Olesoxime improves cerebral mitochondrial dysfunction and enhances Aß levels in preclinical models of Alzheimer's disease.
Exp Neurol
; 329: 113286, 2020 07.
Article
em En
| MEDLINE
| ID: mdl-32199815
ABSTRACT
BACKGROUND:
Approved drugs for Alzheimer's disease (AD) only have a symptomatic effects and do not intervene causally in the course of the disease. Olesoxime (TRO19622) has been tested in AD disease models characterized by improved amyloid precursor protein processing (AßPP) and mitochondrial dysfunction.METHODS:
Three months old Thy-1-AßPPSL (tg) and wild type mice (wt) received TRO19622 (100â¯mg/kg b.w.) in supplemented food pellets for 15â¯weeks (tg TRO19622). Mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) levels were determined in dissociated brain cells (DBC). Respiration was analyzed in mitochondria isolated from brain tissue. Citrate synthase (CS) activity and beta-amyloid peptide (Aß1-40) levels were determined in brain tissue. Malondialdehyde (MDA) levels were determined as an indicator for lipid peroxidation. DBC and brain homogenates were additionally stressed with Rotenone and FeCl2, respectively. Mitochondrial respiration and Aß1-40 levels were also determined in HEK-AßPPsw-cells.RESULTS:
Treatment of mice did not affect the body weight. TRO19622 was absorbed after oral treatment (plasma levels 6,2⯵g/ml). Mitochondrial respiration was significantly reduced in brains of tg-mice. Subsequently, DBC isolated from brains of tg-mice showed significantly lower MMP but not ATP levels. TRO19622 increased the activity of respiratory chain complexes and reversed complex IV (CIV) activity and MMP. Moreover, DBC isolated from brains of tg TRO19622 mice were protected from Rotenone induced inhibition of complex I activity. TRO19622 also increased the respiratory activity in HEKsw-cells. MDA basal levels were significantly higher in brain homogenates isolated from tg-mice. TRO19622 treatment had no effects on lipid peroxidation. TRO19622 increased cholesterol levels but did not change membrane fluidity of synaptosomal plasma and mitochondrial membranes isolated from brain of mice. TRO19622 significantly increased levels of Aß1-40 in both, in brains of tg TRO19622 mice and in HEKsw cells.CONCLUSIONS:
TRO19622 improves mitochondrial dysfunction but enhances Aß levels in disease models of AD. Further studies must evaluate whether TRO19622 offers benefits at the mitochondrial level despite the increased formation of Aß, which could be harmful.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Temas:
Geral
Base de dados:
MEDLINE
Assunto principal:
Encéfalo
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Colestenonas
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Peptídeos beta-Amiloides
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Modelos Animais de Doenças
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Doença de Alzheimer
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Mitocôndrias
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Exp Neurol
Ano de publicação:
2020
Tipo de documento:
Article