A Cell Model for the Initial Phase of Sporadic Alzheimer's Disease

Recent data suggest that the combined effect of oxidative stress due to aging and slightly elevated amyloid-beta (A beta) 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 A beta PP gene and artificial aging by complex I inhibition. These cells show slightly elevated A beta 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 A beta PPwt 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 A beta PPwt mitochondria with respect to swelling or loss of cristae. Dystrophic neurites are an early pathological feature of AD. Interestingly, SH-SY5Y A beta PPwt cells exhibit significantly longer neurites, likely due to substantially elevated levels of sA beta PP alpha. Complex I inhibition also shows substantial effects on mitochondrial dynamics, impairs neuritogenesis, and elevates A beta levels in both cell types. In SH-SY5Y A beta PPwt cells, these defects were more pronounced due to a relatively elevated A beta and a reduced sA beta PP alpha production. Our findings suggest that the progression from low A beta 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.