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Chronic allopregnanolone elevation cause altered plaque production in Swe/PS1 mice
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi. (UNC)
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi. (UNC)
Umecrine AB. (UNC)
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Obstetrik och gynekologi. (UNC)
Visa övriga samt affilieringar
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

Abstract. We have previously shown that chronic elevation of the neurosteroid allopregnanolone caused learning dysfunction and increased levels of soluble Aβ in the Swe/PS1 mouse model. The mechanism behind these findings is however unknown. We further investigated the brain tissue of these mice to identify any effects on congophilic plaque burden, Aβ42-specific plaque burden and synaptic function. We found a significant reduction in the average size of the congophilic core of neuritic plaques after chronic allopregnanolone treatment compared to vehicle. This seems to be caused by an altered plaque production, leading to more abundant, but smaller neuritic plaques. We may also have detected a decrease in the amount of synaptophysin, and thus synaptic function among the same mice. However, the long interval between the end of treatment and tissue collection possibly allowed time for recovery and only minor differences were noted. We found that the natural relationship between levels of insoluble Aβ, congophilic and Aβ42-specific plaque load was disrupted after chronically elevated allopregnanolone levels. Furthermore, the levels of syn-aptophysin and insoluble Aβ became more important in the relationship to learning and memory. The causality of these factors is still unknown and further studies are required to fully understand the effect of neurosteroids on AD development.

Nyckelord [en]
Alzheimer's disease, allopregnanolone, neuroendocrinology, GABA, beta-amyloid, synaptophysin, chronic stress
Nationell ämneskategori
Neurovetenskaper
Forskningsämne
obstetrik och gynekologi; medicinsk farmakologi; medicinsk beteendevetenskap; neurologi
Identifikatorer
URN: urn:nbn:se:umu:diva-66574OAI: oai:DiVA.org:umu-66574DiVA, id: diva2:608562
Forskningsfinansiär
Vetenskapsrådet, 4x-11198Tillgänglig från: 2013-02-28 Skapad: 2013-02-25 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
Ingår i avhandling
1. Stress steroids as accelerators of Alzheimer's disease.: Effects of chronically elevated levels of allopregnanolone in transgenic AD models.
Öppna denna publikation i ny flik eller fönster >>Stress steroids as accelerators of Alzheimer's disease.: Effects of chronically elevated levels of allopregnanolone in transgenic AD models.
2013 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Alternativ titel[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.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet, 2013. s. 66
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1553
Nyckelord
Allopregnanolone, Alzheimer's disease, beta-amyloid, synaptophysin, chronic stress, Morris water maze
Nationell ämneskategori
Neurovetenskaper
Forskningsämne
obstetrik och gynekologi; medicinsk farmakologi; neurologi; geriatrik; medicinsk beteendevetenskap
Identifikatorer
urn:nbn:se:umu:diva-66572 (URN)978-91-7459-565-9 (ISBN)
Disputation
2013-03-22, Hörsal Betula, Norrlands Universitetssjukhus, Byggnad 6M, Umeå, 09:00 (Svenska)
Opponent
Handledare
Tillgänglig från: 2013-03-01 Skapad: 2013-02-25 Senast uppdaterad: 2018-06-08Bibliografiskt granskad

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Bengtsson, SaraLundgren, PerJohansson, MajaBäckström, TorbjörnWang, Mingde

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