Olesoxime improves cerebral mitochondrial dysfunction and enhances Aβ levels in preclinical models of Alzheimer's disease

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 (AβPP) and mitochondrial dysfunction.

Methods: Three months old Thy-1-AβPP_SL (tg) and wild type mice (wt) received TRO19622 (100 mg/kg b.w.) in supplemented food pellets for 15 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 (Aβ_1-40) 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 Aβ_1-40 levels were also determined in HEK-AβPP_sw-cells.

Results: Treatment of mice did not affect the body weight. TRO19622 was absorbed after oral treatment (plasma levels: 6,2 μg/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 Aβ_1-40 in both, in brains of tg TRO19622 mice and in HEK_sw cells.

Conclusions: TRO19622 improves mitochondrial dysfunction but enhances Aβ levels in disease models of AD. Further studies must evaluate whether TRO19622 offers benefits at the mitochondrial level despite the increased formation of Aβ, which could be harmful.

Keywords: Alzheimer; AβPP processing; Beta-amyloid; Cholesterol; Mitochondrial dysfunction; Neurodegenerative diseases; Olesoxime; Oxime.