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Abstract
The work presented herein illustrates the dynamic role of mitochondria in age-dependent neurodegeneration and adds to the growing body of work that supports mitochondria-targeted therapeutics as a viable option for oxidative stress-ridden neurological disorders, particularly Alzheimers disease (AD). The results implicate mitochondria-derived oxidative stress as a prominent mediator of AD pathogenesis prior to and after disease onset. To further elucidate the role of mitochondria-derived oxidative stress in AD progression, the mitochondria-targeted antioxidant MitoQ was used to examine the effect of AD-like pathologies in an Alzheimers disease mouse model aged well past the manifestation of AD-like pathologies and cognitive impairment. 3xTg-AD female mice were treated for five months with MitoQ ad libitum in drinking water starting twelve months after birth. Eighteen-month-old untreated littermate controls exhibited significant cognitive deficiency and AD-like pathology, while MitoQ improved memory retention compared to untreated 3xTg-AD controls. Additionally, MitoQ reduced brain oxidative stress, synapse loss, astrogliosis, microglial proliferation, A accumulation, caspase activation, and tau hyperphosphorylation. Furthermore, MitoQ increased the lifespan of 3xTg-AD mice compared to that of non-transgenic controls. These findings provide solid evidence of a role for mitochondria-derived oxidative stress in age-dependent neurodegeneration and further highlight the significant influence of mitochondria in AD. Consequently, these results further support the use of mitochondria-targeted therapies for AD treatment.