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Stress steroids as accelerators of Alzheimer's disease. : Effects of chronically elevated levels of allopregnanolone in transgenic AD models.
2013 (English)Doktorsavhandling, sammanläggning (Other academic)
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, pages
Umeå: Umeå universitet, 2013. 66 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1553
Keyword [en]
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)oai:DiVA.org:umu-66572 (OAI)
Public defence
2013-03-22, Hörsal Betula, Norrlands Universitetssjukhus, Byggnad 6M, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from2013-03-01 Created:2013-02-25 Last updated:2013-03-01Bibliographically approved
List of papers
1. Chronic Allopregnanolone Treatment Accelerates Alzheimer's Disease Development in A beta PP(Swe)PSEN1(Delta E9) Mice
Open this publication in new window or tab >>Chronic Allopregnanolone Treatment Accelerates Alzheimer's Disease Development in A beta PP(Swe)PSEN1(Delta E9) Mice
2012 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, Vol. 31, no 1, 71-84Artikel i tidskrift (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.

Keyword
Allopregnanolone, Alzheimer's disease, amyloid-beta, amyloid-beta(1-40), amyloid-beta(1-42), cognition, physiological stress
National Category
Neurosciences
Identifiers
urn:nbn:se:umu:diva-57556 (URN)10.3233/JAD-2012-120268 (DOI)000306122900009 (ISI)
Available from2012-08-13 Created:2012-08-06 Last updated:2013-03-01Bibliographically approved
2. Brief but Chronic Increase in Allopregnanolone Cause Accelerated ADPathology Differently in Two Mouse Models
Open this publication in new window or tab >>Brief but Chronic Increase in Allopregnanolone Cause Accelerated ADPathology Differently in Two Mouse Models
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2013 (English)In: Current Alzheimer Research, ISSN 1567-2050, Vol. 10, no 1, 38-47Artikel i tidskrift (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.

Bentham Science Publishers, 2013
Keyword
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:nbn:se:umu:diva-66571 (URN)
Funder
Swedish Research Council
Available from2013-02-28 Created:2013-02-25 Last updated:2013-03-28Bibliographically approved
3. Chronic allopregnanolone elevation cause altered plaque production in Swe/PS1 mice
Open this publication in new window or tab >>Chronic allopregnanolone elevation cause altered plaque production in Swe/PS1 mice
Show others...
(English)Manuskript (preprint) (Other academic)
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.

Keyword
Alzheimer's disease, allopregnanolone, neuroendocrinology, GABA, beta-amyloid, synaptophysin, chronic stress
National Category
Neurosciences
Research subject
Obstetrics and Gynaecology, Medical Pharmacology, medicinsk beteendevetenskap, Neurology
Identifiers
urn:nbn:se:umu:diva-66574 (URN)
Funder
Swedish Research Council
Available from2013-02-28 Created:2013-02-25 Last updated:2013-03-27Bibliographically approved

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