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GABA-A Receptor Modulating Steroids in Acute and Chronic Stress; Relevance for Cognition and Dementia?

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GABA-A receptor modulating steroids in acute and chronic stress; relevance for cognition and dementia? Item Type Article Authors Bengtsson, S K S; Bäckström, T; Brinton, R; Irwin, R W; Johansson, M; Sjöstedt, J; Wang, M D Citation Bengtsson, S., Bäckström, T., Brinton, R., Irwin, R., Johansson, M., Sjöstedt, J., & Wang, M. (2020). GABA-A receptor modulating steroids in acute and chronic stress; relevance for cognition and dementia?. Neurobiology Of Stress, 12, 100206. doi: 10.1016/ j.ynstr.2019.100206 DOI 10.1016/j.ynstr.2019.100206 Publisher ELSEVIER SCIENCE INC Journal NEUROBIOLOGY OF STRESS Rights Copyright © 2019 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/BY-NC-ND/4.0/). Download date 01/10/2021 20:29:33 Item License https://creativecommons.org/licenses/BY-NC-ND/4.0/ Version Final published version Link to Item http://hdl.handle.net/10150/641877 Neurobiology of Stress 12 (2020) 100206 Contents lists available at ScienceDirect Neurobiology of Stress journal homepage: www.elsevier.com/locate/ynstr GABA-A receptor modulating steroids in acute and chronic stress; relevance for cognition and dementia? T ∗ S.K.S. Bengtssona, T. Bäckströma, , R. Brintonb, R.W. Irwinc, M. Johanssona, J. Sjöstedta, M.D. Wanga a Umeå Neurosteroid Research Center, Department of Clinical Sciences, University of Umeå, Sweden b Center for Innovation in Brain Science, Professor Departments of Pharmacology and Neurology, College of Medicine, University of Arizona, Tucson, AZ, USA c Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90089, USA ARTICLE INFO ABSTRACT Keywords: Cognitive dysfunction, dementia and Alzheimer's disease (AD) are increasing as the population worldwide ages. Allopregnanolone Therapeutics for these conditions is an unmet need. This review focuses on the role of the positive GABA-A GABA-A receptor modulating steroids receptor modulating steroid allopregnanolone (APα), it's role in underlying mechanisms for impaired cognition GABA-A receptor modulating steroid and of AD, and to determine options for therapy of AD. On one hand, APα given intermittently promotes antagonists neurogenesis, decreases AD-related pathology and improves cognition. On the other, continuous exposure of Learning APα impairs cognition and deteriorates AD pathology. The disparity between these two outcomes led our groups Memory ff ff α Dementia to analyze the mechanisms underlying the di erence. We conclude that the e ects of AP depend on admin- istration pattern and that chronic slightly increased APα exposure is harmful to cognitive function and worsens AD pathology whereas single administrations with longer intervals improve cognition and decrease AD pa- thology. These collaborative assessments provide insights for the therapeutic development of APα and APα antagonists for AD and provide a model for cross laboratory collaborations aimed at generating translatable data for human clinical trials. 1. The object of this review the regeneration of neurons and restore learning and memory in a transgenic Alzheimer mice model (Chen et al., 2011; Singh et al., 2012; In this review, steroids modulating the γ-amino-butyric-acid (GABA) Brinton, 2013). Taken together, APα can act as both a disturber and an receptor type A (GABA-A) receptor are discussed concerning acute and enhancer of memory function in AD models. The purpose of this review chronic stress and how stress influences learning and memory. Focus is is to give a summary of the background to and findings of this see- on disturbances in normal individuals, in persons and rodents with non- mingly contradiction especially about the hypothesis that two very dementia cognitive impairment and in rodents and humans with de- different mechanisms are operating in parallel giving opposite results in mentia. The steroids that enhance/activates the GABA-A receptor are AD animal models. However, before we discuss APα′seffect in Alz- referred to as positive GABA-A receptor modulating steroids (GAMS). heimer's disease we give a background of APα related to acute and Three steroids are mainly discussed: allopregnanolone (APα), and tet- chronic stress in non-demented and normal individuals. In addition, we rahydrodeoxycorticosterone (THDOC) both increasing at stress (Purdy discuss GAMS exposure concerning learning and memory disturbances, et al., 1991) and medroxyprogesterone-acetate (MPA) given con- and take examples from disorders like chronic stress disorders tinuously exogenously to postmenopausal women. Chronically in- (Johansson et al., 2010; Lupien et al., 2005; Wang et al., 2012a; Yaffe creased concentrations of GAMS, especially APα, are shown to induce et al., 2010), risk of dementia in Alzheimer's disease (Sindi et al., 2017), memory and learning disturbances (Johansson et al., 2002; Vallee et al., Parkinson's dementia (Backstrom et al., 2015, 2018) and hepatic en- 2001), accelerate dementia development in AD mice models (Bengtsson cephalopathy (HE) (Weissenborn et al., 2005; Monfort et al., 2009; et al., 2012, 2013) and MPA to double the risk of developing dementia Bianchi et al., 2012). We also discuss consequences these findings may in postmenopausal women (Shumaker et al., 2003). Concurrently in- have for possible treatments of memory and learning disturbances in termittent administration of single dosages of APα is shown to increase non-demented individuals and especially Alzheimer's dementia. From a ∗ Corresponding author. Department of clinical scienses, Norrlands University Hospital, Building 6M, 4th floor, 901 85, Umeå, Sweden. E-mail addresses: [email protected] (S.K.S. Bengtsson), [email protected] (T. Bäckström), [email protected] (R. Brinton), [email protected] (R.W. Irwin), [email protected] (M. Johansson), [email protected] (J. Sjöstedt), [email protected] (M.D. Wang). https://doi.org/10.1016/j.ynstr.2019.100206 Received 12 September 2019; Received in revised form 13 November 2019; Accepted 18 December 2019 Available online 20 December 2019 2352-2895/ © 2019 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/). S.K.S. Bengtsson, et al. Neurobiology of Stress 12 (2020) 100206 Abbreviations is replaced by glycine. fMRI Functional magnetic resonance imaging 3α/β-HSD 3α/β-hydroxysteroid dehydrogenase GABA γ-amino butyric acid 3α5α-adiol 5α-androstane-3α, 20-diol GABA-A γ-amino butyric acid (receptor) type A 3xTgAD The triple transgenic mouse model carries mutant human GAMS GABA-A (receptor) modulating steroid APPSwe, PS1M146v, and TAUP301L. GAMSA GABA-A modulating steroid antagonist 17β-HSD10 17β-hydroxysteroid dehydrogenase type 10 HE Hepatic Encephalopathy ACTH Adrenocorticotropic hormone K595N/M596L The Swedish mutation: Amino acid number 595, AD Alzheimer's disease lysine, is replaced by asparagine and amino acid number APP/AβPP Amyloid precursor protein 596, methionine, is replaced by leucine APPSwe/Arc The transgenic mouse model for AD that carries the LTD Long-term depression gene for APP with the Swe and the Arc mutations LTP Long-term potentiation APPSwe/PS1 The transgenic mouse model for AD that carries the MPA Medroxyprogesterone acetate gene for APP with the Swe mutation, and the gene for PS1 MWM Morris water maze with ΔE9 mutation NMDA N-methyl-D-aspartate receptor APα Allopregnanolone PAM Positive allosteric modulator Arc Arctic mutation, see also E693G PS Pregnenolone sulfate Aβ β-amyloid (exists in various sub-types) PS1 Presenilin-1 Aβ40 β-amyloid 1–40 – sub-type consisting of amino acids 1-40 SGZ Hippocampal dentate gyrus subgranular zone Aβ42 β-amyloid 1–42 – sub-type consisting of amino acids 1–42 SVZ Subventricular zone BrdU 5-bromo-2-deoxyuridine StAR Steroidogenic acute regulatory protein CAA Cerebral amyloid angiopathy Swe The Swedish mutation, see also K595N/M596L CNS Central nervous system THDOC Tetrahydrodeoxycorticosterone DHEAS Dehydroepiandrosterone sulfate TSPO The cholesterol translocator protein DOC Deoxycorticosterone WHIMS Women's Health Initiative Memory Study E693G The arctic mutation – amino acid number 693, glutamate, therapeutic standpoint, the lack of an effective treatment for memory and how it influences long-term memory directly is not the focus of this disorders extends beyond neuro-degeneration to a wide range of neu- publication. ropsychiatric disorders, such as depression, hepatic encephalopathy, schizophrenia and burn out syndrome. While information about the 2.2. Memory and cognitive function in chronic stress role of GAMS in the mechanisms behind cognitive impairment in these disorders is indeed relevant and urgent, this discussion is only super- Chronic stress is a multifaceted condition as it includes many forms, ficially dealt with in this review and lies beyond the scope of the current such as post-traumatic stress disorder (PTSD), psychological stress, or review. psychosocial work related stress, sometimes followed by burnout syn- drome or chronic fatigue disorder (Lupien et al., 2005; Fava et al., 2. Memory and cognitive function at acute and chronic stress in 2019; Marin et al., 2011; Tiihonen-Möller et al., 2016; Tiihonen Moller non-demented individuals et al., 2014). Chronic burnout syndrome in humans affects cognition negatively and high adrenal activity through increased cortisol levels is Take-home message: Acute stress can increase strength
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