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Cited by 287Alzheimer's disease research and treatmentsMitochondrial Function and PathologyParkinson's Disease Mechanisms and Treatments

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

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Keil, Uta, Bonert, Astrid, Marques, Celio A., Scherping, Isabel, Weyermann, Jörg, Strosznajder, Joanna B., Müller-Spahn, Franz, Haass, Christian +4 more·2004·Journal of Biological Chemistry
DOI 10.1074/jbc.m405600200
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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 beta (Abeta) 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 Abeta levels, have increased NO levels and reduced ATP levels. The inhibition of intracellular Abeta production by a functional gamma-secretase inhibitor normalizes NO and ATP levels, indicating a direct involvement of Abeta in these processes. Extracellular treatment of PC12 cells with comparable Abeta concentrations only leads to weak changes, demonstrating the important role of intracellular Abeta. In 3-month-old APP transgenic (tg) mice, which exhibit no plaques but already detectable Abeta 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 Abeta 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.

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  • Aβ induces production of superoxide (O2·-), nitric oxide (NO·), and multiple reactive species downstream of these radicals in many cells, including cortical neurons.

    “Aβ induces production of O2·- nitric oxide (NO·), and multiple RS downstream of these radicals in many cells, including cortical neurons (Keller et al., 1998; Longo et al., 2000; Keil et al., 2004; Malinski, 2007; Stepanichev et al., 2008; Díaz et al., 2010).”

    From The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease (2011) · cites this paper as Keil et al., 2004

    The Discussion reports that increased Aβ levels led to increased nitric oxide production in APP-transfected PC12 and HEK cells, and discusses reactive nitrogen species and possible peroxynitrite-mediated damage. The passages do not establish Aβ-induced superoxide production or production of multiple downstream reactive species in cortical neurons; the neuronal-culture passage concerns mitochondrial activity, not those species. Page numbers are unavailable in our copy. (LLM, conf=0.87)

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Research works printed but not linked: 3

  1. Masters, C. L., Simms, G., Weinman, N. A., Multhaup, G., McDonald, B. L., and Beyreuther, K. (1985) Proc. Natl. Acad. Sci. U. S. A. 82, 4245-4249
  2. Sarti, P., Arese, M., and Giuffre, A. (2003) Ital. J. Biochem. (Engl. Ed.) 52, 37-42
  3. Almeida, A., Almeida, J., Bolanos, J. P., and Moncada, S. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 15294 -15299

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Authors
Keil, U., Bonert, A., Marques, C. A., Scherping, I., Weyermann, J., Strosznajder, J. B., Müller-Spahn, F., Haass, C., Czech, C., Pradier, L., Müller, W. E., & Eckert, A.
Affiliations
  • Goethe University Frankfurt (DE)
  • Polish Academy of Sciences (PL)
  • Adolf-Butenandt-Institut für Physiologische Chemie, Physikalische Biochemie und Zellbiologie (DE)
  • Sanofi (France) (FR)
  • Universitäre Psychiatrische Kliniken Basel (CH)
Corresponding author
Eckert, Anne
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2004-11
Volume
279
Issue
48
Pages
50310-50320
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m405600200
OpenAlex
W2124881367
Cited by
287
References
9
Citations by year
2026: 7 · 2025: 6 · 2024: 2 · 2023: 4 · 2022: 6 · 2021: 3 · 2020: 7 · 2019: 6 · 2018: 18 · 2017: 12 · 2016: 9 · 2015: 17 · 2014: 9 · 2013: 13 · 2012: 18
FWCI
12.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Alzheimer Forschung Initiative
  • Deutsche Forschungsgemeinschaft
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
Keywords
amyloid-beta, nitric oxide, mitochondrial dysfunction, apoptosis, Alzheimer's disease, amyloid precursor protein, gamma-secretase inhibition, ATP depletion, cytochrome c oxidase, mitochondrial membrane potential, APP transgenic mice, PC12 cells
MeSH terms
Alzheimer Disease, Animals, Electron Transport Complex IV, Humans, Mice, Transgenic, Mitochondria, Nitric Oxide, Blotting, Western, Amyloid beta-Peptides, Apoptosis, Oxidative Stress, Nitric Oxide Synthase, Proto-Oncogene Proteins c-bcl-2, Mice

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