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Cited by 87Medicinal Plants and NeuroprotectionAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice

Open access
Matthews, Donald G, Caruso, Maya, Murchison, Charles F, Zhu, Jennifer Y, Wright, Kirsten M, Harris, Christopher J, Gray, Nora E, Quinn, Joseph F +1 more·2019·Antioxidants
DOI 10.3390/antiox8120630PMC PMC6943631
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Abstract

Centella asiatica (CA) herb is a traditional medicine, long reputed to provide cognitive benefits. We have reported that CA water extract (CAW) treatment improves cognitive function of aged Alzheimer’s disease (AD) model Tg2576 and wild-type (WT) mice, and induces an NRF2-regulated antioxidant response in aged WT mice. Here, CAW was administered to AD model 5XFAD female and male mice and WT littermates (age: 7.6 +/ − 0.6 months), and object recall and contextual fear memory were tested after three weeks treatment. CAW’s impact on amyloid-β plaque burden, and markers of neuronal oxidative stress and synaptic density, was assessed after five weeks treatment. CAW antioxidant activity was evaluated via nuclear transcription factor (erythroid-derived 2)-like 2 (NRF2) and NRF2-regulated antioxidant response element gene expression. Memory improvement in both genders and genotypes was associated with dose-dependent CAW treatment without affecting plaque burden, and marginally increased synaptic density markers in the hippocampus and prefrontal cortex. CAW treatment increased Nrf2 in hippocampus and other NRF2 targets (heme oxygenase-1, NAD(P)H quinone dehydrogenase 1, glutamate-cysteine ligase catalytic subunit). Reduced plaque-associated SOD1, an indicator of oxidative stress, was observed in the hippocampi and cortices of CAW-treated 5XFAD mice. We postulate that CAW treatment leads to reduced oxidative stress, contributing to improved neuronal health and cognition.

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Written from the paper’s full text.

TL;DR

Centella asiatica water extract (CAW) improved memory in 5XFAD and wild-type mice in a dose-dependent manner without changing amyloid-β plaque burden. CAW also increased hippocampal NRF2/ARE antioxidant gene expression and reduced plaque-associated SOD1, suggesting an antioxidative mechanism.

Key findings

  • CAW produced dose-dependent memory improvement across genotypes and genders: 2 h novel object recognition (NORT) F = 15.0, p < 0.001; 24 h NORT F = 21.2, p < 0.001; conditioned fear response (CFR) F = 9.12, p < 0.001. All CAW doses improved NORT, while 500 and 1000 mg/kg/d improved CFR.
  • CAW did not alter amyloid-β plaque burden in cortex or hippocampus (particle count cortex F = 0.41, p = 0.66; hippocampus F = 0.30, p = 0.74; total plaque area cortex F = 0.07, p = 0.93; hippocampus F = 0.14, p = 0.86).
  • Hippocampal antioxidant response element genes increased dose-dependently with CAW: Nrf2 F = 4.22, p = 0.007; Ho-1 F = 7.84, p < 0.001; Nqo1 F = 9.29, p < 0.001; Gclc F = 8.76, p < 0.001, regardless of gender or genotype.
  • CAW reduced plaque-associated SOD1 particle number in hippocampus (F = 15.5, p < 0.001) and cortex (F = 5.67, p = 0.008) of 5XFAD mice. Synaptic marker effects were marginal and inconsistent, primarily driven by male 5XFAD mice.

Methods

  • CAW was prepared from dried Centella asiatica aerial parts as a water extract and given ad libitum in drinking water to 5XFAD and WT littermates of both genders (age 7.6 ± 0.6 months) at estimated doses of 0, 200, 500, or 1000 mg/kg/d for five weeks, with 16 groups total.
  • Memory was tested during weeks 3–4 using NORT and CFR. After five weeks, qPCR measured hippocampal and cortical Nrf2, Ho-1, Nqo1, Gclc, synaptophysin, and Psd95; immunohistochemistry measured pan-Aβ plaque burden and SOD1.
  • Analyses used ordinary least squares regression and multi-way ANOVA, with dose as a 4-level factor versus vehicle; p < 0.01 was globally significant and p < 0.05 was considered a trend.

Limitations

  • The paper states that the in vivo models used (Tg2576, 5XFAD) do not possess tau tangles, and that CAW effects on ER stress, calcium dys-homeostasis, mitochondrial dysfunction, and downstream oxidative stress were not analyzed.
  • The paper states that the impact of CAW on 5XFAD amyloid plaque burden should be resolved in future experiments, that synaptic marker data are inconclusive and suggest possible gender-specific effects requiring further study, and that a time course of oxidative stress and ARE response is needed.
  • Evident from the text: CAW doses were estimated from water bottle consumption and may be lower than calculated ranges; several outcomes were trends rather than significant after the p < 0.01 threshold, and cortical ARE gene changes were less consistent than hippocampal changes.

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

Integrity signals

Registry

Crossref · 10.3390/antiox8120630

Cites

114 of 114 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 104 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    CAW positively impacts antioxidant and synaptic gene expression in the hippocampus (and, to a lesser extent, in the frontal cortex) over untreated levels regardless of pathology.

    “CAW positively impacted antioxidant and synaptic gene expression in the hippocampus (and, to a lesser extent, in the frontal cortex) over untreated levels regardless of pathology.”
    Quote in the paperSubstantial claim
  • Findingown data

    CAW treatment increases Nrf2 in hippocampus.

    “CAW treatment increased Nrf2 in hippocampus”
    Quote in the paperSubstantial claim
  • Findingown data

    CAW treatment marginally increases synaptic density markers in the hippocampus and prefrontal cortex.

    “marginally increased synaptic density markers in the hippocampus and prefrontal cortex”
    Quote in the paperNot a substantial claim
  • Findingown data

    CAW treatment increases other NRF2 targets (heme oxygenase-1, NAD(P)H quinone dehydrogenase 1, glutamate-cysteine ligase catalytic subunit) in hippocampus.

    “CAW treatment increased Nrf2 in hippocampus and other NRF2 targets (heme oxygenase-1, NAD(P)H quinone dehydrogenase 1, glutamate-cysteine ligase catalytic subunit).”
    Quote in the paperSubstantial claim
  • Findingown data

    CAW treatment reduces plaque-associated SOD1 in hippocampi and cortices of 5XFAD mice.

    “Reduced plaque-associated SOD1, an indicator of oxidative stress, was observed in the hippocampi and cortices of CAW-treated 5XFAD mice.”
    Quote in the paperSubstantial claim
  • May combine two claims. 41
  • Classified as probably not a substantial claim. 15

  • May combine two claims.

    Findingown data

    CAW treatment improves memory in 5XFAD and WT mice in a dose-dependent manner regardless of gender or pathology.

    “Memory improvement in both genders and genotypes was associated with dose-dependent CAW treatment without affecting plaque burden”
    • Also stated in: § 3.1. CAW Improves Memory in a Dose-Dependent Manner Regardless of Gender or Pathology · plain
      “A dose-dependent response to CAW treatment promoting a gain in memory function was observed for all testing paradigms”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    A pathology-dependent memory deficit during CFR testing was observed, but not seen upon NORT evaluation.

    “A pathology-dependent memory deficit during CFR testing was observed as expected, but was not seen upon NORT evaluation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    CAW improved working and contextual fear memory in the present study without impacting Aβ plaque burden.

    “Here, CAW improved working and contextual fear memory, again without impacting Aβ plaque burden.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CAW treatment significantly increased hippocampal synaptophysin transcript levels only in 5XFAD male mice at 1000 mg/kg/d vs WT CAW 1000 male mice and vs 5XFAD CAW 1000 female mice.

    “Hippocampal synaptophysin transcript levels were found to be significantly increased by CAW treatment only in 5XFAD male mice at the highest CAW dose of 1000 mg/kg/d vs WT CAW 1000 mg/kg/d male mice (t = 2.86, p = 0.006) and vs 5XFAD CAW 1000 mg/kg/d female mice (t = 2.73, p = 0.008).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Compared to untreated controls, CAW at 1000 mg/kg/d significantly reduced cortical SOD1 particle number, with a non-significant trend at 500 mg/kg/d.

    “a reduction in cortical SOD1 particle number was only observed at the higher dose of 1000 mg/kg/d dose (t = −3.041, p = 0.005) with a non-significant trend at 500 mg/kg/d (t = 2.75, p = 0.010).”
    Quote in the paperSubstantial claim

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

    Findingown data

    Male mice performed slightly worse than females on 2 h NORT and CFR, as a non-significant trend.

    “Gender difference was noted as a non-significant trend, where males performed slightly worse than females on 2 h NORT (F = 5.34, p = 0.022) and CFR (F = 6.51, p = 0.011)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Increased cortical expression of Nqo1 was observed at 500 mg/kg/d in mice regardless of gender or genotype, but not at 1000 mg/kg/d.

    “Although increased cortical expression of Nqo1 was observed at 500 mg/kg/d in mice regardless of gender or genotype (t = 3.44, p < 0.001), this effect was not observed at a dose of 1000 mg/kg/d.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neither gender nor pathology modulated the effects of CAW on memory.

    “neither gender nor pathology were observed to modulate the effects of CAW on memory.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CAW treatment increased hippocampal synaptophysin expression in general, moderated by pathology in 5XFAD vs WT CAW-treated mice.

    “The elevation of hippocampal synaptophysin expression with CAW treatment in general, was moderated by pathology in 5XFAD mice vs WT CAW-treated mice (F = 3.99, p = 0.009)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    500 mg/kg/d CAW significantly increased hippocampal expression of Nrf2, Ho-1, and Nqo1, but not Gclc, compared to untreated controls.

    “the middle dose of 500 mg/kg/d increased expression for every gene except Gclc (Nrf2: t = 3.20, p = 0.002; Ho-1: t = 3.22, p = 0.002; Nqo1: t = 3.06, p = 0.003) in hippocampal samples.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was no significant effect of pathology on synaptophysin or Psd95 in hippocampus or cortex, or effect of gender on these synaptic markers in hippocampus.

    “There was not a significant effect of pathology on synaptophysin or Psd95 in the hippocampus or cortex or an effect of gender on these synaptic markers in the hippocampus.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    CAW treatment-dependent increase in synaptic markers in cortex was statistically significant, while there was a significant increase in synaptophysin in hippocampus and an increasing trend in Psd95 (p=0.026) with CAW treatment.

    “We found a statistically significant CAW treatment-dependent increase in these synaptic markers in the cortex, while there was a significant increase in synaptophysin in the hippocampus and an increasing trend in Psd95 (p=0.026) with CAW treatment.”
    Quote in the paperSubstantial claim

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

    Findingown data

    During CFR, a trending elevated baseline fear memory in female mice versus males was observed.

    “During CFR, a trending elevated baseline fear memory in female mice versus males was also observed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    CAW treatment did not significantly reduce total SOD1 area in hippocampus, and only a non-significant trend in cortex.

    “only a non-significant trend in a reduction of total SOD1 area was observed in the cortex (F = 3.55, p = 0.042) with no effect observed in the hippocampus (F = 1.01, p = 0.38).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Neither pathology nor gender influenced the relationship between hippocampal gene expression and CAW treatment.

    “Neither pathology nor gender influenced the relationship between hippocampal gene expression and CAW treatment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CAW treatment increased synaptophysin expression in the cortices of female mice and higher expression of hippocampal Psd95 in males.

    “We observed increased expression of synaptophysin in the cortices of female mice and higher expression of hippocampal Psd95 in males.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The 5XFAD model allows an accelerated timetable of cognitive dysfunction associated with Alzheimer's Aβ pathology compared to Tg2576 and models hippocampal neuron loss.

    “The 5XFAD model of AD allows for an accelerated timetable of cognitive dysfunction associated with Alzheimer’s Aβ pathology compared to the Tg2576 model, in addition to modeling the hippocampal neuron loss indicative of AD, which is absent from the Tg2576 model [34,35].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [34] Irizarry, 1997, APPSw transgenic mice develop age-related A beta deposits and neuropil abnormalities, but no neuronal loss in CA1, J. Neuropathol. Exp. Neurol. source

      Not checked in the free run.

    • cites [35] Oakley, 2006, Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: Potential factors in amyloid plaque formation, J. Neurosci. source

      Not checked in the free run.

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

    Study design and conductnone given

    All procedures were approved by the Institutional Animal Care and Use Committee of the Portland VA Medical Center.

    “were approved by the Institutional Animal Care and Use Committee of the Portland VA Medical Center (IACUC #: 3260-17).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    CAW increases spine density and dendritic arborization in Tg2576 primary hippocampal neurons.

    “increases spine density and dendritic arborization in Tg2576 primary hippocampal neurons [28].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Gray, 2017, Centella asiatica attenuates Abeta-induced neurodegenerative spine loss and dendritic simplification, Neurosci. Lett. source

      Not checked in the free run.

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

    Study design and conductnone given

    Mice failing to explore either object for 12 s were excluded from NORT analysis.

    “Mice failing to participate in the study (i.e., explore either object for a period of 12 s) were excluded from analysis.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Ho-1 and NQO1 are upregulated in AD patients.

    “Ho-1 and NQO1 are upregulated in AD patients [22,23]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Tanji, 2013, Keap1 is localized in neuronal and glial cytoplasmic inclusions in various neurodegenerative diseases, J. Neuropathol. Exp. Neurol. source

      Not checked in the free run.

    • cites [23] Raina, 1999, Quinone reductase (NQO1), a sensitive redox indicator, is increased in Alzheimer’s disease, Redox Rep. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Observed CAW effects were predominantly gender-independent, suggesting a potential benefit to both men and women in upcoming clinical trials.

    “The observed CAW effects were predominantly gender-independent, suggesting a potential benefit to both men and women in upcoming clinical trials.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: CAW's effects observed in 5XFAD and WT mice are predictive of benefits in humans.

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

    Premisecitation

    GCLC is the main regulating protein for glutathione production, a process impacted by AD pathology.

    “GCLC is the main regulating protein for glutathione production, a process impacted by AD pathology [24,25,26].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [24] Saharan, 2014, The emerging role of glutathione in Alzheimer’s disease, J. Alzheimers Dis. source

      Not checked in the free run.

    • cites [25] Volkel, 2006, Increased brain levels of 4-hydroxy-2-nonenal glutathione conjugates in severe Alzheimer’s disease, Neurochem. Int. source

      Not checked in the free run.

    • cites [26] Cecchi, 1999, Gluthatione level is altered in lymphoblasts from patients with familial Alzheimer’s disease, Neurosci. Lett. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    5XFAD mice accumulate detectable Aβ42 within neurons by six weeks and extracellular Aβ by eight weeks, leading to ubiquitous plaque formation in hippocampus and cortex at six months, coinciding with start of neuronal loss.

    “5XFAD mice accumulate detectable Aβ42 within neurons by six weeks of age, and extracellular deposits of Aβ by eight weeks, leading to ubiquitous plaque formation in the hippocampus and cortex at six months, coinciding with the start of neuronal loss [35,36].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [35] Oakley, 2006, Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: Potential factors in amyloid plaque formation, J. Neurosci. source

      Not checked in the free run.

    • cites [36] Eimer, 2013, Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Abeta42 accumulation and Caspase-3 activation, Mol. Neurodegener. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    NORT video scoring was performed by a technician blinded to experimental condition.

    “All video was scored by a technician blinded to the experimental condition”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    CAW treatment leads to reduced oxidative stress, contributing to improved neuronal health and cognition.

    “We postulate that CAW treatment leads to reduced oxidative stress, contributing to improved neuronal health and cognition.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    CAW increases NRF2-regulated gene transcripts and reduces Aβ-associated ROS in vitro.

    “CAW increases NRF2-regulated gene transcripts, reduces Aβ-associated ROS [27]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Gray, 2017, Centella asiatica Attenuates Mitochondrial Dysfunction and Oxidative Stress in Abeta-Exposed Hippocampal Neurons, Oxid. Med. Cell. Longev. source

      Not checked in the free run.

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

    Premisecitation

    Female 5XFAD mice demonstrate increased levels of Aβ42 and Aβ40 compared to males.

    “female mice demonstrated increased levels of Aβ42 and Aβ40 compared to males.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Oakley, 2006, Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: Potential factors in amyloid plaque formation, J. Neurosci. source

      Not checked in the free run.

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

    Study design and conductreasoning

    Statistical significance was globally defined as p < 0.01 to account for multiplicity, while p < 0.05 was considered a trend.

    “significance was globally defined as p < 0.01 to account for multiplicity, while p < 0.05 was merely considered a trend.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Female 5XFAD mice have increased BACE1 activity, leading to increased amyloid plaque burden compared to male 5XFAD mice.

    “Females also appear to have increased BACE1 activity, a β-secretase processing enzyme which cleaves pAPP and produces pathogenic Aβ fragments [40,41], ultimately leading to increased amyloid plaque burden compared to male 5XFAD mice [41,42].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [40] Sadleir, 2015, Abeta reduction in BACE1 heterozygous null 5XFAD mice is associated with transgenic APP level, Mol. Neurodegener. source

      Not checked in the free run.

    • cites [41] Devi, 2010, Sex- and brain region-specific acceleration of beta-amyloidogenesis following behavioral stress in a mouse model of Alzheimer’s disease, Mol. Brain source

      Not checked in the free run.

    • cites [42] Bhattacharya, S., Haertel, C., Maelicke, A., and Montag, D. (2014). Galantamine slows down plaque formation and behavioral decline in the 5XFAD mouse model of Alzheimer’s disease. PLoS ONE, 9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CAW (200 mg/kg/day for five weeks) improves cognitive function in female Tg2576 APP mice without impacting Aβ levels.

    “our laboratory reported the cognitive benefits of a CA water extract (CAW; 200 mg/kg/day for five weeks) in females from the Tg2576 APP mouse model of AD [13], but, notably, without an impact on Aβ levels.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Soumyanath, 2012, Centella asiatica Extract Improves Behavioral Deficits in a Mouse Model of Alzheimer’s Disease: Investigation of a Possible Mechanism of Action, Int. J. Alzheimers Dis.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    APP mouse models of AD demonstrate cognitive decline with pathology comprising Aβ plaques closely associated with areas of high oxidative stress and dystrophic neurites.

    “APP mouse models of AD demonstrate cognitive decline with pathology, comprising Aβ plaques closely associated with areas of high oxidative stress and dystrophic neurites [14,15].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Kurata, 2011, Atorvastatin and pitavastatin improve cognitive function and reduce senile plaque and phosphorylated tau in aged APP mice, Brain Res. source

      Not checked in the free run.

    • cites [15] Tong, 2009, Simvastatin improves cerebrovascular function and counters soluble amyloid-beta, inflammation and oxidative stress in aged APP mice, Neurobiol. Dis. source

      Not checked in the free run.

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

    Premisecitation

    Increased SOD expression is associated with dystrophic neurites adjacent to Aβ plaques in IHC analysis of AD models.

    “increased SOD expression is associated with dystrophic neurites adjacent to Aβ plaques in immunohistochemistry (IHC) analysis of AD models [20,21].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Aucoin, 2005, Selective cholinergic denervation, independent from oxidative stress, in a mouse model of Alzheimer’s disease, Neuroscience source

      Not checked in the free run.

    • cites [21] Ferrer, 2002, Differential expression of phosphorylated translation initiation factor 2 alpha in Alzheimer’s disease and Creutzfeldt-Jakob’s disease, Neuropathol. Appl. Neurobiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CA extracts have positive effects on neurite elongation, neurodegeneration, antioxidant activity, and mitochondrial dysfunction.

    “CA extracts have demonstrated positive effects on neurite elongation [6], neurodegeneration [29], antioxidant activity [30], and mitochondrial dysfunction [31].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [6] Soumyanath, 2005, Centella asiatica accelerates nerve regeneration upon oral administration and contains multiple active fractions increasing neurite elongation in-vitro, J. Pharm. Pharmacol. source

      Not checked in the free run.

    • cites [29] Defillipo, 2012, Inhibition of cPLA2 and sPLA2 activities in primary cultures of rat cortical neurons by Centella asiatica water extract, Nat. Prod. Commun.

      Not checked in the free run.

    • cites [30] Pittella, 2009, Antioxidant and cytotoxic activities of Centella asiatica (L) Urb, Int. J. Mol. Sci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 5XFAD pathology, spine loss (4-9 months) occurs subsequent to cognitive dysfunction (3-6 months) and Aβ plaque formation (two months).

    “An interesting observation in the progression of 5XFAD pathology is that spine loss (4–9 months) [62] occurs subsequent to cognitive dysfunction (3–6 months) [35,63,64,65,66] and Aβ plaque formation (two months) [67].”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [62] Crowe, 2013, In vivo characterization of a bigenic fluorescent mouse model of Alzheimer’s disease with neurodegeneration, J. Comp. Neurol. source

      Not checked in the free run.

    • cites [35] Oakley, 2006, Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: Potential factors in amyloid plaque formation, J. Neurosci. source

      Not checked in the free run.

    • cites [63] Izquierdo, 2018, Environmental Enrichment Improves Cognitive Deficits, AD Hallmarks and Epigenetic Alterations Presented in 5xFAD Mouse Model, Front. Cell. Neurosci. source

      Not checked in the free run.

    • cites [64] Gu, 2018, Myelin changes at the early stage of 5XFAD mice, Brain Res. Bull. source

      Not checked in the free run.

    • cites [65] Jawhar, 2012, Motor deficits, neuron loss, and reduced anxiety coinciding with axonal degeneration and intraneuronal Abeta aggregation in the 5XFAD mouse model of Alzheimer’s disease, Neurobiol. Aging source

      Not checked in the free run.

    • cites [66] Wu, 2018, LINGO-1 antibody ameliorates myelin impairment and spatial memory deficits in the early stage of 5XFAD mice, CNS Neurosci. Ther. source

      Not checked in the free run.

    • cites [67] Richard, 2015, Gene Dosage Dependent Aggravation of the Neurological Phenotype in the 5XFAD Mouse Model of Alzheimer’s Disease, J. Alzheimers Dis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Previous CAW treatment (200 mg/kg/d for four weeks) of 20 month old Tg2576 female mice improves spatial memory and learning without impacting Aβ1-40 or Aβ1-42 levels in cortex.

    “Previous studies in our laboratory have shown CAW treatment (single dose of 200 mg/kg/d for four weeks) of 20 month old Tg2576 female mice improves spatial memory and learning (as measured by Morris water maze) without impacting Aβ1-40 or Aβ1-42 levels in the cortex [13].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Soumyanath, 2012, Centella asiatica Extract Improves Behavioral Deficits in a Mouse Model of Alzheimer’s Disease: Investigation of a Possible Mechanism of Action, Int. J. Alzheimers Dis.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This progression is different from Tg2576, which manifests synaptic damage at an early stage (4.5 months) with a corresponding decrease in synaptic density markers prior to Aβ plaque development (10 months) and cognitive deficiencies (one year).

    “This is different from the progression in Tg2576, which manifests synaptic damage at an early stage of pathological development (4.5 months) [68,69] with a corresponding decrease in synaptic density markers [70] prior to Aβ plaque development (10 months) [71] and cognitive deficiencies (one year) [72,73].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [68] Lanz, 2003, Dendritic spine loss in the hippocampus of young PDAPP and Tg2576 mice and its prevention by the ApoE2 genotype, Neurobiol. Dis. source

      Not checked in the free run.

    • cites [69] Jacobsen, 2006, Early-onset behavioral and synaptic deficits in a mouse model of Alzheimer’s disease, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

    • cites [70] Manczak, 2016, Protective effects of reduced dynamin-related protein 1 against amyloid beta-induced mitochondrial dysfunction and synaptic damage in Alzheimer’s disease, Hum. Mol. Genet.

      Not checked in the free run.

    • cites [71] Hsiao, 1996, Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    IHC for SOD1 labels areas of high oxidative stress, specifically around Aβ plaques, and is associated with dystrophic neurites.

    “IHC for SOD1 labels areas of high oxidative stress, specifically around Aβ plaques, and is associated with dystrophic neurites [21,48].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] Ferrer, 2002, Differential expression of phosphorylated translation initiation factor 2 alpha in Alzheimer’s disease and Creutzfeldt-Jakob’s disease, Neuropathol. Appl. Neurobiol. source

      Not checked in the free run.

    • cites [48] Aso, 2012, Amyloid generation and dysfunctional immunoproteasome activation with disease progression in animal model of familial Alzheimer’s disease, Brain Pathol. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Plant identity was verified by visual inspection and Fourier transform Infra-Red spectroscopy at the suppliers.

    “Plant identity was verified at the suppliers by visual inspection and Fourier transform Infra-Red spectroscopy”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Caffeoylquinic acids found in CA induce Nrf2 and Ho-1 signaling and positively impact glutathione levels.

    “Caffeoylquinic acids found in CA [28,96,97], are also known to induce Nrf2 and Ho-1 signaling, and positively impact glutathione levels [98,99].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [28] Gray, 2017, Centella asiatica attenuates Abeta-induced neurodegenerative spine loss and dendritic simplification, Neurosci. Lett. source

      Not checked in the free run.

    • cites [96] Ncube, 2016, Stimulatory Effects of Acibenzolar-S-Methyl on Chlorogenic Acids Biosynthesis in Centella asiatica Cells, Front. Plant Sci. source

      Not checked in the free run.

    • cites [97] Satake, 2007, The anti-thrombotic active constituents from Centella asiatica, Biol. Pharm. Bull. source

      Not checked in the free run.

    • cites [98] Cao, 2010, 1,5-Dicaffeoylquinic acid-mediated glutathione synthesis through activation of Nrf2 protects against OGD/reperfusion-induced oxidative stress in astrocytes, Brain Res. source

      Not checked in the free run.

    • cites [99] Hwang, 2009, Protective mechanisms of 3-caffeoyl, 4-dihydrocaffeoyl quinic acid from Salicornia herbacea against tert-butyl hydroperoxide-induced oxidative damage, Chem. Biol. Interact. source

      Not checked in the free run.

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

    Premisecitation

    In a PSAPP mouse model, ethanolic extract of CA at 2500-5000 mg/kg/d for 2-8 months reduced Aβ.

    “However, a study in a PSAPP mouse model of AD has shown a reduction of Aβ following treatment with an ethanolic extract of CA (which would have a different chemical profile to CAW) [12] when administered at a higher dose for a longer duration of time (2500–5000 mg/kg/d for 2–8 months).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] Dhanasekaran, 2009, Centella asiatica extract selectively decreases amyloid beta levels in hippocampus of Alzheimer’s disease animal model, Phytother. Res. source

      Not checked in the free run.

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

    Premisecitation

    ARE activation occurs in Alzheimer's patients.

    “which is consistent with ARE activation in Alzheimer’s patients [101]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Wojsiat, 2018, Oxidant/Antioxidant Imbalance in Alzheimer’s Disease: Therapeutic and Diagnostic Prospects, Oxid. Med. Cell. Longev. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Compounds in CA such as ferulic acid and asiatic acid induce Nrf2 and its ARE-regulated targets, exhibiting a neuroprotective effect.

    “Compounds such as the phenolic ferulic acid [89,90] and the triterpene asiatic acid [2,91], induce Nrf2 and its ARE-regulated targets, exhibiting a neuroprotective effect [92,93,94,95].”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [89] Kumari, 2016, In vitro and In vivo Antioxidant, Anti-hyperlipidemic Properties and Chemical Characterization of Centella asiatica (L.) Extract, Front. Pharmacol. source

      Not checked in the free run.

    • cites [90] Ramesh, 2014, Comparative study on anti-oxidant and anti-inflammatory activities of Caesalpinia crista and Centella asiatica leaf extracts, J. Pharm. Bioallied Sci. source

      Not checked in the free run.

    • cites [2] Xu, 2012, Asiatic acid, a pentacyclic triterpene in Centella asiatica, attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Y cells, Acta Pharmacol. Sin source

      Not checked in the free run.

    • cites [91] Krishnamurthy, 2009, Asiatic acid, a pentacyclic triterpene from Centella asiatica, is neuroprotective in a mouse model of focal cerebral ischemia, J. Neurosci. Res. source

      Not checked in the free run.

    • cites [92] Welbat, J.U., Chaisawang, P., Pannangrong, W., and Wigmore, P. (2018). Neuroprotective Properties of Asiatic Acid against 5-Fluorouracil Chemotherapy in the Hippocampus in an Adult Rat Model. Nutrients, 10. source

      Not checked in the free run.

    • cites [93] Kamble, 2018, Asiatic Acid Ameliorates Doxorubicin-Induced Cardiac and Hepato-Renal Toxicities with Nrf2 Transcriptional Factor Activation in Rats, Cardiovasc. Toxicol. source

      Not checked in the free run.

    • cites [94] Jiang, 2016, Neuroprotective effect of asiatic acid against spinal cord injury in rats, Life Sci. source

      Not checked in the free run.

    • cites [95] Huang, 2012, Tacrine-6-ferulic acid, a novel multifunctional dimer against Alzheimer’s disease, prevents oxidative stress-induced neuronal death through activating Nrf2/ARE/HO-1 pathway in HT22 cells, CNS Neurosci. Ther. source

      Not checked in the free run.

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

    Premisecitation

    Numerous other studies demonstrate both an increase and decrease in ARE gene expression in AD brain tissue, with an initial heightened antioxidant response due to oxidative stress followed by eventual exhaustion with decrease of ARE pathway signaling.

    “Numerous other studies demonstrate both an increase and decrease in ARE gene expression in AD brain tissue, citing an initial heightened antioxidant response due to oxidative stress [22,86,87], followed by its eventual exhaustion with the decrease of ARE pathway signaling [88].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [22] Tanji, 2013, Keap1 is localized in neuronal and glial cytoplasmic inclusions in various neurodegenerative diseases, J. Neuropathol. Exp. Neurol. source

      Not checked in the free run.

    • cites [86] SantaCruz, 2004, Regional NAD(P)H:quinone oxidoreductase activity in Alzheimer’s disease, Neurobiol. Aging source

      Not checked in the free run.

    • cites [87] Wang, 2000, NAD(P)H:quinone oxidoreductase activity is increased in hippocampal pyramidal neurons of patients with Aalzheimer’s disease, Neurobiol. Aging source

      Not checked in the free run.

    • cites [88] Ramsey, 2007, Expression of Nrf2 in neurodegenerative diseases, J. Neuropathol. Exp. Neurol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    These data are inconclusive but suggest a possible gender-specific impact on synaptic density in the hippocampus after CAW treatment.

    “These data are inconclusive but suggest a possible gender-specific impact on synaptic density in the hippocampus after CAW treatment, which requires further study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    CAW treatment promotes an antioxidative response in opposition to increased oxidative stress driven by Aβ pathology, which mitigates neuritic dystrophy in neurons surrounding amyloid plaques and ultimately maintains cognitive function.

    “Therefore, we postulate that CAW treatment promotes an antioxidative response in opposition to increased oxidative stress driven by Aβ pathology, which mitigates neuritic dystrophy in neurons surrounding the amyloid plaques that ultimately maintains cognitive function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Certain CAW active compounds increase learning and memory and provide neuroprotection in rodents in vivo.

    “The neurological effects of certain CAW active compounds are also observed in vivo, increasing learning and memory while providing neuroprotection in rodents [2,13,112].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [2] Xu, 2012, Asiatic acid, a pentacyclic triterpene in Centella asiatica, attenuates glutamate-induced cognitive deficits in mice and apoptosis in SH-SY5Y cells, Acta Pharmacol. Sin source

      Not checked in the free run.

    • cites [13] Soumyanath, 2012, Centella asiatica Extract Improves Behavioral Deficits in a Mouse Model of Alzheimer’s Disease: Investigation of a Possible Mechanism of Action, Int. J. Alzheimers Dis.

      Not checked in the free run.

    • cites [112] Han, 2010, Neuroprotective effect of 3,5-di-O-caffeoylquinic acid on SH-SY5Y cells and senescence-accelerated-prone mice 8 through the up-regulation of phosphoglycerate kinase-1, Neuroscience source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Memory improvement with CAW treatment may be attributed to an increase in ARE gene expression primarily in the hippocampus, indicating a putative reduction in oxidative stress.

    “The memory improvement with CAW treatment may be attributed to an increase in ARE gene expression, primarily in the hippocampus, indicating a putative reduction in oxidative stress in addition to the natural cellular response to pathology.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In vitro studies show CAW whole extract and isolated compounds facilitate neurite outgrowth and elicit neuroprotection.

    “Previously, in vitro studies have shown that both CAW whole extract and isolated compounds (detailed in a review [32]) facilitate neurite outgrowth [6,28,106], and elicit neuroprotection [107,108,109,110,111].”
    Quote in the paperNot a substantial claim0 of 9 sources checked
    • cites [32] Gray, 2018, Centella asiatica: Phytochemistry and mechanisms of neuroprotection and cognitive enhancement, Phytochem. Rev. source

      Not checked in the free run.

    • cites [6] Soumyanath, 2005, Centella asiatica accelerates nerve regeneration upon oral administration and contains multiple active fractions increasing neurite elongation in-vitro, J. Pharm. Pharmacol. source

      Not checked in the free run.

    • cites [28] Gray, 2017, Centella asiatica attenuates Abeta-induced neurodegenerative spine loss and dendritic simplification, Neurosci. Lett. source

      Not checked in the free run.

    • cites [106] Nalinratana, 2018, Differences in Neuritogenic Activity and Signaling Activation of Madecassoside, Asiaticoside, and Their Aglycones in Neuro-2a cells, Planta Med. source

      Not checked in the free run.

    • cites [107] Zhang, 2012, Asiatic acid protects primary neurons against C2-ceramide-induced apoptosis, Eur. J. Pharmacol. source

      Not checked in the free run.

    • cites [108] Park, 2017, Asiatic acid attenuates methamphetamine-induced neuroinflammation and neurotoxicity through blocking of NF-kB/STAT3/ERK and mitochondria-mediated apoptosis pathway, J. Neuroinflamm. source

      Not checked in the free run.

    • cites [109] Murakami, 2011, SOD1 (copper/zinc superoxide dismutase) deficiency drives amyloid beta protein oligomerization and memory loss in mouse model of Alzheimer disease, J. Biol. Chem. source

      Not checked in the free run.

    • cites [110] Sun, 2015, Nerve Protective Effect of Asiaticoside against Ischemia-Hypoxia in Cultured Rat Cortex Neurons, Med. Sci. Monit. source

      Not checked in the free run.

    • cites [111] Lee, 2014, Neuroprotective effect of asiatic acid in rat model of focal embolic stroke, Biol. Pharm. Bull. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Previous studies observed increased hippocampal and cortical mitochondrial gene expression and increased mitochondrial activity in response to CAW treatment.

    “We have previously observed increased hippocampal and cortical mitochondrial gene expression [46] and increased mitochondrial activity [33] in response to CAW treatment.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [46] Gray, 2016, Centella asiatica modulates antioxidant and mitochondrial pathways and improves cognitive function in mice, J. Ethnopharmacol. source

      Not checked in the free run.

    • cites [33] Gray, 2018, Centella asiatica attenuates hippocampal mitochondrial dysfunction and improves memory and executive function in beta-amyloid overexpressing mice, Mol. Cell. Neurosci. source

      Not checked in the free run.

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

    Premisecitation

    Cell culture models show CAW mitigates tau expression and phosphorylation.

    “although we have implemented cell culture models which show CAW’s ability to mitigate tau expression and phosphorylation [113].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Gray, 2014, Caffeoylquinic acids in Centella asiatica protect against amyloid-beta toxicity, J. Alzheimers Dis. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    CAW provides a neuroprotective effect against Aβ toxicity through attenuation of oxidative stress and possible mitigation of neuritic dystrophy around plaques.

    “We interpret the improvement in behavior to mean that CAW provides a neuroprotective effect against Aβ toxicity through the attenuation of oxidative stress and possible mitigation of neuritic dystrophy around the plaques, as the brain Aβ load is unchanged by treatment (Figure 7).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Previous research using antioxidant therapies reduced oxidative stress and demonstrated reversible neuritic dystrophy in APP/PS1 transgenic mice.

    “This is supported by previous research, which utilized antioxidant therapies to reduce oxidative stress and demonstrated the reversible nature of the neuritic dystrophy observed due to AD pathology in APP/PS1 transgenic mice [105].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [105] Dodwell, 2006, Plaque-derived oxidative stress mediates distorted neurite trajectories in the Alzheimer mouse model, J. Neuropathol. Exp. Neurol. source

      Not checked in the free run.

53 of 53

  • The paper relies on this without support.

    CAW's effects observed in 5XFAD and WT mice are predictive of benefits in humans.

    “suggesting a potential benefit to both men and women in upcoming clinical trials.”

  • The paper relies on this without support.

    In WT mice, only baseline levels of oxidative stress are present.

    “where only baseline levels of oxidative stress would be expected to be present.”
2 of 2

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?

  • Activation of Nrf2 by Centella asiatica extracts improved mitochondrial and cognitive function and enhanced synaptic density in Alzheimer's disease and aging mouse models.

    “Another Nrf2 activating compound is Centella asiatica extracts, which can activate Nrf2 in neuroblastoma cells, isolated primary neurons and in the brains of AD and aging mouse models. This activation improved mitochondrial and cognitive function, and enhanced synaptic density [113,114,115].”

    From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [115]

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.

  • Prior Tg2576 treatment duration differs

    Minor

    The same prior study of female Tg2576 mice at 200 mg/kg/day is described as lasting five weeks in the introduction but four weeks in the discussion.

  • Cortical SOD1 trend has the opposite effect sign

    Minor

    The 500 mg/kg/d cortical SOD1 result is presented as a trend toward the reduction seen at 1000 mg/kg/d, but its t-statistic is positive while the reduction at 1000 mg/kg/d has a negative t-statistic. For comparisons against the same untreated control, those signs indicate opposite directions.

2 of 2

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Related

Authors
Matthews, D. G., Caruso, M., Murchison, C. F., Zhu, J. Y., Wright, K. M., Harris, C. J., Gray, N. E., Quinn, J. F., & Soumyanath, A.
Affiliations
Oregon Health & Science University (US)
Corresponding author
Soumyanath, Amala
ORCID
Venue
Antioxidants
Publisher
MDPI AG
Published
2019-12-08
Volume
8
Issue
12
Pages
630
ISSN
2076-3921 (ISSN-L)
DOI
10.3390/antiox8120630
PMC
PMC6943631
OpenAlex
W2993032584
Semantic Scholar
1ea73924fd4da6a189545c0575f4775b15177e43
Cited by
86
References
116
Citations by year
2026: 10 · 2025: 15 · 2024: 17 · 2023: 9 · 2022: 12 · 2021: 14 · 2020: 8 · 2018: 1
FWCI
10.96
Type
journal article
Language
en
Open access
Licence
Locations
  • Antioxidants (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Center for Complementary and Integrative Health (R01AT008099, 5T32AT002688-14, R00AT008831)
  • U.S. Department of Veterans Affairs (IO1BX003440)
Topics
  • Health Sciences › Medicine › Complementary and alternative medicine › Medicinal Plants and Neuroprotection
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
Centella asiatica, 5xFAD mice, Alzheimer's disease, memory enhancement, cognitive function, oxidative stress, Nrf2, antioxidant response, amyloid plaques, synaptic density, heme oxygenase-1, GCLC, SOD1, hippocampus, prefrontal cortex, traditional medicine

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 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

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