Mitochondrion. 2014 Jul;17:106-15. doi: 10.1016/j.mito.2014.07.004.

Inhibition of stress induced premature senescence in presenilin-1 mutated cells with water soluble Coenzyme Q10.

Ma D, Stokes K, Mahngar K, Domazet-Damjanov D, Sikorska M, Pandey S.

Department of Chemistry and Biochemistry, University of Windsor, Windsor ON, Canada, N9B3P4

 

Abstract

A water-soluble formulation of CoQ10 (WS-CoQ10) was shown to stabilize mitochondria and prevent oxidative stress-induced neuronal death. Presenilin-1 (PS-1)-mutated Alzheimer’s Disease (AD) fibroblasts (PSAF) were used for studying the effects of PS-1 mutation. PS-1 mutation correlated to increased reactive oxygen species (ROS) production and stress induced premature senescence (SIPS) in PSAF; WS-CoQ10 treatment decreased ROS generation, increased population doublings, and postponed SIPS. Treated PSAF had higher PCNA expression, and lower levels of MnSOD, p21, p16Ink4A, and Rb. WS-CoQ10 caused the resumption of autophagy in PSAF. Thus, WS-CoQ10 as inhibitor of SIPS and ameliorator of autophagy could be an effective prophylactic/therapeutic agent for AD.

PMID: 25034304

 

Supplement:

Alzheimer’s disease (AD) is the most frequent form of dementia, characterized by protein aggregates, synaptic loss and death of neurons in the hippocampus and cerebral cortex (Alzheimer, 1907). In the earliest stages of AD, mitochondrial dysfunction and increased production of reactive oxygen species (ROS) has been observed in both neurons and peripheral tissue cells such as fibroblasts (Zhu et al., 2013; Bonda et al., 2010). Elevated levels of ROS in neurons can lead to apoptosis, however, such stress can lead to the onset of stress-induced premature senescence (SIPS) in fibroblasts. Mutations in the presenilin-1 (PS-1) gene have been associated with the onset of AD and give rise to increased levels of oxidative stress and wild type function for this gene has been found vital for lysosomal proteolysis and autophagy; thus, mutations in PS-1 lead to defects in autophagy, a vital process for neuron maintenance and survival.

Our water soluble formulation of Coenzyme Q10 (WS-CoQ10), an antioxidant and mitochondrial stabilizer, has been shown to be more bioavailable than oil soluble formulations that have failed clinical trials for neurodegenerative diseases. Interestingly, our formulation has been show to have neuroprotection in in vivo models of Parkinson’s disease at a dose of 6 mg/kg/day (100 time lower than the oil soluble formulation). When we cultured PS-1 mutated AD familial type 3 fibroblasts (PSAF) with WS-CoQ10 we were able to delay the onset of SIPS, decrease levels of ROS, and partially ameliorate mitochondria dysfunction.

It was found that fibroblasts with wild type PS-1 had higher levels of autophagy than PSAF by monitoring various autophagic markers. However, treatment with WS-CoQ10 was able to partially restore autophagy in PSAF.

Such findings suggest WS-CoQ10 to partially ameliorate putative cellular events leading to AD. This warrants further investigation in animal models to evaluate WS-CoQ10 as a potential therapeutic for AD.

 

 

 

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