Functional mitochondria are required for amyloid β‐mediated neurotoxicity
Open accessAbstract
The role of mitochondria in amyloid βpeptide (Aβ)‐induced cytotoxicity is unclear. We therefore exposed NT2 cells, a clonal human teratocarcinoma cell line capable of differentiation into terminal neurons, to Aβ 25–35 or to Aβ 1–42 to evaluate cell viability and altered mitochondrial function. A 24‐h incubation of native NT2 cells (ρ+ cells) with Aβ 25–35 or with Aβ 1–42 produced a dose‐dependent decline in MTT reduction. Aβ 1–42 was shown to be more toxic compared with Aβ 25–35. Aβ 25–35 toxicity was prevented or diminished by a 22‐h preincubation with antioxidants (vitamin E, melatonin, and idebenone), as well as by simultaneous incubation with GSH or the nicotinic receptor agonist nicotine. Aβ 25–35 exposure was also associated with (1) inhibition of mitochondrial respiratory chain complexes (I, NADH‐ubiquinone oxidoreductase; II/III, succinate‐cytochrome c oxidoreductase; and IV, cytochrome c oxidase), (2) ATP depletion, and (3) reduction of the mitochondrial membrane potential. In contrast, NT2 cells rendered incapable of oxidative phosphorylation via depletion of their mitochondrial DNA (ρ0 cells) were unaffected by exposure to Aβ 25–35 or Aβ 1–42. These data indicate that Aβ can disrupt mitochondrial function and that such disruption causes oxidative stress. It is further suggested that a functional mitochondrial respiratory chain is required for Aβ toxicity.
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Considerable evidence suggests that toxicity induced by both endogenous Aβ and extracellularly applied Aβ is mediated, at least in part, via the intrinsic, mitochondria-dependent apoptotic pathway.
“Considerable evidence suggests that toxicity induced by both endogenous Aβ and extracellularly applied Aβ is mediated, at least in part, via the intrinsic, mitochondria-dependent apoptotic pathway (Harada and Sugimoto, 1999; Cardoso et al., 2001; Casley et al., 2002b; Caspersen et al., 2005; Hansson Petersen et al., 2008; Cho et al., 2009; Takuma et al., 2009).”
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 Cardoso et al., 2001
The Discussion reports that externally applied Aβ25-35 and Aβ1-42 were toxic to NT2 cells with functional mitochondria but not to cells lacking a functional electron transport chain. The paper does not establish toxicity from endogenous Aβ or show that the toxicity proceeds through the intrinsic apoptotic pathway; it measures cell viability and mitochondrial function. (LLM, conf=0.88)
Experimental — accuracy not yet measuredClinical studies showed that increased levels of plasma Aβ40, but not Aβ42, significantly correlate with a heightened risk of AD.
“Also, clinical studies showed that increased levels of plasma Aβ40, but not Aβ42, significantly correlate with a heightened risk of AD (51,52, 53,54).”
From Alzheimer's Disease–Associated Amyloid-β Precursor Protein Prevents Aging Stress–Induced Mitophagy and Fumarate Depletion to Improve Antitumor Immunity (2025) · cites this paper as [54]
The Abstract discusses amyloid-β peptides and mitochondrial dysfunction, while the cell-toxicity Results examine peptide exposure in NT2 cells. Neither reports clinical plasma Aβ40 or Aβ42 levels or their association with Alzheimer’s disease risk (searched: plasma Aβ40 and circulating Aβ40 versus Aβ42). (LLM, conf=0.76)
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- Authors
- Cardoso, S. M., Santos, S., Swerdlow, R. H., & Oliveira, C. R.
- Affiliations
- University of Coimbra (PT)
- University of Virginia (US)
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2001-04-18
- Volume
- 15
- Issue
- 8
- Pages
- 1439-1441
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- OpenAlex
- W2040929937
- Cited by
- 203
- References
- 5
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 9 · 2023: 10 · 2022: 2 · 2021: 8 · 2020: 6 · 2019: 6 · 2018: 8 · 2017: 6 · 2016: 3 · 2015: 6 · 2014: 7 · 2013: 5 · 2012: 14
- FWCI
- 2.99
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- Locations
- The FASEB Journal (publishedVersion)
- PubMed (publishedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion)
- Funders
- Fundação para a Ciência e a Tecnologia
- American Parkinson's Disease Foundation
- 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, neurotoxicity, mitochondrial dysfunction, mitochondrial respiratory chain, oxidative stress, NT2 cells, amyloid beta 25-35, amyloid-beta 42, antioxidants, nicotinic acetylcholine receptors, nicotine, mitochondrial membrane potential, ATP depletion, mitochondrial DNA depletion, Alzheimer's disease
- MeSH terms
- Adenosine Triphosphate, Alzheimer Disease, Membrane Potentials, Mitochondria, Neurotoxins, Peptide Fragments, Amyloid beta-Peptides
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