| 1. |
- Bengtsson, Sara, 1978-, et al.
(author)
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Brief but Chronic Increase in Allopregnanolone Cause Accelerated ADPathology Differently in Two Mouse Models
- 2013
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In: Current Alzheimer Research. - : Bentham Science Publishers. - 1567-2050. ; 10:1, s. 38-47
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Journal article (peer-reviewed)abstract
- 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.
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| 2. |
- Bengtsson, Sara K., et al.
(author)
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Chronic Allopregnanolone Treatment Accelerates Alzheimer's Disease Development in A beta PP(Swe)PSEN1(Delta E9) Mice
- 2012
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In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 31:1, s. 71-84
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Journal article (peer-reviewed)abstract
- 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.
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| 3. |
- Bengtsson, Sara, 1978-
(author)
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Stress steroids as accelerators of Alzheimer's disease. : Effects of chronically elevated levels of allopregnanolone in transgenic AD models.
- 2013
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Doctoral thesis (other academic/artistic)abstract
- 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.
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| 4. |
- Wang, Mingde
(author)
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Neurosteroids and brain aging
- 2013
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In: Minerva Ginecologica. - : Edizioni Minerva Medica. - 0026-4784 .- 1827-1650. ; 65:6, s. 587-605
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Journal article (peer-reviewed)abstract
- Patients with Alzheimer's disease (AD) or dementia are increasing in numbers as the population worldwide ages. Mid-life psychological stress, psychosocial stress and posttraumatic stress disorder have been shown to cause cognitive dysfunction and lead to increased risk for dementia. The mechanisms behind stress-induced AD or dementia are not known. Solid amyloid plaques in the affected brain tissues characterize AD. However, over the last decade it has been concluded that the level of soluble beta-amyloid proteins (Aβ) are reliable diagnostic markers as they correlate to cognitive performance while plaques do not. The soluble Aβ accumulate intracellularly and disturb the synaptic function. In addition, it has been shown that the levels of intracellular Aβ depend on neuronal activity. Previous studies in animal models have shown that deceased neuronal activity cause increased levels of Aβ inside neurons and cognitive decline. Allopregnanolone is produced in the brain at stress. It enhances the activity of the GABAergic neurotransmission and affects neuronal activities. In a series of studies using in transgenic Alzheimer's disease model, we have shown that chronically elevated levels of allopregnanolone accelerated AD development. After a period of exposure to chronically elevated levels of allopregnanolone, impaired learning and memory pattern occurred in the AD mice. Accordingly, increased levels of β-amyloids were also observed in AD mice. We have also demonstrated that high levels of β-amyloids corresponded to dysfunction among brain synapses. This was seen after a period of chronically elevated levels of allopregnanolone, but not after placebo treatment. This effect of allopregnanolone treatment was identified early in the disease development when AD mice normally have intact memory function. This review covers a wide topic of neurosteroids and brain aging, and provides insight on the mechanisms behind stress-induced AD or dementia.
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| 5. |
- Wang, Mingde
(author)
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Neurosteroids and GABA-A receptor function
- 2011
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In: Frontiers in Neuroendocrine science. - : Frontiers Media SA. ; 2:44, s. 1-23
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Journal article (peer-reviewed)abstract
- Neurosteroids represent a class of endogenous steroids that are synthesized in the brain, the adrenals, and the gonads and have potent and selective effects on the GABAA-receptor. 3α-hydroxy A-ring reduced metabolites of progesterone, deoxycorticosterone, and testosterone are positive modulators of GABAA-receptor in a non-genomic manner. Allopregnanolone (3α-OH-5α-pregnan-20-one), 5α-androstane-3α, 17α-diol (Adiol), and 3α5α-tetrahydrodeoxycorticosterone (3α5α-THDOC) enhance the GABA-mediated Cl- currents acting on a site (or sites) distinct from the GABA, benzodiazepine, barbiturate, and picrotoxin binding sites. 3α5α-P and 3α5α-THDOC potentiate synaptic GABAA-receptor function and activate δ-subunit containing extrasynaptic receptors that mediate tonic currents. On the contrary, 3β-OH pregnane steroids and pregnenolone sulfate (PS) are GABAA-receptor antagonists and induce activation-dependent inhibition of the receptor. The activities of neurosteroid are dependent on brain regions and types of neurons. In addition to the slow genomic action of the parent steroids, the non-genomic, and rapid actions of neurosteroids play a significant role in the GABAA-receptor function and shift in mood and memory function. This review describes molecular mechanisms underlying neurosteroid action on the GABAA-receptor, mood changes, and cognitive functions.
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