Mitochondria-Targeted Antioxidants Protect Against Amyloid-β Toxicity in Alzheimer's Disease Neurons

Abstract

Alzheimer’s disease (AD) is a progressive, neurodegenerative disease characterized by progressive decline of memory and cognitive functions. Despite tremendous progress that has been made in understanding disease progression and therapeutics of AD, we still do not have drugs that are capable of slowing its progression. The purpose of our study was to investigate the effects of the mitochondria-targeted antioxidants (MTAs) MitoQ and SS31, and the anti-aging agent resveratrol on neurons from a mouse model of Alzheimer’s disease (AD) (Tg2576 line) and on mouse neuroblastoma (N2a) cells incubated with the amyloid beta (Aβ) peptide. Using electron and confocal microscopy, gene expression analysis, and biochemical methods, we studied mitochondrial structure and function, and neurite outgrowth in N2a cells treated with MitoQ, SS31, and resveratrol, and then incubated with Aβ. In N2a cells only incubated with the Aβ, we found increased expressions of mitochondrial fission genes and decreased expression of fusion genes, and also decreased expression of peroxiredoxins, endogenous cytoprotective antioxidant enzymes. Electron microscopy of the N2a cells incubated with Aβ revealed a significantly increased number of mitochondria, indicating that Aβ fragments mitochondria. Biochemical analysis revealed that function is defective in mitochondria. Neurite outgrowth was significantly decreased in Aβ-incubated N2a cells, indicating that Aβ affects neurite outgrowth. However, in N2a cells treated with MitoQ, SS31, and resveratrol, and then incubated with Aβ, abnormal expression of peroxiredoxins and mitochondrial structural genes were prevented and mitochondrial function was normal; intact mitochondria were present and neurite outgrowth was significantly increased. In primary neurons from amyloid beta precursor protein (AβPP) transgenic mice that were treated with MitoQ and SS31, neurite outgrowth was significantly increased and cyclophilin D expression was significantly decreased. These findings suggest that the MTAs, MitoQ and SS31 prevent Aβ toxicity in mitochondria, which would warrant the study of MitoQ and SS31 as potential drugs to treat patients with AD.

Recent progress and concerns in dementia: Distinguishing Alzheimer's disease and dementia with Lewy bodies via biochemical markers in the cerebrospinal fluid

“…Taken together, these findings further support the idea that oxidative stress is involved in the pathological process of neurodegenerative diseases, and oxidative stressassociated biomarkers may be useful for the disease diagnosis, as well as antioxidant therapy is reasonable treatment for neurodegenerative diseases [67].…”

Mitochondrial division ensures the survival of postmitotic neurons by suppressing oxidative damage

“…elongated mitochondria similar to Drp1KO MEFs. Similarly, a mitochondria-targeted antioxidant, MitoQ (Manczak et al, 2010), suppressed mitochondrial swelling (Fig. S5), suggesting that ROS from both mitochondria and the cytosol contribute to changing mitochondrial shape.…”

Mitochondrial dynamics in neuronal injury, development and plasticity

“…Degradation of Aβ in a cell line overexpressing amyloid precursor protein (APP) prevents mitochondrial fragmentation (Wang et al, 2008). Conversely, introduction of Aβ into a neuroblastoma cell line causes mitochondrial fission (Manczak et al, 2010). Additionally, a direct interaction between Drp1 and Aβ, as well as evidence for increased mitochondrial fission, was observed in samples of human AD patients; here, increased association of Drp1 with Aβ was indicative of disease progression .…”