Amyloid β-induced Changes in Nitric Oxide Production and Mitochondrial Activity Lead to Apoptosis

Abstract

Increasing evidence suggests an important role of mitochondrial dysfunction in the pathogenesis of Alzheimer's disease. Thus, we investigated the effects of acute and chronic exposure to increasing concentrations of amyloid ␤ (A␤) on mitochondrial function and nitric oxide (NO) production in vitro and in vivo. Our data demonstrate that PC12 cells and human embryonic kidney cells bearing the Swedish double mutation in the amyloid precursor protein gene (APPsw), exhibiting substantial A␤ levels, have increased NO levels and reduced ATP levels. The inhibition of intracellular A␤ production by a functional ␥-secretase inhibitor normalizes NO and ATP levels, indicating a direct involvement of A␤ in these processes. Extracellular treatment of PC12 cells with comparable A␤ concentrations only leads to weak changes, demonstrating the important role of intracellular A␤. In 3-month-old APP transgenic (tg) mice, which exhibit no plaques but already detectable A␤ levels in the brain, reduced ATP levels can also be observed showing the in vivo relevance of our findings. Moreover, we could demonstrate that APP is present in the mitochondria of APPsw PC12 cells. This presence might be directly involved in the impairment of cytochrome c oxidase activity and depletion of ATP levels in APPsw PC12 cells. In addition, APPsw human embryonic kidney cells, which produce 20-fold increased A␤ levels compared with APPsw PC12 cells, and APP tg mice already show a significantly decreased mitochondrial membrane potential under basal conditions. We suggest a hypothetical sequence of pathogenic steps linking mutant APP expression and amyloid production with enhanced NO production and mitochondrial dysfunction finally leading to cell death.

Amyloid-β and tau synergistically impair the oxidative phosphorylation system in triple transgenic Alzheimer's disease mice

“…Complex IV activity was decreased in APP/PS2 and triple AD cortices at 8 months of age, but not in pR5, confirming related findings that it is mainly the A␤ pathology that affects complex IV activity, both in vivo and in vitro (22,25). In APP/PS2 compared with wild-type mice, an impairment of OXPHOS as detected by decreased oxygen consumption was seen at this age, suggesting an earlier and stronger effect of the A␤/APP pathway on this vulnerable mitochondrial system compared with tau, as oxygen consumption of pR5 mitochondria was reduced, but not until the mice reached 24 months of age (4).…”

Senescence-accelerated OXYS rats: A model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease

“…82,83 It has been shown that the decreased expression of mitochondrial respiratory chain complexes (I and III) and the impairment of mitochondrial respiration are detected before accumulation of Aβ and formation of plaques, 92,93 suggesting that mitochondrial dysfunction and oxidative stress may play a role at an early stage of AD. 94,95 In addition, a stronger reduction in mitochondrial membrane potential and in ATP levels was found in double transgenic APP/ PS1 (APPS/L/PS1 M141L) mice. 96 Overall, these data imply that Aβ-dependent mitochondrial dysfunction starts early and accelerates substantially with age.…”

Genetic Ablation of Calcium-independent Phospholipase A2γ Leads to Alterations in Hippocampal Cardiolipin Content and Molecular Species Distribution, Mitochondrial Degeneration, Autophagy, and Cognitive Dysfunction

“…1). Increasing evidence has implicated mitochondrial dysfunction as a critical mechanism underlying the pathologic development of many progressive neurodegenerative disorders, including Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and Huntington diseases (2)(3)(4)(5)(6).…”