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Cited by 433Alzheimer's disease research and treatmentsMitochondrial Function and PathologyDementia and Cognitive Impairment Research

The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer’s disease

Open access
McManus, Meagan J., Murphy, Michael P., Franklin, James L.·2011·The Journal of Neuroscience
DOI 10.1523/jneurosci.0552-11.2011PMC PMC3334845
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Abstract

Considerable evidence suggests that mitochondrial dysfunction and oxidative stress contribute to the progression of Alzheimer's disease (AD). We examined the ability of the novel mitochondria-targeted antioxidant MitoQ (mitoquinone mesylate: [10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cycloheexadienl-yl) decyl triphenylphosphonium methanesulfonate]) to prevent AD-like pathology in mouse cortical neurons in cell culture and in a triple transgenic mouse model of AD (3xTg-AD). MitoQ attenuated β-amyloid (Aβ)-induced neurotoxicity in cortical neurons and also prevented increased production of reactive species and loss of mitochondrial membrane potential (Δψ(m)) in them. To determine whether the mitochondrial protection conferred by MitoQ was sufficient to prevent the emergence of AD-like neuropathology in vivo, we treated young female 3xTg-AD mice with MitoQ for 5 months and analyzed the effect on the progression of AD-like pathologies. Our results show that MitoQ prevented cognitive decline in these mice as well as oxidative stress, Aβ accumulation, astrogliosis, synaptic loss, and caspase activation in their brains. The work presented herein suggests a central role for mitochondria in neurodegeneration and provides evidence supporting the use of mitochondria-targeted therapeutics in diseases involving oxidative stress and metabolic failure, namely AD.

AI snapshot

Written from the paper’s full text.

TL;DR

MitoQ, a mitochondria-targeted antioxidant, prevented Aβ-induced oxidative stress and mitochondrial depolarization in cultured cortical neurons and blocked early cognitive decline and neuropathology in young female 3xTg-AD mice. The authors conclude that mitochondria-derived reactive species contribute centrally to early AD-like progression and that mitochondria-targeted therapy warrants further testing.

Key findings

  • In cortical neuron cultures, Aβ(22–35) reduced survival to ~35% of untreated controls by 48 h; low nanomolar MitoQ (1–100 nM) greatly inhibited this toxicity, and 1 nM MitoQ also prevented death induced by full-length Aβ(1–40).
  • Aβ(22–35) for 24 h increased CM-H2DCFDA intensity 3.4 ± 0.2-fold and depolarized Δψm; MitoQ (1 and 5 nM) prevented the reactive-species increase and maintained Δψm at control levels. In 3xTg-AD cortical cultures, 25 μM Aβ(22–35) increased CM-H2DCFDA 3.4 ± 0.2-fold (n = 34), and 10 nM MitoQ prevented this (0.3 ± 0.19-fold, n = 49).
  • In female 3xTg-AD mice treated with 100 μM MitoQ in drinking water from 2–7 months of age, MitoQ prevented the long-term spatial memory retention deficit in the Morris water maze; acquisition performance was significantly improved versus untreated 3xTg-AD (p < 0.01), while the control compound dTPP had no effect (p > 0.05).
  • MitoQ prevented brain oxidative stress markers (GSH/GSSG decrease, MDA increase, 3-nitrotyrosine increase), synaptic loss (synaptophysin), astrogliosis (GFAP), soluble and intraneuronal Aβ(1–42) accumulation, and caspase 3/7 activation; untreated 7-month 3xTg-AD mice showed a 3.0 ± 0.6-fold increase in cerebral caspase 3/7 activity versus nonTg, which MitoQ completely blocked.

Methods

  • In vitro: primary mouse cortical neurons treated with Aβ(22–35) or Aβ(1–40), with or without MitoQ or dTPP; survival counted by phase-bright morphology, reactive species measured with CM-H2DCFDA, and mitochondrial membrane potential measured with TMRM+ confocal microscopy.
  • In vivo: female 3xTg-AD and nonTg mice received 100 μM MitoQ or 100 μM dTPP continuously in drinking water from 2 to 7 months of age (5 months); a total of 117 mice were used. Spatial learning and memory retention were assessed by Morris water maze after 4.5 months of treatment.
  • Postmortem analyses at 7 months included immunohistochemistry for Aβ(1–42), immunoblotting for Δtau, 3-nitrotyrosine, synaptophysin, and GFAP, ELISA for soluble Aβ(1–42), TBARS for lipid peroxidation, GSH/GSSG assay, and caspase 3/7 activity assay; statistics used Kruskal–Wallis one-way ANOVA on ranks with post hoc pairwise comparisons.

Limitations

  • The paper states that only female mice were studied to minimize sex-related variability and reduce animal numbers, so findings may not generalize to male 3xTg-AD mice.
  • The study assessed only early AD-like pathologies; the authors note that testing effects on neurofibrillary tangle formation would require treatment for up to 18 months, and Δtau was below detectable levels in 7-month-old untreated 3xTg-AD mice.
  • The caspase assay does not distinguish between caspase 3 and caspase 7 activities. Evident from the text: in vivo MitoQ was adsorbed to cyclodextrin in a 1:2 complex, whereas the dTPP control was not cyclodextrin-complexed, so a cyclodextrin/vehicle effect was not fully controlled.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1523/jneurosci.0552-11.2011

Cites

136 of 136 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

48 of 166 cited sources checked · 15 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    None of the tested antioxidant compounds have proven effective for treating Alzheimer's disease to date.

    “To date, none of the tested compounds have proven effective (Sano et al., 1997; Petersen et al., 2005; Pham and Plakogiannis, 2005; DeKosky et al., 2008).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Sano et al., 1997 source

      The Discussion reports that selegiline and alpha-tocopherol were beneficial in delaying the primary outcome of disease progression in patients with Alzheimer's disease. The paper does not report improved cognition, and the unadjusted analysis found no significant difference, but its adjusted analysis found significant delays. Its conclusion therefore runs contrary to the claim that none of the tested compounds had proven effective. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites Petersen et al., 2005 source

      The primary outcome measures report that vitamin E did not significantly reduce progression from mild cognitive impairment to Alzheimer’s disease. That supports a narrower claim about one antioxidant in a prevention trial, not a claim about all tested antioxidants treating Alzheimer’s disease. The paper’s introductory passage also reports evidence that vitamin E could delay important milestones in patients with moderately severe Alzheimer’s disease. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites DeKosky et al., 2008

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Findingcitation

    Brief incubation with FCCP caused the loss of most CM-H2DCFDA fluorescence in Aβ(22-35)-treated cortical neurons (Fig. 2B).

    “Consistent with the findings of others (Saraiva et al., 2010), brief incubation with FCCP caused the loss of most CM-H2DCFDA fluorescence in Aβ(22–35)-treated cortical neurons (Fig. 2 B), suggesting that the RS detected by this dye was primarily of mitochondrial origin (Duchen, 1999).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Saraiva et al., 2010 source
  • Premisecitation

    Alterations in glucose metabolism and mitochondrial energetics occur along with accumulation of oxidative damage before the cardinal signs of Alzheimer's disease pathogenesis in the brains of transgenic animal models and patients.

    “Extensive evidence indicates that alterations in glucose metabolism and mitochondrial energetics occur along with the accumulation of oxidative damage before the cardinal signs of AD pathogenesis in the brains of transgenic animal models and patients (Hoyer, 1996; Hirai et al., 2001; Rinaldi et al., 2003; Butterfield et al., 2006; Lin and Beal, 2006; Sultana et al., 2006a,b; Mosconi et al., 2008a;”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Hoyer, 1996 source
    • cites Hirai et al., 2001 source
    • cites Yao et al., 2009 source

      The Results and Discussion report early mitochondrial dysfunction, altered glycolysis, and oxidative stress in female 3xTg-AD mice; the Discussion says mitochondrial dysfunction precedes plaque formation. It also describes reduced glucose use as an early finding in people at risk of AD, but does not establish that oxidative damage precedes the cardinal signs of AD in patients. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    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).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Keller et al., 1998 source

      The Discussion links Aβ-induced apoptosis to superoxide and resulting peroxynitrite formation, and the results report increased peroxynitrite-related signals after Aβ exposure in PC6 cells (page unavailable in our copy). The paper does not show that Aβ induces nitric oxide production; it treats an NO-generating compound as a separate insult. The cited Aβ experiments also do not establish the claim specifically in cortical neurons or across many cell types. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites Longo et al., 2000 source
    • cites Keil et al., 2004 source

      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)

      Experimental — accuracy not yet measured
  • Premisecitation

    Mitochondrial function and oxidative stress have been fully characterized only in female 3xTg-AD mice.

    “Furthermore, mitochondrial function and oxidative stress have been fully characterized only in female 3xTg-AD mice (Yao et al., 2009).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Yao et al., 2009 source

      The Results and Discussion (page not provided) characterize mitochondrial function and oxidative stress in female 3xTg-AD mice. The paper does not establish the broader claim that these measures had been fully characterized only in females. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Classified as probably not a substantial claim. 30
  • May combine two claims. 25

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Aβ(22-35) rapidly aggregates in aqueous solutions.

    “It has the experimental advantage for in vitro studies of rapidly aggregating in aqueous solutions (Pike et al., 1993).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Pike et al., 1993 source

      The PAP aggregation section and Table 1 (p. 1687) show that freshly prepared Aβ(25–35) forms visible aggregates in aqueous stock solution. The cited paper reports this for Aβ(25–35), not the claimed Aβ(22–35), so it does not establish that the specified fragment rapidly aggregates. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    MitoQ enhances neurite outgrowth in cultured hippocampal neurons from AβPP-expressing mice.

    “They also demonstrated that MitoQ enhances neurite outgrowth in cultured hippocampal neurons from AβPP-expressing mice but did not present direct evidence of a protective effect of MitoQ on the mitochondria in these cells.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Manczak et al., 2010 source

  • May combine two claims.

    Premisecitation

    MitoQ possesses the qualities of crossing the blood-brain barrier and selectively concentrating in mitochondria.

    “The recently developed, mitochondria-targeted antioxidant MitoQ (mitoquinone mesylate: [10-(4,5-dimethoxy-2-methyl-3,6-dioxo-1,4-cycloheexadienlyl) decyl triphenylphosphonium methanesulfonate]) possesses these qualities (James et al., 2005, 2007; Murphy and Smith, 2007).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites James et al., 2005 source

      The passage labeled Abstract states that MitoQ10 selectively accumulates within mitochondria in isolated preparations, cells, and in vivo. It does not establish that MitoQ crosses the blood-brain barrier; a search for blood-brain barrier and brain penetration found no supporting passage in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites James et al., 2007 source

      The Abstract states that MitoQ10 accumulates within mitochondria, driven by its triphenylphosphonium cation. The supplied passages and a search of our copy for blood–brain barrier and brain penetration do not establish that MitoQ crosses the blood–brain barrier. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Murphy and Smith, 2007 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    MitoQ protects mitochondria from Aβ-induced toxicity in N2a cells.

    “Manczak et al. (2010) recently demonstrated that MitoQ protects mitochondria from Aβ-induced toxicity in N2a cells.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Manczak et al., 2010 source

  • May combine two claims.

    Study design and conductcitation

    CM-H2DCFDA is trapped in neurons, is insensitive to pH changes within the physiological range, and is not photo-oxidized by the laser power and exposure time used in these experiments.

    “This characterization shows that CM-H2DCFDA is trapped in neurons, is insensitive to pH changes within the physiological range, and is not photo-oxidized by the laser power and exposure time used in these experiments.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Kirkland and Franklin, 2001 source

      The ROS measurement section (page unavailable) says CM-H2DCFDA is trapped inside cells and reports no significant leakage from neurons. The mitochondrial ROS section finds that the acidification tested did not quench the dye, but does not establish insensitivity across the physiological pH range. The ROS measurement section calls the dye relatively insensitive to photo-oxidation at low laser intensity; it does not say photo-oxidation was absent at the laser power and exposure time claimed. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Kirkland et al., 2002 source

      The ROS measurement section (page not specified) says CM-H2DCFDA is trapped in cells and reports little dye leakage from neurons. It does not establish that the dye is insensitive to physiological pH changes or that the laser power and exposure time used prevent photo-oxidation; searches for those properties found only the microscopy settings. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    MitoQ cannot substitute for endogenous ubiquinone in the electron transport chain but primarily acts as an antioxidant capable of continuous regeneration by complex II.

    “Therefore, it cannot substitute for endogenous ubiquinone in the electron transport chain but primarily acts as an antioxidant capable of continuous regeneration by complex II (James et al., 2005, 2007; Rodriguez-Cuenca et al., 2010).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites James et al., 2005 source
    • cites James et al., 2007 source
    • cites Rodriguez-Cuenca et al., 2010

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Aβ increases reactive species in neurons via multiple mechanisms, including direct Aβ-induced RS production, elevated NADPH oxidase activity, interaction with mitochondria-associated Aβ alcohol dehydrogenase, inhibition of cytochrome oxidase (respiratory complex IV), and leakage of electrons from the mitochondrial electron transport chain.

    “Aβ is reported to increase RS in neurons via multiple mechanisms, including direct Aβ-induced RS production, elevated NADPH oxidase activity, interaction with mitochondria-associated Aβ alcohol dehydrogenase, inhibition of cytochrome oxidase (respiratory complex IV), and by causing leakage of electrons from the mitochondrial electron transport chain (Hensley et al., 1994; Canevari et al., 1999; L”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Hensley et al., 1994 source

      The Results and Discussion report that Aβ peptides generate free radicals and that the Aβ(25–35) fragment produces reactive oxygen species in cell-free experiments. They do not establish increased reactive species in neurons or address the listed NADPH oxidase, Aβ alcohol dehydrogenase, cytochrome oxidase, and mitochondrial electron-leakage mechanisms. No page numbers are available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Canevari et al., 1999 source
    • cites Lustbader et al., 2004 source

  • May combine two claims.

    Premisecitation

    The earliest pathological changes in 3xTg-AD mice involve mitochondrial impairment and increased oxidative stress.

    “Notably, the earliest pathological changes in 3xTg-AD mice involve mitochondrial impairment and increased oxidative stress (Resende et al., 2008; Yao et al., 2009).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Resende et al., 2008 source

      The Results and Discussion report increased oxidative stress in 3–5-month-old 3×Tg-AD mice before plaques and tangles appear. They do not establish mitochondrial impairment as an early change in these mice; the Discussion’s mention of mitochondrial vulnerability concerns a different tau-transgenic model. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Yao et al., 2009 source

      The Discussion identifies elevated oxidative stress as among the earliest indicators of dysfunction and says mitochondrial dysfunction preceded plaque formation. The study examined female 3xTg-AD mice, so it does not establish the same sequence for 3xTg-AD mice generally. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Executioner caspases 3 and 7 may contribute to tau pathology by cleaving tau after Asp421 to yield a cytotoxic Δtau fragment.

    “Recent evidence suggests that executioner caspases 3 and 7 may contribute to tau, the protein responsible for forming NFTs, pathology by cleaving tau after Asp421 to yield a cytotoxic Δtau fragment (Rissman et al., 2004; Rohn et al., 2008; de Calignon et al., 2010).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Rissman et al., 2004 source
    • cites Rohn et al., 2008 source

      The Results section (page unavailable) reports caspase-cleaved tau at Asp421 in the mouse model, and the Discussion links caspase cleavage of tau to NFT pathology. The paper identifies caspase-3 as an executioner caspase, but the passages do not identify caspase-7 as a tau-cleaving enzyme or describe the resulting fragment as cytotoxic Δtau. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites de Calignon et al., 2010 source

      The supplied Abstract passage says caspases cleave tau at Asp421, producing truncated tau associated with tangles, and reports that a caspase-3/7 probe colocalized with tangles. It implicates caspase 3 and caspase 6 in cleavage, however; it does not establish that caspase 7 cleaves tau or that the resulting fragment is cytotoxic. The paper instead suggests that soluble tau species may be the critical toxic form. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    The amyloid hypothesis is supported by early Aβ accumulation in autosomal dominant AD, transgenic mice, and studies suggesting mitochondrial Aβ may cause synaptic degeneration and cognitive impairment.

    “This hypothesis is supported by the early Aβ accumulation in the rare, autosomal dominant forms of AD, by transgenic mice harboring these human mutations (Hardy and Selkoe, 2002), and by recent studies suggesting that mitochondrial Aβ may be responsible for synaptic degeneration and the onset of cognitive impairment in AD models of Aβ enrichment (Zhao et al., 2010).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Hardy and Selkoe, 2002 source
    • cites Zhao et al., 2010 source

  • May combine two claims.

    Premisecitation

    Among these markers were decreased levels of GSH, increased levels of GSSG, and increased levels of malondialdehyde (MDA).

    “Among these markers were decreased levels of GSH, increased levels of GSSG, and increased levels of malondialdehyde (MDA), a marker for lipid peroxidation.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Resende et al. (2008) source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Lipid-derived radicals may contribute to nitration of proteins associated with biological membranes.

    “Lipid-derived radicals may contribute to nitration of proteins associated with biological membranes (Bartesaghi et al., 2010).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Bartesaghi et al., 2010 source

  • Classified as probably not a substantial claim.

    Premisecitation

    The intrinsic apoptotic pathway may involve mitochondrial RS generation.

    “Because the intrinsic apoptotic pathway may involve mitochondrial RS generation (Kirkland et al., 2001), we hypothesized that the decrease in oxidative stress caused by MitoQ treatment may prevent aberrant caspase activity in the 3xTg-AD model (Rohn et al., 2008).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Kirkland et al., 2001 source

  • Classified as probably not a substantial claim.

    Premisecitation

    The amyloid hypothesis states that Aβ peptides lie upstream of all the pathological events occurring in AD, including NFT formation, synaptic dysfunction, and neuronal death.

    “The amyloid hypothesis states that Aβ peptides lie upstream of all the pathological events occurring in AD, including NFT formation, synaptic dysfunction, and neuronal death (Oddo et al., 2003b; Hardy, 2006).”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Oddo et al., 2003b

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Hardy, 2006 source

      The passage labeled Abstract (page unavailable) describes amyloid deposition as central to the amyloid hypothesis and discusses Aβ toxicity and electrophysiological effects. It does not state that Aβ lies upstream of all AD pathology, specifically NFT formation, synaptic dysfunction, and neuronal death. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Modification of mitochondrial enzymes and components of the respiratory chain by RS may contribute to impaired glucose metabolism in preclinical AD subjects.

    “Modification of mitochondrial enzymes and components of the respiratory chain by RS may contribute to impaired glucose metabolism found in preclinical AD subjects”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Sultana and Butterfield, 2009

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Yao et al., 2009 source

      The Discussion reports that oxidative damage to mitochondrial proteins impairs oxidative phosphorylation, and links reduced PDH and COX activity to altered glucose metabolism in AD-model mice. It also cites decreased glucose uptake in people at increased risk of AD. It does not establish that reactive-species modification of respiratory-chain components causes the impaired glucose metabolism observed in preclinical human subjects. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Several antioxidants are reported to lessen pathologies found in transgenic mouse models of AD.

    “Several antioxidants are reported to lessen pathologies found in transgenic mouse models of AD”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Lim et al., 2001 source

      The Discussion and the section on plaque burden report that curcumin, an antioxidant, reduced oxidative damage and amyloid pathology in APPSw transgenic mice. The paper establishes this result for curcumin, not for several antioxidants, so the claim’s plural generalization is not supported by this source. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites Stackman et al., 2003 source
    • cites Nicolakakis et al., 2008 source

  • May combine two claims.

    Findingown data

    These concentrations also blocked an Aβ-induced increase in NO·-associated RS and Aβ-induced depolarization of Δψm.

    “These concentrations also blocked an Aβ-induced increase in NO·-associated RS and Aβ-induced depolarization of Δψm.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MitoQ enhanced learning and spatial memory retention in 3xTg-AD mice.

    “Rather, MitoQ enhanced learning and spatial memory retention.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Aβ(22-35) forms amyloid fibrils in vitro resembling those of β-amyloid protein in senile plaques and exhibits a toxicity profile that parallels that of full-length Aβ(1-40) and Aβ(1-42) in hippocampal and cortical neurons in cell culture.

    “Aβ(22–35) forms amyloid fibrils in vitro resembling those of the β-amyloid protein in senile plaques and exhibits a toxicity profile that parallels that of full-length Aβ(1–40) and Aβ(1–42) in hippocampal and cortical neurons in cell culture (Pike et al., 1995; Casley et al., 2002b).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Pike et al., 1995 source
    • cites Casley et al., 2002b

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A similar amyloid fragment has been reported to impair mitochondrial function in isolated brain mitochondria.

    “A similar amyloid fragment has been reported to impair mitochondrial function in isolated brain mitochondria (Canevari et al., 1999).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Canevari et al., 1999 source

  • May combine two claims.

    Premisecitation

    The concentrations of MitoQ used here have no impact on mitochondrial functions such as ATP production, membrane potential, or ROS production in cells or mitochondria, but do prevent mitochondrial oxidative damage under conditions that lead to oxidative stress.

    “There is extensive in vitro evidence that the concentrations of MitoQ used here have no impact on mitochondrial functions, such as ATP production, membrane potential, or ROS production in cells or mitochondria, but do prevent mitochondrial oxidative damage under conditions that lead to oxidative stress (Kelso et al., 2001; Jauslin et al., 2003; Saretzki et al., 2003; Asin-Cayuelaa et al., 2004).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Kelso et al., 2001 source
    • cites Jauslin et al., 2003 source
    • cites Saretzki et al., 2003 source

  • May combine two claims.

    Premisecitation

    Aβ and its precursor APP localize, in part, to mitochondria in which they can cause mitochondrial dysfunction as evidenced by increased production of RS, enzyme inhibition, loss of cytochrome c, and depolarization of Δψm.

    “Aβ, and its precursor APP, localize, in part, to mitochondria in which they can cause mitochondrial dysfunction as evidenced by increased production of RS, enzyme inhibition, loss of cytochrome c, and depolarization of Δψm (Casley et al., 2002a; Kim et al., 2002; Anandatheerthavarada et al., 2003; Jang and Surh, 2003; Lustbader et al., 2004; Liang et al., 2009; Takuma et al., 2009).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Casley et al., 2002a

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Kim et al., 2002 source
    • cites Lustbader et al., 2004 source

  • May combine two claims.

    Premisecitation

    MitoQ rapidly crosses the blood-brain barrier and neuronal membranes and concentrates several hundred-fold in mitochondria.

    “MitoQ rapidly crosses the blood– brain barrier and neuronal membranes and concentrates several hundred-fold in mitochondria driven by the high membrane potential across the inner mitochondrial membrane (IMM; Murphy and Smith, 2007).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Murphy and Smith, 2007 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The EC50 for MitoQ in cultured cells is <0.5 nM, and the protective effect plateaus over several logs of concentration.

    “In other studies, the EC50 for MitoQ in cultured cells was <0.5 nM, and the protective effect then plateaued over several logs of concentration (Jauslin et al., 2003).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Jauslin et al., 2003 source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Δψm influences reactive species generation and other critical mitochondrial functions, such as NAD reduction, ATP synthesis, and Ca+ sequestration, and is considered the primary dictator of mitochondrial energetics and an indicator of overall mitochondrial health in neurons.

    “Δψm not only influences RS generation but other critical mitochondrial functions, such as nicotinamide adenine dinucleotide reduction, ATP synthesis, and Ca+ sequestration, and is therefore considered the primary dictator of mitochondrial energetics as well as an indicator of the overall health of mitochondria in neurons (Nicholls and Ward, 2000).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Nicholls and Ward, 2000 source

  • May combine two claims.

    Premisecitation

    When MitoQ is administered to in vivo animal models of pathologies, it reduces both oxidative damage and the pathologies.

    “A number of studies show that, when MitoQ is administered to in vivo animal models of pathologies, it reduces both oxidative damage and the pathologies (Adlam et al., 2005; Lowes et al., 2008; Graham et al., 2009; Supinski et al., 2009; Chacko et al., 2010; Smith and Murphy 2010).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Adlam et al., 2005 source
    • cites Lowes et al., 2008 source
    • cites Graham et al., 2009 source

  • Classified as probably not a substantial claim.

    Premisereasoning

    A possible explanation for failures of antioxidant trials is that tested compounds did not achieve sufficient concentrations at mitochondria, the site of most reactive species production.

    “One possible explanation for these failures is that the compounds tested were not efficient at detoxifying relevant reactive species (RS), perhaps because they did not achieve sufficient concentrations at the site of most RS production, mitochondria.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The findings in neuronal cells are consistent with other studies.

    “Therefore, our findings in neuronal cells are consistent with other studies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Cortical neuron survival was determined by blinded counting of phase-bright/morphologically intact cells in 10 randomly selected fields of view per treatment.

    “Cortical neuron survival was determined by blinded counting of phase-bright/morphologically intact cells in 10 randomly selected fields of view per treatment and was normalized to the average percentage survival of nontreated, sibling cultures.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Cued acquisition trials were conducted after the last probe trial to determine whether differences in learning and memory could be attributed to impaired eyesight, swimming ability, or motivation to escape.

    “Cued acquisition trials were conducted after the last probe trial to determine whether differences in learning and memory could be attributed to impaired eyesight, swimming ability, or motivation to escape (Morris, 1984).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Morris, 1984 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Confocal pinhole and gain were maintained at constant levels during each experiment.

    “Confocal pinhole and gain were maintained at constant levels during each experiment.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    An even shorter peptide [Aβ(25-35)] causes memory impairment when injected into rat brains.

    “An even shorter peptide [Aβ(25–35)] causes memory impairment when injected into rat brains (Díaz et al., 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Díaz et al., 2010

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    When administered to wild-type mice for several months, MitoQ has no effect on the function of subsequently isolated mitochondria, mtDNA, nuclear or mitochondrial gene expression, whole-body metabolism, whole-body motor function, or food and liquid consumption.

    “When administered to wild-type mice for several months, MitoQ has no effect on the function of subsequently isolated mitochondria, on mtDNA, on nuclear or mitochondrial gene expression, on whole-body metabolism, on whole-body motor function, or on food and liquid consumption (Rodriguez-Cuenca et al., 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rodriguez-Cuenca et al., 2010 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All animal procedures were in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

    “All animal procedures were in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The rate of metabolic decline within the medial temporal lobe predicts progression of cognitive deterioration from normal aging to AD.

    “the rate of metabolic decline within the medial temporal lobe predicts the progression of cognitive deterioration from normal aging to AD”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Mosconi et al., 2008a

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Mosconi et al., 2008b

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Premisecitation

    Tyrosine nitration provides a footprint for free radical-mediated damage involving oxidation of NO· to ONOO− or products of its subsequent decomposition and the formation of a tyrosyl radical intermediate.

    “Tyrosine nitration provides a footprint for free radical-mediated damage involving oxidation of NO· to ONOO− or products of its subsequent decomposition and the formation of a tyrosyl radical intermediate (Halliwell and Gutteridge, 2007; Malinski, 2007).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Halliwell and Gutteridge, 2007

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Malinski, 2007 source

  • May combine two claims.

    Interpretationown data

    The effect of MitoQ on rate of learning in 3xTg-AD mice could not be explained by a stimulatory effect of MitoQ or by an effect of MitoQ on vision.

    “The effect of MitoQ on rate of learning in the 3xTg-AD mice could not be explained by a stimulatory effect of MitoQ or by an effect of MitoQ on vision.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Motor performance was the same for all groups and MitoQ did not have a stimulatory effect.

    “The average swim speed was ~ 21 cm/s for each group (p = 0.84), indicating that motor performance was the same for all and that the MitoQ did not have a stimulatory effect.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Overexpression of MnSOD decreases Aβ-processing in a transgenic mouse AD model.

    “overexpression of MnSOD decreases Aβ-processing”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Li et al., 2004

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Esposito et al., 2006 source
    • cites Massaad et al., 2009 source

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Auxiliary approaches may be required for optimal therapeutic benefit and the effective prevention of AD.

    “auxiliary approaches may be required for optimal therapeutic benefit and the effective prevention of AD.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    The death was associated with mitochondrial dysfunction and was caused by mitochondrial-derived RS.

    “The data suggest that the death was associated with mitochondrial dysfunction and that it was caused by mitochondrial-derived RS.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Aβ enhances production of cellular RS, and these RS contribute to Aβ toxicity.

    “Aβ appears to enhance production of cellular RS, and these RS in turn may to contribute to Aβ toxicity.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Misonou et al., 2000 source
    • cites Tamagno et al., 2002, 2005

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Lin and Beal, 2006 source

  • May combine two claims.

    Premisecitation

    Aβ increases cellular RS, and these RS may in turn increase production of Aβ in a destructive autocatalytic cycle.

    “Evidence also suggests that not only does Aβ increase cellular RS but that these RS may in turn increase production of Aβ in a destructive autocatalytic cycle (Misonou et al., 2000; Tamagno et al., 2002, 2005; Lin and Beal, 2006; Quiroz-Baez et al., 2009).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Misonou et al., 2000 source
    • cites Tamagno et al., 2002, 2005

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Lin and Beal, 2006 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Metabolic impairment induced by thiamine deficiency or respiratory chain inhibition augments β-secretase expression and activity.

    “Metabolic impairment induced by thiamine deficiency or respiratory chain inhibition augments β-secretase expression and activity”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Karuppagounder et al., 2009

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Zhang et al., 2011

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Overexpression of MnSOD preserves synaptic integrity in a transgenic mouse AD model.

    “preserves synaptic integrity”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Li et al., 2004

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Esposito et al., 2006 source
    • cites Massaad et al., 2009 source

  • May combine two claims.

    Premisecitation

    The 3xTg-AD mouse strain develops cognitive dysfunction as well as both plaque and neurofibrillary tangle pathology in AD-relevant brain regions in an age-dependent manner, closely resembling AD progression in humans.

    “This mouse strain develops cognitive dysfunction as well as both plaque and neurofibrillary tangle pathology in AD-relevant brain regions in an age-dependent manner, closely resembling AD progression in humans (Oddo et al., 2003b).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Oddo et al., 2003b

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Spatial retention deficits emerge in 3xTg-AD mice by 4-6 months of age and are reminiscent of spatial learning deficits in patients with mild cognitive impairment (MCI), a condition proposed to be prodromal for AD.

    “Spatial retention deficits emerge in 3xTg-AD mice by 4–6 months of age and are reminiscent of spatial learning deficits in patients with mild cognitive impairment (MCI), a condition proposed to be prodromal for AD (Grundman et al., 2004; Mosconi et al., 2008a).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Grundman et al., 2004

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Mosconi et al., 2008a

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Caspases may generate Aβ by directly cleaving APP (caspase 3).

    “which may generate Aβ by directly cleaving APP (caspase 3)”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Newcombe et al., 2004

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Chae et al., 2010 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    γ-secretase may be upregulated by RS.

    “may also be upregulated by RS”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Minopoli et al., 2007

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Guglielmotto et al., 2010

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Oda et al., 2010 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    MitoQ has been through two phase II trials for other conditions.

    “MitoQ has been though two phase II trials for other conditions”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Snow et al., 2010 source

  • May combine two claims.

    Premisecitation

    Intracellular Aβ may enter mitochondria and induce additional RS and magnify metabolic deficit.

    “Intracellular Aβ may then enter the mitochondria in which it induces additional RS and magnifies the metabolic deficit”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Lustbader et al., 2004 source
    • cites Hansson Petersen et al., 2008 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Caspases may generate Aβ via a process involving β-secretase (caspases 2 and 8).

    “or via a process involving β-secretase (caspases 2 and 8”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Newcombe et al., 2004

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Chae et al., 2010 source
52 of 52

  • The paper relies on this without support.

    Cognitive impairment in 3xTg-AD mice emerges as a long-term retention deficit at 4–6 months of age and further develops in an age-dependent manner.

    “Cognitive impairment in 3xTg-AD mice emerges as a long-term retention deficit at 4–6 months of age and further develops in an age-dependent manner.”

  • The paper relies on this without support.

    Cyclodextrin is widely used in drug delivery and is not thought to have any significant effects.

    “Cyclodextrin is widely used in drug delivery and is not thought to have any significant effects.”

  • The paper relies on this without support.

    By decreasing the proton gradient across the inner mitochondrial membrane, FCCP increases the rate of electron transport through the respiratory chain, thereby inhibiting electron leakage and consequently mitochondrial O2·- production.

    “By decreasing the proton gradient across the IMM, FCCP increases rate of electron transport through the respiratory chain, thereby inhibiting electron leakage and consequently mitochondrial O2·- production.”

  • The paper relies on this without support.

    Nitro-oxidative modification to proteins may dramatically alter their structure and biological activity and may play an important role in AD development.

    “Nitro-oxidative modification to proteins may dramatically alter their structure and biological activity and may play an important role in AD development.”

  • The paper relies on this without support.

    The brains of human AD patients exhibit extensive astrogliosis, a process indicative of neuronal damage.

    “The brains of human AD patients exhibit extensive astrogliosis, a process indicative of neuronal damage.”

  • The paper relies on this without support.

    The predominant pathway of Aβ production occurs by sequential cleavage of APP by β- and γ-secretases.

    “The predominant pathway of Aβ production occurs by sequential cleavage of APP by β- and γ-secretases.”

  • The paper relies on this without support.

    These antioxidants are nonspecific and should interact with ROS in all areas of the brain.

    “However, these antioxidants are nonspecific and should interact with ROS in all areas of the brain.”

  • The paper relies on this without support.

    MitoQ operates only within mitochondria.

    “an antioxidant that only operates within mitochondria is protective”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • CoQ10 led to decreased Aβ pathology in aged transgenic mice with human AD presenilin-1 mutation, and MitoQ improved memory and neuropathology in a transgenic mouse model of AD.

    “CoQ10 led to decreased Aβ pathology in aged transgenic mice with human AD presenilin-1 mutation, and in a different study, a quinone-containing derivative of CoQ10 (MitoQ) that targets mitochondria, improved memory, and neuropathology in a transgenic mouse model of AD [152,153].”

    From Mitochondrial Oxidative and Nitrosative Stress and Alzheimer Disease (2020) · cites this paper as [153]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Results lists five treatment groups but says there were six

    Minor

    The Results description specifies three 3xTg-AD groups and two nonTg groups, then refers to "these six groups." The Methods describes a nonTg group receiving dTPP, but the Results description says nonTg mice received either no treatment or MitoQ.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Newcombe, 2004, Caspase-3-mediated proteolyis of amyloid precursor protein and the production of amyloid A-beta in human acute and chronic compressive myleopathy, J Bone Joint Surg Br, 86B, 462

Cited by

Sorted by citations

Related

Authors
McManus, M. J., Murphy, M. P., & Franklin, J. L.
Affiliations
  • University of Georgia (US)
  • MRC Mitochondrial Biology Unit (GB)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2011-11-02
Volume
31
Issue
44
Pages
15703-15715
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.0552-11.2011
PMC
PMC3334845
OpenAlex
W1988664434
Cited by
432
References
135
Citations by year
2026: 18 · 2025: 29 · 2024: 29 · 2023: 28 · 2022: 39 · 2021: 47 · 2020: 39 · 2019: 33 · 2018: 28 · 2017: 17 · 2016: 37 · 2015: 17 · 2014: 23 · 2013: 30 · 2012: 18
FWCI
15.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of Neurological Disorders and Stroke (R29NS037110, NS37110, R01NS037110)
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 › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
MitoQ, mitochondria-targeted antioxidants, Alzheimer's disease, 3xTg-AD mice, mitochondrial dysfunction, oxidative stress, amyloid-beta toxicity, mitochondrial membrane potential, cognitive decline, astrocyte activation, synaptic loss, caspase activation, neurodegeneration, mitochondrial protection
MeSH terms
Age Factors, Alzheimer Disease, Analysis of Variance, Animals, Animals, Newborn, Antioxidants, Cells, Cultured, Cerebral Cortex, Disease Models, Animal, Enzyme Inhibitors, Enzyme-Linked Immunosorbent Assay, Glial Fibrillary Acidic Protein, Gliosis, Glutathione, Humans, Memory Disorders, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria, Neurons, Organophosphorus Compounds, Peptide Fragments, Retention, Psychology, Rhodamines, Space Perception, Time Factors, Tyrosine, Ubiquinone, Lipid Peroxidation, Amyloid beta-Peptides, Cell Death, Oxidative Stress, Maze Learning, Caspases, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-11-02.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-02.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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