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A cell model for the initial phase of sporadic Alzheimer's disease.

Journal of Alzheimer's disease : JAD (2014-06-06)
Carola Stockburger, Vicki A M Gold, Thea Pallas, Natalie Kolesova, Davide Miano, Kristina Leuner, Walter E Müller
ABSTRACT

Recent data suggest that the combined effect of oxidative stress due to aging and slightly elevated amyloid-β (Aβ) levels initiate Alzheimer's disease (AD) long before the clinical onset. Investigations of this early phase are hampered by the lack of cellular or animal models reflecting this scenario. We used SH-SY5Y cells stably transfected with an additional copy of the human AβPP gene and artificial aging by complex I inhibition. These cells show slightly elevated Aβ levels, moderately decreased ATP levels, impaired mitochondrial membrane potential, and decreased mitochondrial respiration. Assessing mitochondrial dynamics with three different methods reveals a distinct shift toward mitochondrial fission and fragmentation in SH-SY5Y AβPPwt cells. We also performed electron cryo-tomography of isolated mitochondria to reveal that there were no major differences between SH-SY5Y control and SH-SY5Y AβPPwt mitochondria with respect to swelling or loss of cristae. Dystrophic neurites are an early pathological feature of AD. Interestingly, SH-SY5Y AβPPwt cells exhibit significantly longer neurites, likely due to substantially elevated levels of sAβPPα. Complex I inhibition also shows substantial effects on mitochondrial dynamics, impairs neuritogenesis, and elevates Aβ levels in both cell types. In SH-SY5Y AβPPwt cells, these defects were more pronounced due to a relatively elevated Aβ and a reduced sAβPPα production. Our findings suggest that the progression from low Aβ levels to the beginning of AD takes place in the presence of oxidative stress during normal aging. This mechanism not only results from additive effects of both mechanisms on mitochondrial function but might also be additionally aggravated by altered amyloidogenic processing.

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