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Brief but Chronic Increase in Allopregnanolone Cause Accelerated ADPathology Differently in Two Mouse Models
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. (UNC)
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. (UNC)
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology. (UNC)
University of Zürich, Division of Psychiatry Research and Psychogeriatric Medicine,.
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2013 (English)In: Current Alzheimer Research, ISSN 1567-2050, Vol. 10, no 1, 38-47 p.Article in journal (Refereed) Published
Abstract [en]

Abstract: Previously, we have shown that chronic treatment with allopregnanolone (ALLO) for three months impaired learning function in the Swe/PS1 mouse model. ALLO is a neurosteroid, produced in the CNS and a GABAA receptor agonist. ALLO modulates the general inhibitory system in the CNS by enhancing the effect of GABA. Chronic treatment with other GABAA receptor active compounds, such as benzodiazepines, ethanol and medroxy-progesterone acetate has been associated to cognitive decline and/or increased risk for dementia. In this study, we sufficed with a treatment period of one month for the Swe/PS1 mouse, and included another Alzheimer’s disease mouse model; the Swe/Arc model. We found that one month of chronic treatment with elevated ALLO levels within physiological range impaired learning and memory function in the Swe/Arc female and male mice. Male Swe/PS1 mice also showed marginally impaired function, while the female mice did not. Furthermore, the chronic ALLO treatment caused increased levels of soluble Aβ in the Swe/PS1 mouse model while the levels were unchanged in the Swe/Arc model. Therefore, both Swe/Arc and Swe/PS1 mice showed signs of accelerated disease progression. Still, further studies are required to determine the mechanisms behind the cognitive impairment and the increased Aβ-levels caused by mildly elevated ALLO-levels. learning function in the Swe/PS1 mouse model. ALLO is a neurosteroid, produced in the CNS and a GABAA receptor agonist. ALLO modulates the general inhibitory system in the CNS by enhancing the effect of GABA. Chronic treatment with other GABAA receptor active compounds, such as benzodiazepines, ethanol and medroxy-progesterone acetate has been associated to cognitive decline and/or increased risk for dementia. In this study, we sufficed with a treatment period of one month for the Swe/PS1 mouse, and included another Alzheimer’s disease mouse model; the Swe/Arc model. We found that one month of chronic treatment with elevated ALLO levels within physiological range impaired learning and memory function in the Swe/Arc female and male mice. Male Swe/PS1 mice also showed marginally impaired function, while the female mice did not. Furthermore, the chronic ALLO treatment caused increased levels of soluble Ab in the Swe/PS1 mouse model while the levels were unchanged in the Swe/Arc model. Therefore, both Swe/Arc and Swe/PS1 mice showed signs of accelerated disease progression. Still, further studies are required to determine the mechanisms behind the cognitive impairment and the increased Aβ-levels caused by mildly elevated ALLO-levels.

Place, publisher, year, edition, pages
Bentham Science Publishers , 2013. Vol. 10, no 1, 38-47 p.
Keyword [en]
Alzheimer's disease, beta-amyloid proteins, allopregnanolone, chronic stress, transgenic mouse models, synaptophysin, amyloid plaques
National Category
Neurosciences
Research subject
Obstetrics and Gynaecology; Neurology; Medical Pharmacology; Geriatrics
Identifiers
URN: urn:nbn:se:umu:diva-66571OAI: oai:DiVA.org:umu-66571DiVA: diva2:608560
Funder
Swedish Research Council, 4x-11198
Available from: 2013-02-28 Created: 2013-02-25 Last updated: 2013-03-28Bibliographically approved
In thesis
1. Stress steroids as accelerators of Alzheimer's disease.: Effects of chronically elevated levels of allopregnanolone in transgenic AD models.
Open this publication in new window or tab >>Stress steroids as accelerators of Alzheimer's disease.: Effects of chronically elevated levels of allopregnanolone in transgenic AD models.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Accelererar stressteroider Alzheimers sjukdom? : Effekter av kroniskt förhöjda allopregnanolonnivåer i transgena AD modeller.
Abstract [en]

Background Alzheimer’s disease (AD) and dementia are devastating con­ditions not only for the affected patients but also for their families.  The economical costs for the society are tremendous. Mid-life psychological stress, psychosocial stress and post-traumatic stress disorder cause cognitive dysfunction and lead to increased risk for dementia. However, the mecha­nisms behind stress-induced AD and dementia are not known. AD is char­acterized by solid amyloid plaques in the CNS. However, over the last decade it has been concluded that the levels of soluble beta-amyloid (Aβ) correlate to cognitive performance while plaques often do not. The soluble Aβ accu­mulate intracellularly and disturb the synaptic function. Interestingly, the levels of intracellular Aβ depend on neuronal activity. Previous studies have shown that decreased neuronal activity cause increased intracellular levels of Aβ and cognitive decline. Stress steroids produced in the brain, e.g. allopreg­nanolone, enhance the activity of the GABAergic system, i.e. the main in­hibitory system of the brain. Consequently, allopregnanolone affects neu­ronal activity. Therefore, it is possible that elevated levels of allopreg­nanolone (due to e.g. stress) cause increased intracellular levels of Aβ. This could be a mechanism behind stress-induced AD. The purpose of this thesis was to investigate if elevation of allopregnanolone is a possible link in the mechanism behind stress-induced AD by investigating the effects of chroni­cally elevated levels of allopregnanolone in transgenic mouse models for AD.

Methods Swe/PS1 and Swe/Arc mice (transgenic models for AD) were treated chronically with elevated allopregnanolone levels, comparable to those at mild stress. After an interval of no treatment, the mice were tested for learning and memory performance in the Morris water maze. The brain tissue of the mice was then analyzed for disease markers, i.e. soluble and insoluble Aβ40 and Aβ42 using enzyme-linked immunosorbent assay, and amyloid plaques using immunohistochemistry and Congo red staining tech­nique. The brain tissue was also analyzed for a marker of synaptic function, i.e. synaptophysin.

Results Chronic treatment of allopregnanolone caused impaired learning performance in both the Swe/PS1 and the Swe/Arc mouse models. The Swe/PS1 mice had increased levels of soluble Aβ in both hippocampus and cortex. Interestingly, the levels of soluble Aβ were unchanged in the Swe/Arc mice. Three months of allopregnanolone treatment in the Swe/PS1 mouse model caused decreased plaque size, predominantly in hippocampus. It may be concluded that chronic allopregnanolone elevation caused smaller but more abundant congophilic plaques as both total plaque area and number of plaques were increased in mice with poor learning ability. Additional spots for accumulation of Aβ, predominantly the more toxic Aβ42, and thus addi­tional starting points for plaque production could be a part of the mechanism behind stress-induced Alzheimer’s disease.

Conclusions The conclusion of this thesis is that chronic elevation of allo­pregnanolon accelerated the development of Alzheimer’s disease in the Swe/PS1 and the Swe/Arc transgenic mouse models. Allopregnanolone may be an important link in the mechanism behind stress-induced AD. However, further studies are required to grasp the extent of its pathological influence.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2013. 66 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1553
Keyword
Allopregnanolone, Alzheimer's disease, beta-amyloid, synaptophysin, chronic stress, Morris water maze
National Category
Neurosciences
Research subject
Obstetrics and Gynaecology; Medical Pharmacology; Neurology; Geriatrics; medicinsk beteendevetenskap
Identifiers
urn:nbn:se:umu:diva-66572 (URN)978-91-7459-565-9 (ISBN)
Public defence
2013-03-22, Hörsal Betula, Norrlands Universitetssjukhus, Byggnad 6M, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2013-03-01 Created: 2013-02-25 Last updated: 2013-03-01Bibliographically approved

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