(3):327–335
Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI (1986) Abnormal phosphorylation of the microtubule-associated protein tau in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 83:4913–4917
Heneka MT, Nadrigny F, Regen T, Martinez-Hernandez A, Dumitrescu-Ozimek L, Terwel D, Jardanhazi-Kurutz D, Walter J, Kirchhoff F, Hanisch UK, Kummer MP (2010) Locus ceruleus controls Alzheimer’s disease pathology by modulating microglial functions through norepinephrine. Proc Natl Acad Sci USA 107(13):6058–6063
Ikeda Y, Ishiguro K, Fujita SC (2007) Ether stress-induced Alzheimer-like tau phosphorylation in the normal mouse brain. FEBS Lett 581(5):891–897
Iqbal K, Alonso Adel C, Chen S, Chohan MO, El-Akkad E, Gong CX, Khatoon S, Li B, Liu F, Rahman A, Tanimukai H, Grundke-Iqbal I (2005) Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta 1739:198–210
Joëls M, Baram TZ (2009) The neuro-symphony of stress. Nat Rev Neurosci 10(6):459–466
Korneyev A, Binder L, Bernardis J (1995) Rapid reversible phosphorylation of rat brain tau proteins in response to cold water stress. Neurosci Lett 191(1–2):19–22
Kovacech B, Skrabana R, Novak M (2010) Transition of tau protein from disordered to misordered in Alzheimer’s disease. Neurodegener Dis 7(1–3):24–27
Kvetnansky R, Mikulaj L (1970) Adrenal and urinary catecholamines in rats during adaptation to repeated immobilization stress. Endocrinology 87:738–743
Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685
McEwen BS, Sapolsky RM (1995) Stress, cognitive function. Curr Opin Neurobiol 5(2):205–216
Muglia L, Jacobson L, Majzoub JA (1996) Production of corticotropin-releasing hormone-deficient mice by targeted mutation in embryonic stem cells. Ann N Y Acad Sci 780:49–59
Novak M (1994) Truncated tau protein as a new marker for Alzheimer’s disease. Acta Virol 38:173–189
Palkovits M (1973) Isolated removal of hypothalamic or other brain nuclei of the rat. Brain Res 59:449–450
Palkovits M, Brownstein M (1988) Maps and guide to microdissection of the rat brain. Elsevier Science, New York
Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates, 2nd edn. Academic Press, New York
Pei JJ, Sersen E, Iqbal K, Grundke-Iqbal I (1994) Expression of protein phosphatases (PP-1, PP-2A, PP-2B and PTP-1B) and protein kinases (MAP kinase and P34cdc2) in the hippocampus of patients with Alzheimer disease and normal aged individuals. Brain Res 655(1–2):70–76
Rissman RA (2009) Stress-induced tau phosphorylation: functional neuroplasticity or neuronal vulnerability? J Alzheimers Dis 18(2):453–457
Rissman RA, Lee KF, Vale W, Sawchenko PE (2007) Corticotropin-releasing factor receptors differentially regulate stress-induced tau phosphorylation. J Neurosci 27(24):6552–6562
Skrabana R, Sevcik J, Novak M (2006) Intrinsically disordered proteins in the neurodegenerative processes: formation of tau protein paired helical filaments and their analysis. Cell Mol Neurobiol 26(7–8):1085–1097
Sotiropoulos I, Catania C, Pinto LG, Silva R, Pollerberg GE, Takashima A, Sousa N, Almeida OF (2011) Stress acts cumulatively to precipitate Alzheimer’s disease-like tau pathology and cognitive deficits. J Neurosci 31(21):7840–7847
Swaab DF, Bao AM, Lucassen PJ (2005) The stress system in the human brain in depression and neurodegeneration. Ageing Res Rev 4(2):141–194
Tsigos C, Chrousos GP (2002) Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress. J Psychosom Res 53:865–871
Zarow C, Lyness SA, Mortimer JA, Chui HC (2003) Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol 60(3):337–341
Acknowledgments
This study was supported by research grant: APVV No. 0088-10, APVV No. 0634-07, LPP 0354-06 and VEGA 2/0204/10, VEGA 2/0033/11, an international agency ICGEB grant No. CRP/SVK08-01 and research grant from Axon Neuroscience.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Filipcik, P., Novak, P., Mravec, B. et al. Tau Protein Phosphorylation in Diverse Brain Areas of Normal and CRH Deficient Mice: Up-Regulation by Stress. Cell Mol Neurobiol 32, 837–845 (2012). https://doi.org/10.1007/s10571-011-9788-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10571-011-9788-9