A neuronal model of Alzheimer's disease: An insight into the mechanisms of oxidative stress–mediated mitochondrial injury

• Published in: Neuroscience Vol. 153; no. 1; pp. 120 - 130
• Main Authors: Sompol, P, Ittarat, W, Tangpong, J, Chen, Y, Doubinskaia, I, Batinic-Haberle, I, Abdul, H.M, Butterfield, D.A, St. Clair, D.K
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 22.04.2008; Elsevier
• Subjects: Aldehydes - metabolism; Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - physiopathology; Alzheimer's disease; Amyloid beta-Protein Precursor - genetics; Animals; Animals, Newborn; APP/PS1; Biological and medical sciences; Brain - metabolism; Brain - physiopathology; Cell Respiration - drug effects; Cell Respiration - physiology; Cells, Cultured; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Fundamental and applied biological sciences. Psychology; Humans; Medical sciences; Membrane Potential, Mitochondrial - genetics; Metalloporphyrins - pharmacology; Mice; Mice, Transgenic; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondrial Diseases - metabolism; Mitochondrial Diseases - physiopathology; MnSOD; Mutation - genetics; Neurology; Neurons - drug effects; Neurons - metabolism; oxidative stress; Oxidative Stress - drug effects; Oxidative Stress - genetics; Presenilin-1 - genetics; Protein Carbonylation - physiology; SOD mimetic; Superoxide Dismutase - metabolism; Superoxide Dismutase-1; Tyrosine - analogs & derivatives; Tyrosine - metabolism; Vertebrates: nervous system and sense organs; β-amyloid; RCR; APP; nuclear factor kappa B; respiratory control ratio; SDS, sodium dodecyl sulfate; 4-hydroxy-2-trans-nonenal; PS1; BSA; NF-κB; CuZnSOD; MnTE-2-PyP 5; 4-HNE; amyloid precursor protein; copper–zinc superoxide dismutase; 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolocarbocyanine iodide; manganese superoxide dismutase; nitroblue tetrazolium; 3-nitrotyrosine; Alzheimer's disease; β-amyloid; NBT; AD; hydroxynonenal; SOD mimetic; presenilin 1; MCI; APP/PS1; MnSOD; 3-NT; mild cognitive impairment; oxidative stress; bovine serum albumin; HNE; JC-1; Oxidative stress; Nervous system diseases; Alzheimer disease; Cerebral disorder; Mitochondria; β Amyloid protein; Central nervous system disease; Degenerative disease; Models; Lesion
• DOI: 10.1016/j.neuroscience.2008.01.044
• ISSN: 0306-4522

Abstract Alzheimer's disease (AD) is associated with β-amyloid accumulation, oxidative stress and mitochondrial dysfunction. However, the effects of genetic mutation of AD on oxidative status and mitochondrial manganese superoxide dismutase (MnSOD) production during neuronal development are unclear. To investigate the consequences of genetic mutation of AD on oxidative damages and production of MnSOD during neuronal development, we used primary neurons from new born wild-type (WT/WT) and amyloid precursor protein (APP) (NLh/NLh) and presenilin 1 (PS1) (P264L) knock-in mice (APP/PS1) which incorporated humanized mutations in the genome. Increasing levels of oxidative damages, including protein carbonyl, 4-hydroxynonenal (4-HNE) and 3-nitrotyrosine (3-NT), were accompanied by a reduction in mitochondrial membrane potential in both developing and mature APP/PS1 neurons compared with WT/WT neurons suggesting mitochondrial dysfunction under oxidative stress. Interestingly, developing APP/PS1 neurons were significantly more resistant to β-amyloid 1–42 treatment, whereas mature APP/PS1 neurons were more vulnerable than WT/WT neurons of the same age. Consistent with the protective function of MnSOD, developing APP/PS1 neurons have increased MnSOD protein and activity, indicating an adaptive response to oxidative stress in developing neurons. In contrast, mature APP/PS1 neurons exhibited lower MnSOD levels compared with mature WT/WT neurons indicating that mature APP/PS1 neurons lost the adaptive response. Moreover, mature APP/PS1 neurons had more co-localization of MnSOD with nitrotyrosine indicating a greater inhibition of MnSOD by nitrotyrosine. Overexpression of MnSOD or addition of MnTE-2-PyP5+ (SOD mimetic) protected against β-amyloid-induced neuronal death and improved mitochondrial respiratory function. Together, the results demonstrate that compensatory induction of MnSOD in response to an early increase in oxidative stress protects developing neurons against β-amyloid toxicity. However, continuing development of neurons under oxidative damage conditions may suppress the expression of MnSOD and enhance cell death in mature neurons.