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Chronic Allopregnanolone Treatment Accelerates Alzheimer's Disease Development in A beta PP(Swe)PSEN1(Delta E9) Mice
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynaecology.
2012 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 31, no 1, 71-84 p.Article in journal (Refereed) Published
Abstract [en]

The endogenous neurosteroid allopregnanolone alters neuronal excitability via modulation of the GABA(A) receptor and causes decreased neurotransmission. In Alzheimer's disease (AD), neurotransmission seems to alter the levels of toxic intracellular amyloid-beta (A beta) oligomers, which are implicated in AD pathogenesis and cause cognitive decline. Inhibition of synaptic activity has been shown to increase levels of intracellular A beta. Allopregnanolone at endogenous stress levels inhibits synaptic activity and could have similar effects. By using a transgenic A beta PP(Swe)PSEN1(Delta E9) mouse model for AD, we observed that chronic allopregnanolone treatment for three months with stress levels of allopregnanolone impaired learning in the Morris water maze. The learning impairment was seen one month after the end of treatment. Chronic allopregnanolone treatment also led to increased levels of soluble A beta in the brain, which could be a sign of advanced pathogenesis. Since the learning and memory of wild-type mice was not affected by the treatment, we propose that chronic allopregnanolone treatment accelerates the pathogenesis of AD. However, further studies are required in order to determine the underlying mechanism.

Place, publisher, year, edition, pages
2012. Vol. 31, no 1, 71-84 p.
Keyword [en]
Allopregnanolone, Alzheimer's disease, amyloid-beta, amyloid-beta(1-40), amyloid-beta(1-42), cognition, physiological stress
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:umu:diva-57556DOI: 10.3233/JAD-2012-120268ISI: 000306122900009OAI: oai:DiVA.org:umu-57556DiVA: diva2:544061
Available from: 2012-08-13 Created: 2012-08-06 Last updated: 2017-12-07Bibliographically 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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