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Cited by 99Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Neuronally-directed effects of RXR activation in a mouse model of Alzheimer’s disease

Open access
Mariani, M. M., Malm, T., Lamb, R., Jay, T. R., Neilson, L., Casali, B., Medarametla, L., Landreth, G. E.·2017·Scientific Reports
DOI 10.1038/srep42270PMC PMC5311933
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Abstract

Alzheimer’s disease (AD) is characterized by extensive neuron loss that accompanies profound impairments in memory and cognition. We examined the neuronally directed effects of the retinoid X receptor agonist bexarotene in an aggressive model of AD. We report that a two week treatment of 3.5 month old 5XFAD mice with bexarotene resulted in the clearance of intraneuronal amyloid deposits. Importantly, neuronal loss was attenuated by 44% in the subiculum in mice 4 months of age and 18% in layer V of the cortex in mice 8 months of age. Moreover, bexarotene treatment improved remote memory stabilization in fear conditioned mice and improved olfactory cross habituation. These improvements in neuron viability and function were correlated with significant increases in the levels of post-synaptic marker PSD95 and the pre-synaptic marker synaptophysin. Moreover, bexarotene pretreatment improved neuron survival in primary 5XFAD neurons in vitro in response to glutamate-induced excitotoxicity. The salutary effects of bexarotene were accompanied by reduced plaque burden, decreased astrogliosis, and suppression of inflammatory gene expression. Collectively, these data provide evidence that bexarotene treatment reduced neuron loss, elevated levels of markers of synaptic integrity that was linked to improved cognition and in an aggressive model of AD.

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Written from the paper’s full text.

TL;DR

In an aggressive 5XFAD mouse model of Alzheimer’s disease, two weeks of bexarotene treatment reduced intraneuronal APP/Aβ, attenuated neuronal loss, improved remote memory and olfactory discrimination, and increased synaptic markers. The effects were accompanied by reduced plaque burden, decreased astrogliosis, and suppressed inflammatory gene expression.

Key findings

  • Bexarotene reduced intraneuronal 6E10 staining in layer V neurons of 4-month-old 5XFAD mice, including both the number of 6E10-positive neurons and their mean fluorescence intensity; smaller significant reduction in layer IV, no effect in layer II/III.
  • In the subiculum, 5XFAD mice had 39% fewer neurons than non-transgenic mice, while bexarotene-treated 5XFAD mice had only a 22% reduction, corresponding to a 44% increase in survival after two weeks of treatment. In cortical layer V at 8 months, 5XFAD mice lost 27% of neurons; bexarotene attenuated loss by 18%, but this trend did not reach significance.
  • Bexarotene improved remote memory stabilization in fear-conditioned mice at 4 or 8 months and improved olfactory cross-habituation at 8 months. Treatment also increased PSD95 and synaptophysin levels.
  • Bexarotene reduced plaque area, decreased GFAP area in the subiculum, and decreased mRNA levels of IL-6, IL-1β, and TNF-α; Iba-1 area was not significantly reduced. No significant reductions in Aβ40 or Aβ42 were found after 15 days in 4-month 5XFAD mice, while at 8 months treatment significantly reduced both soluble and insoluble Aβ40.

Methods

  • 5XFAD mice were treated with bexarotene (Targretin) by oral gavage at 100 mg/kg daily for 15 days beginning at either 3.5 or 7.5 months of age; vehicle-treated mice received water only. Treatment groups were gender-balanced littermates (n = 9–14), randomly assigned.
  • Outcomes included immunohistochemistry for 6E10, NeuN, GFAP, Iba-1, Aβ40, Aβ42, APP, β-CTF, and APLP2; western blotting for PSD95, synaptophysin, ApoE, ABCA1, and ABCG1; qRT-PCR for inflammatory genes; ELISA for soluble/insoluble Aβ40/42; primary cortical neuronal cultures with glutamate excitotoxicity; and behavioral tests for olfactory cross-habituation and remote memory stabilization.
  • Statistical analysis used one-way ANOVA with repeated measures, post-hoc Tukey tests, and paired t-tests for plaque area and number; significance was set at p < 0.05.

Limitations

  • The paper states that it cannot yet clearly distinguish the direct neuronal actions of bexarotene from its glial actions, and that the ability of bexarotene to broadly stimulate autophagy remains speculative.
  • The paper reports that the cortical layer V attenuation of neuronal loss did not reach significance, likely reflecting the longer period of neuronal loss relative to the short drug treatment.
  • The paper notes that prior literature shows drug formulation critically affects bexarotene pharmacodynamics, which may explain variability in plaque and soluble Aβ results across studies.

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Integrity signals

Registry

Crossref · 10.1038/srep42270

Cites

64 of 64 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

0 of 74 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In 4-month-old 5XFAD cortex, neurons show immunoreactivity to both N-terminal and β-CTF specific antibodies.

    “We found immunoreactivity to both N-terminal and β-CTF specific antibodies in the cells located in the cortex (Fig. 1).”
    Quote in the paperSubstantial claim
  • Findingown data

    Bexarotene treatment significantly improved odor discrimination in 8-month-old 5XFAD mice.

    “which was significantly improved after bexarotene treatment (Fig. 6).”
    Quote in the paperSubstantial claim
  • Findingown data

    Olfaction cross-habituation deficits were first detected at 8 months of age in 5XFAD mice.

    “Olfaction cross-habituation deficits were first detected first at 8 months of age”
    Quote in the paperNot a substantial claim
  • Findingown data

    After 15 days of treatment, bexarotene decreased all three inflammatory mediators IL-6, IL-1β, and TNF-α in cortical and hippocampal brain homogenates of 4-month-old 5XFAD mice.

    “After 15 days of treatment, bexarotene decreased all three inflammatory mediators examined (Fig. 8).”
    Quote in the paperSubstantial claim
  • Findingreasoning

    Bexarotene treatment increased survival of subicular neurons by 44% with two weeks of drug treatment.

    “Thus bexarotene treatment increased survival of subicular neurons by 44% with two weeks of drug treatment.”
    Quote in the paperSubstantial claim
  • The quote only partly states this claim. 3
  • May combine two claims. 31
  • Classified as probably not a substantial claim. 17

  • The quote only partly states this claim.

    Findingown data

    SORLA extensively accumulates throughout 6E10 positive neurons in the cortex of 4-month-old 5XFAD mice.

    “Typically, SORLA is found on endosomes, however we observed the extensive accumulation of this protein throughout the 6E10 positive neurons in the cortex (Fig. 2)”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Aβ42 represents only a small fraction of the intraneuronal material in 4-month-old 5XFAD cortex and is found with a punctate distribution.

    “However, examination of Aβ42 deposition, the principal Aβ peptide present in this model, revealed that this species represented only a small fraction of the material detected intraneuronally and was found with a punctate distribution, as reported previously (Fig. 1)13.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    APLP2 accumulates in the same neurons bearing elevated 6E10 immunoreactivity and with a similar distribution in 4-month-old 5XFAD cortex.

    “APLP2 was accumulated in the same neurons bearing elevated levels of 6E10 immunoreactivity and with a similar distribution (Fig. 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Bexarotene treatment modestly attenuated neuronal loss in layer V cortex at 8 months by 18%, but this trend did not reach significance.

    “Bexarotene treatment modestly attenuated the neuronal loss (18%), but this trend did not reach significance (Fig. 4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Plaque area was significantly reduced upon bexarotene treatment in either the subiculum at 4 months of age or in the cortex at 8 months of age.

    “Plaque area was significantly reduced upon treatment in either the subiculum at 4 months of age or in the cortex at 8 months of age (Supplemental Fig. 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Bexarotene treatment increased APOE expression and lipidation status, as well as ABCA1 and ABCG1 expression.

    “As expected, bexarotene treatment increased APOE expression and lipidation status, as well as, ABCA1 and ABCG1 expression providing a positive control for drug action in the brain (Supplemental Fig. 2, data not shown)8.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Both the number of 6E10 positive neurons in layer V and their mean fluorescence intensity were reduced after bexarotene treatment.

    “We found that both the number of 6E10 positive neurons in layer V and their mean fluorescence intensity were reduced after bexarotene treatment (Fig. 3).”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data

    Bexarotene treatment produced a quantitatively smaller but significant reduction in 6E10 positive neurons in Layer IV.

    “There was a quantitatively smaller, but significant reduction in Layer IV neurons”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    At 8 months of age, 15 day bexarotene treatment significantly reduced both soluble and insoluble Aβ40.

    “Interestingly, at 8 months of age, 15 day treatment significantly reduced both soluble and insoluble Aβ40 (Supplemental Fig. 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Neither SORLA nor APLP2 is overexpressed in the 5XFAD mouse, yet pyramidal neurons display florid co-staining with 6E10.

    “Neither SORLA nor APLP2 is overexpressed in the 5XFAD mouse, yet pyramidal neurons display florid co-staining with 6E10 (Fig. 1).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Bexarotene has been reported to improve memory, cognition, and pathology in mouse models of Alzheimer's disease and aging.

    “Bexarotene has been reported to improve memory, cognition, and pathology in mouse models of AD819 and aging11 and is now in early phase clinical trials2021.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [8] Cramer, P. E. et al. ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science 335, 1503–1506, doi: 10.1126/science.1217697 (2012). source

      Not checked in the free run.

    • cites [19] Fitz, N. F., Cronican, A. A., Lefterov, I. & Koldamova, R. Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”. Science 340, 924-c, doi: 10.1126/science.1235809 (2013). source

      Not checked in the free run.

    • cites [11] Tachibana, M. et al. Rescuing effects of RXR agonist bexarotene on aging-related synapse loss depend on neuronal LRP1. Experimental neurology 277, 1–9, doi: 10.1016/j.expneurol.2015.12.003 (2015). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Nuclear receptors exhibit a broad range of neuronally-directed actions.

    “However, it has recently been appreciated that these nuclear receptors exhibit a broad range of neuronally-directed actions91011121314.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [9] Boehm-Cagan, A. & Michaelson, D. M. Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene. The Journal of neuroscience: the official journal of the Society for Neuroscience 34, 7293–7301, doi: 10.1523/JNEUROSCI.5198-13.2014 (2014). source

      Not checked in the free run.

    • cites [10] Bomben, V. et al. Bexarotene reduces network excitability in models of Alzheimer’s disease and epilepsy. Neurobiology of aging 35, 2091–2095, doi: 10.1016/j.neurobiolaging.2014.03.029 (2014). source

      Not checked in the free run.

    • cites [11] Tachibana, M. et al. Rescuing effects of RXR agonist bexarotene on aging-related synapse loss depend on neuronal LRP1. Experimental neurology 277, 1–9, doi: 10.1016/j.expneurol.2015.12.003 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    5XFAD mice have robust neuritic dystrophy, extracellular amyloid deposition, and gliosis.

    “Moreover, these mice have robust neuritic dystrophy, extracellular amyloid deposition, and gliosis.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [16] Oakley, H. et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. The Journal of neuroscience: the official journal of the Society for Neuroscience 26, 10129–10140, doi: 10.1523/JNEUROSCI.1202-06.2006 (2006). source

      Not checked in the free run.

    • cites [17] Moon, M. et al. Intracellular amyloid-beta accumulation in calcium-binding protein-deficient neurons leads to amyloid-beta plaque formation in animal model of Alzheimer’s disease. Journal of Alzheimer’s disease: JAD 29, 615–628, doi: 10.3233/JAD-2011-111778 (2012). source

      Not checked in the free run.

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

    Premisecitation

    Bexarotene has recently been shown to be effective in murine models of Parkinson's disease, ALS, multiple sclerosis, and stroke.

    “Moreover, bexarotene has recently been shown to be effective in murine models of Parkinson’s22, ALS23, multiple sclerosis24 and stroke25.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [22] McFarland, K. et al. Low dose bexarotene treatment rescues dopamine neurons and restores behavioral function in models of Parkinson’s disease. ACS chemical neuroscience 4, 1430–1438, doi: 10.1021/cn400100f (2013). source

      Not checked in the free run.

    • cites [23] Riancho, J., Ruiz-Soto, M., Berciano, M. T., Berciano, J. & Lafarga, M. Neuroprotective Effect of Bexarotene in the SOD1(G93A) Mouse Model of Amyotrophic Lateral Sclerosis. Frontiers in cellular neuroscience 9, 250, doi: 10.3389/fncel.2015.00250 (2015). source

      Not checked in the free run.

    • cites [24] Natrajan, M. S. et al. Retinoid X receptor activation reverses age-related deficiencies in myelin debris phagocytosis and remyelination. Brain: a journal of neurology 138, 3581–3597, doi: 10.1093/brain/awv289 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The 5XFAD model exhibits neuronal death in pyramidal neurons in the subiculum and layer V of the cortex at 4 and 8 months of age, respectively, as well as behavioral deficits.

    “Importantly, the model exhibits neuronal death in pyramidal neurons in the subiculum and layer V of the cortex, at 4 and 8 months of age, respectively as well as behavioral deficits1617.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [16] Oakley, H. et al. Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer’s disease mutations: potential factors in amyloid plaque formation. The Journal of neuroscience: the official journal of the Society for Neuroscience 26, 10129–10140, doi: 10.1523/JNEUROSCI.1202-06.2006 (2006). source

      Not checked in the free run.

    • cites [17] Moon, M. et al. Intracellular amyloid-beta accumulation in calcium-binding protein-deficient neurons leads to amyloid-beta plaque formation in animal model of Alzheimer’s disease. Journal of Alzheimer’s disease: JAD 29, 615–628, doi: 10.3233/JAD-2011-111778 (2012). source

      Not checked in the free run.

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

    Premisecitation

    Several studies have strongly linked accumulation of intraneuronal Aβ to neuron death.

    “Several studies have strongly linked accumulation of intraneuronal Aβ to neuron death17262728.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [17] Moon, M. et al. Intracellular amyloid-beta accumulation in calcium-binding protein-deficient neurons leads to amyloid-beta plaque formation in animal model of Alzheimer’s disease. Journal of Alzheimer’s disease: JAD 29, 615–628, doi: 10.3233/JAD-2011-111778 (2012). source

      Not checked in the free run.

    • cites [26] Christensen, D. Z., Bayer, T. A. & Wirths, O. Intracellular Ass triggers neuron loss in the cholinergic system of the APP/PS1KI mouse model of Alzheimer’s disease. Neurobiology of aging 31, 1153–1163, doi: 10.1016/j.neurobiolaging.2008.07.022 (2010). source

      Not checked in the free run.

    • cites [27] Hu, X. et al. Amyloid seeds formed by cellular uptake, concentration, and aggregation of the amyloid-beta peptide. Proceedings of the National Academy of Sciences of the United States of America 106, 20324–20329, doi: 10.1073/pnas.0911281106 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The robust 6E10 immunoreactivity suggests intraneuronal APP/Aβ processing products are accumulating within neurons, reflecting a generalized impairment of protein processing and trafficking in affected neurons.

    “The robust 6E10 immunoreactivity suggests intraneuronal APP/Aβ processing products are accumulating within neurons, reflecting a generalized impairment of protein processing and trafficking in the affected neurons.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Bexarotene improves neuron survival and reduces intraneuronal APP/Aβ deposition in an aggressive mouse model of Alzheimer's disease.

    “Here we report that bexarotene improves neuron survival and reduces intraneuronal APP/Aβ deposition in an aggressive mouse model of Alzheimer’s disease.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    5XFAD mice have reduced cathepsin D activity and decreased N-glycosylation of v-ATPase, indicative of elevated lysosomal pH and impairment of normal proteolytic degradation of proteins including Aβ.

    “5XFAD mice have reduced cathepsin D activity and decreased N-glycosylation of v-ATPase, which is indicative of elevated lysosomal pH and impairment of normal proteolytic degradation of proteins including Aβ35.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Avrahami, L. et al. Inhibition of glycogen synthase kinase-3 ameliorates beta-amyloid pathology and restores lysosomal acidification and mammalian target of rapamycin activity in the Alzheimer disease mouse model: in vivo and in vitro studies. The Journal of biological chemistry 288, 1295–1306, doi: 10.1074/jbc.M112.409250 (2013). source

      Not checked in the free run.

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

    Premisecitation

    The plaque-reducing effect of nuclear receptor agonists has recently been shown to result from their actions on plaque-associated macrophages, which licensed and stimulated their phagocytic actions.

    “This effect has recently been shown to result from the actions of nuclear receptor agonists on plaque-associated macrophages, which licensed and stimulated their phagocytic actions6.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Savage, J. C. et al. Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer’s disease. The Journal of neuroscience: the official journal of the Society for Neuroscience 35, 6532–6543, doi: 10.1523/JNEUROSCI.4586-14.2015 (2015). source

      Not checked in the free run.

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

    Premisecitation

    Ohno and colleagues identified full-length APP and β-CTF in the mitochondria of 5XFAD mice.

    “Ohno and colleagues identified full-length APP and β-CTF in the mitochondria of 5XFAD mice.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Devi, L. & Ohno, M. Mitochondrial dysfunction and accumulation of the beta-secretase-cleaved C-terminal fragment of APP in Alzheimer’s disease transgenic mice. Neurobiology of disease 45, 417–424, doi: 10.1016/j.nbd.2011.09.001 (2012). source

      Not checked in the free run.

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

    Premisecitation

    PS1 is essential for v-ATPase targeting to lysosomes and lysosome acidification.

    “The Nixon laboratory has demonstrated that PS1 is essential for v-ATPase targeting to lysosomes and lysosome acidification3637.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [36] Lee, J. H. et al. Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 141, 1146–1158, doi: 10.1016/j.cell.2010.05.008 (2010). source

      Not checked in the free run.

    • cites [37] Wolfe, D. M. et al. Autophagy failure in Alzheimer’s disease and the role of defective lysosomal acidification. The European journal of neuroscience 37, 1949–1961, doi: 10.1111/ejn.12169 (2013). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    A blinded analysis was conducted to assess mean fluorescence intensity of individual neuron's 6E10 staining and the number of 6E10 positive neurons.

    “A blinded analysis was conducted to assess the mean fluorescence intensity of individual neuron’s 6E10 staining, as well as the number of 6E10 positive neurons.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Bexarotene treatment decreased accumulation of Aβ42 and hyperphosphorylated tau in hippocampal neurons, and increased VGluT1 in APOE4-knock-in mice.

    “Moreover, bexarotene treatment decreased accumulation of Aβ42 and hyperphosphorylated tau in hippocampal neurons, and increased vesicular glutamatergic transporter 1 (VGluT1) in the APOE4-knock-in mice9.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Boehm-Cagan, A. & Michaelson, D. M. Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene. The Journal of neuroscience: the official journal of the Society for Neuroscience 34, 7293–7301, doi: 10.1523/JNEUROSCI.5198-13.2014 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Savage et al. demonstrated bexarotene treatment improved ex vivo slice phagocytosis of microglia and macrophage in APP/PS1Δe9 mice, and reduced plaque burden in the hippocampus in vivo.

    “Additionally, Savage et al. demonstrated bexarotene treatment improved ex vivo slice phagocytosis of microglia and macrophage in APP/PS1Δe9 mice, and reduced plaque burden in the hippocampus in vivo6.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Savage, J. C. et al. Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer’s disease. The Journal of neuroscience: the official journal of the Society for Neuroscience 35, 6532–6543, doi: 10.1523/JNEUROSCI.4586-14.2015 (2015). source

      Not checked in the free run.

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

    Premisecitation

    Eimer et al. characterized accumulation of intraneuronal Aβ42 throughout the endosomal-lysosomal system with LAMP-1 and the transferrin receptor co-localized with Aβ42.

    “Moreover, Eimer et al. characterized accumulation of intraneuronal Aβ42 throughout the endosomal-lysosomal system with LAMP-1 and the transferrin receptor co-localized with Aβ4218.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Eimer, W. A. & Vassar, R. Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Abeta42 accumulation and Caspase-3 activation. Molecular neurodegeneration 8, 2, doi: 10.1186/1750-1326-8-2 (2013). source

      Not checked in the free run.

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

    Premisecitation

    Boehem-Cagan et al. reported enhanced apoE lipidation in E4-knock-in mice, restored cognitive performance, and increased synaptic markers with bexarotene treatment.

    “Boehem-Cagan et al. reported enhanced apoE lipidation in E4-knock-in mice, restored cognitive performance, and increased synaptic markers with bexarotene treatment9.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Boehm-Cagan, A. & Michaelson, D. M. Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene. The Journal of neuroscience: the official journal of the Society for Neuroscience 34, 7293–7301, doi: 10.1523/JNEUROSCI.5198-13.2014 (2014). source

      Not checked in the free run.

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

    Premisecitation

    Bexarotene has recently been reported to have salutary effects on a number of animal models of CNS disorders including models of Alzheimer's disease, ALS, Parkinson's disease, multiple sclerosis, epilepsy, hypertension, and stroke.

    “Bexarotene has recently been reported to have salutary effects on a number of animal models of CNS disorders including models of AD, ALS, Parkinson’s disease, multiple sclerosis epilepsy, hypertension, and stroke91022235051.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [9] Boehm-Cagan, A. & Michaelson, D. M. Reversal of apoE4-driven brain pathology and behavioral deficits by bexarotene. The Journal of neuroscience: the official journal of the Society for Neuroscience 34, 7293–7301, doi: 10.1523/JNEUROSCI.5198-13.2014 (2014). source

      Not checked in the free run.

    • cites [10] Bomben, V. et al. Bexarotene reduces network excitability in models of Alzheimer’s disease and epilepsy. Neurobiology of aging 35, 2091–2095, doi: 10.1016/j.neurobiolaging.2014.03.029 (2014). source

      Not checked in the free run.

    • cites [22] McFarland, K. et al. Low dose bexarotene treatment rescues dopamine neurons and restores behavioral function in models of Parkinson’s disease. ACS chemical neuroscience 4, 1430–1438, doi: 10.1021/cn400100f (2013). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    APLP2, like APP, exhibits robust accumulation with the same neuronal vesicular compartments, reflecting a generalized dysregulation of the endolytic system that is ameliorated by bexarotene treatment.

    “APLP2, like APP, exhibits robust accumulation with the same neuronal vesicular compartments, reflecting a generalized dysregulation of the endolytic system that is ameliorated by bexarotene treatment.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    These data corroborate our own data demonstrating that bexarotene can be neuroprotective and can reduce intraneuronal accumulations of APP and β-CTF.

    “These data corroborate our own data demonstrating that bexarotene can be neuroprotective and can reduce intraneuronal accumulations of APP and β-CTF (Fig. 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Bomben et al. demonstrated that bexarotene suppressed Aβ-dependent increases in control network hyperexcitability and reduced seizures in Kv1.1 mice.

    “Bomben et al. demonstrated that bexarotene supressed Aβ-dependent increases in control network hyperexcitability and reduced seizures in Kv1.1 mice10.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Bomben, V. et al. Bexarotene reduces network excitability in models of Alzheimer’s disease and epilepsy. Neurobiology of aging 35, 2091–2095, doi: 10.1016/j.neurobiolaging.2014.03.029 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice expressing the human apoE4 isoform have synaptic deficits and impairment in long-term potentiation, memory and cognition.

    “Mice expressing the human apoE4 isoform have synaptic deficits and impairment in long-term potentiation, memory and cognition41.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Kim, J., Yoon, H., Basak, J. & Kim, J. Apolipoprotein E in synaptic plasticity and Alzheimer’s disease: potential cellular and molecular mechanisms. Molecules and cells 37, 767–776, doi: 10.14348/molcells.2014.0248 (2014). source

      Not checked in the free run.

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    Premisecitation

    Mounier et al. found that bexarotene enhanced dendritic complexity in primary neurons, and improved dendritic structure in the hippocampus of human APOE4 knock in mice which had deficits in dendritic branching.

    “Mounier et al. found that bexarotene enhanced dendritic complexity in primary neurons, and improved dendritic structure in the hippocampus of human APOE4 knock in mice which had deficits in dendritic branching12.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [12] Mounier, A. et al. Bexarotene-Activated Retinoid X Receptors Regulate Neuronal Differentiation and Dendritic Complexity. The Journal of neuroscience: the official journal of the Society for Neuroscience 35, 11862–11876, doi: 10.1523/JNEUROSCI.1001-15.2015 (2015). source

      Not checked in the free run.

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    Premisecitation

    Murine models of Alzheimer's disease exhibit a robust inflammatory response and increased levels of pro-inflammatory cytokines which are postulated to contribute to neuronal death.

    “Murine models of AD exhibit a robust inflammatory response and increased levels of pro-inflammatory cytokines which are postulated to contribute to neuronal death525354.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [52] Lyman, M., Lloyd, D. G., Ji, X., Vizcaychipi, M. P. & Ma, D. Neuroinflammation: the role and consequences. Neuroscience research 79, 1–12, doi: 10.1016/j.neures.2013.10.004 (2014). source

      Not checked in the free run.

    • cites [53] Neumann, H. et al. Tumor necrosis factor inhibits neurite outgrowth and branching of hippocampal neurons by a rho-dependent mechanism. The Journal of neuroscience: the official journal of the Society for Neuroscience 22, 854–862 (2002). source

      Not checked in the free run.

    • cites [54] Ricci, G., Volpi, L., Pasquali, L., Petrozzi, L. & Siciliano, G. Astrocyte-neuron interactions in neurological disorders. Journal of biological physics 35, 317–336, doi: 10.1007/s10867-009-9157-9 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tachibana et al. demonstrated that bexarotene increased pre- and post-synaptic marker expression in aged mice but not in bexarotene treated nLrp1−/− mice.

    “Tachibana et al. have clearly demonstrated that bexarotene increased pre- and post-synaptic marker expression in aged mice but not in bexarotene treated nLrp1−/− mice11.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Tachibana, M. et al. Rescuing effects of RXR agonist bexarotene on aging-related synapse loss depend on neuronal LRP1. Experimental neurology 277, 1–9, doi: 10.1016/j.expneurol.2015.12.003 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Other laboratories were unable to replicate the loss of plaques and the reduction of soluble forms of Aβ was variably observed, including studies in the 5XFAD mice.

    “However, other laboratories were unable to replicate the loss of plaques and the reduction of soluble forms of Aβ was variably observed, including studies in the 5XFAD mice48.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Veeraraghavalu, K. et al. Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”. Science 340, 924-f, doi: 10.1126/science.1235505 (2013). source

      Not checked in the free run.

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

    Premisecitation

    Autophagy may also be increased or improperly functioning, as evidenced by detection of elevated LC3B-II protein levels.

    “Autophagy may also be increased or improperly functioning, as evidenced by detection of elevated LC3B-II protein levels39.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Kandalepas, P. C. et al. The Alzheimer’s beta-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques. Acta neuropathologica 126, 329–352, doi: 10.1007/s00401-013-1152-3 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Collectively, these data indicate that apoE is critical for neuron structure and function, and that increased production or lipidation of apoE through bexarotene administration can overcome apoE4-induced deficits.

    “Collectively, these data indicate that apoE is critical for neuron structure and function, and that increased production or lipidation of apoE through bexarotene administration can overcome apoeE4-induced deficits.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The FDA approved formulation (Targretin TM) is a microcrystalline form which is slowly absorbed, compared to solubilized preparations which are rapidly cleared.

    “The FDA approved formulation (Targretin TM) is a microcrystalline form which is slowly absorbed, compared to solubilized preparations which are rapidly cleared.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Chen, L. et al. Bexarotene nanocrystal-Oral and parenteral formulation development, characterization and pharmacokinetic evaluation. European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 87, 160–169, doi: 10.1016/j.ejpb.2013.12.005 (2014). source

      Not checked in the free run.

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

    Premisecitation

    McFarland reported that bexarotene acted to stimulate the activity of the nuclear receptor Nurr1 in an animal model of Parkinson's disease through Nurr1-RXR heterodimers.

    “Significantly, McFarland reported that bexarotene acted to stimulate the activity of the nuclear receptor Nurr1 in an animal model of PD through Nurr1-RXR heterodimers22.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] McFarland, K. et al. Low dose bexarotene treatment rescues dopamine neurons and restores behavioral function in models of Parkinson’s disease. ACS chemical neuroscience 4, 1430–1438, doi: 10.1021/cn400100f (2013). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The reduced presence of TNFα, IL-1β, and IL-6 in the neuron microenvironment may have improved neuron survival and increased resistance to glutamate excitotoxicity.

    “The reduced presence of TNFα, IL-1β, and IL-6 in the neuron microenvironment may have improved neuron survival and increased resistance to glutamate excitotoxicity60.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Treatment groups were randomly assigned to treatment.

    “Treatment groups were composed of gender balanced littermates (n = 9–14), randomly assigned to treatment.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    Olfactory habituation testing was recorded by a single observer blinded to genotype and treatment.

    “The duration of time spent investigating was defined as snout-oriented sniffing within 1 cm of the odor presentation port, and was recorded across all trials by a single observer blinded to genotype and treatment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Nuclear receptors act to suppress proinflammatory gene expression through transrepression of NF-κB, as well as inducing lipid-dependent suppression of inflammation signaling pathways.

    “Nuclear receptors act to suppress proinflammatory gene expression through transrepression of NF-κB557, as well as inducing lipid-dependent suppression of inflammation signaling pathways5859.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [55] Bhaskar, K. et al. Microglial derived tumor necrosis factor-alpha drives Alzheimer’s disease-related neuronal cell cycle events. Neurobiology of disease 62, 273–285, doi: 10.1016/j.nbd.2013.10.007 (2014). source

      Not checked in the free run.

    • cites [57] Na, S. Y. et al. Retinoids inhibit interleukin-12 production in macrophages through physical associations of retinoid X receptor and NFkappaB. The Journal of biological chemistry 274, 7674–7680 (1999). source

      Not checked in the free run.

    • cites [58] Ito, A. et al. LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling. eLife 4, e08009, doi: 10.7554/eLife.08009 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TNFα, IL-1β, and IL-6 are pro-inflammatory cytokines secreted by microglia and astrocytes, and have been shown to cause neuronal dysfunction and death.

    “TNFα, IL-1β, and IL-6 are pro-inflammatory cytokines secreted by microglia and astrocytes, and have been shown to cause neuronal dysfunction and death53545556.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [53] Neumann, H. et al. Tumor necrosis factor inhibits neurite outgrowth and branching of hippocampal neurons by a rho-dependent mechanism. The Journal of neuroscience: the official journal of the Society for Neuroscience 22, 854–862 (2002). source

      Not checked in the free run.

    • cites [54] Ricci, G., Volpi, L., Pasquali, L., Petrozzi, L. & Siciliano, G. Astrocyte-neuron interactions in neurological disorders. Journal of biological physics 35, 317–336, doi: 10.1007/s10867-009-9157-9 (2009). source

      Not checked in the free run.

    • cites [55] Bhaskar, K. et al. Microglial derived tumor necrosis factor-alpha drives Alzheimer’s disease-related neuronal cell cycle events. Neurobiology of disease 62, 273–285, doi: 10.1016/j.nbd.2013.10.007 (2014). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    NeuN positive neurons were counted and normalized to area by an observer blinded to genotype and treatment.

    “NeuN positive neurons were manually counted, using Photoshop, in the subiculum and cortical layer V from each animal and normalized to area by an observer blinded to genotype and treatment.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Immunoreactivity was quantified by a user blinded to the study groups.

    “Immunoreactivity was quantified with ImagePro Premium (Media Cybernetics, Rockville, MD, USA) by a user blinded to the study groups.”
    Quote in the paperSubstantial claim
47 of 47

  • The paper relies on this without support.

    The composition of intraneuronal Aβ-containing deposits in 5XFAD mice had not been firmly established.

    “However, the composition of intraneuronal Aβ-containing deposits in 5XFAD mice had not been firmly established.”

  • The paper relies on this without support.

    It was unknown whether bexarotene would be effective in a very aggressive model of amyloidosis with neuronal death.

    “However, it was unknown if bexarotene would be effective in a very aggressive model of model of amyloidosis with neuronal death.”
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?

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.

  • Discussion points to the synaptic-marker figure for inflammation results

    Minor

    The Discussion cites Fig. 7 for reduced inflammatory cytokines, but the Results assign cytokine measurements to Fig. 8 and synaptic-marker measurements to Fig. 7.

1 of 1

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Authors
Mariani, M. M., Malm, T., Lamb, R., Jay, T. R., Neilson, L., Casali, B., Medarametla, L., & Landreth, G. E.
Affiliations
  • Case Western Reserve University (US)
  • University of Eastern Finland (FI)
Corresponding author
  • Mariani, M. M.
  • Landreth, G. E.
ORCID
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2017-02-16
Volume
7
Issue
1
Pages
42270-42270
ISSN
2045-2322 (ISSN-L)
DOI
10.1038/srep42270
PMC
PMC5311933
OpenAlex
W2587821175
Cited by
98
References
64
Citations by year
2026: 3 · 2025: 6 · 2024: 4 · 2023: 12 · 2022: 10 · 2021: 14 · 2020: 15 · 2019: 18 · 2018: 9 · 2017: 6 · 2013: 1
FWCI
9.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Scientific Reports (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UEF eRepo (University of Eastern Finland) (submittedVersion, cc-by)
  • UEF eRepo (University of Eastern Finland) (submittedVersion)
Funders
  • Weston Brain Institute
  • National Institutes of Health
  • National Institute on Aging (F32AG046039, RF1AG050597)
  • National Institute of Neurological Disorders and Stroke (R56NS084856)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, bexarotene, retinoid X receptor agonist, 5xFAD mice, amyloid plaque clearance, neuronal loss, subiculum, cortical layer V, remote memory, fear conditioning, PSD-95, synaptophysin, synaptic integrity, glutamate excitotoxicity, astrocyte activation, neuroinflammation, cognitive impairment
MeSH terms
Bexarotene, Alzheimer Disease, Animals, Cell Survival, Disease Models, Animal, Female, Gliosis, Habituation, Psychophysiologic, Hippocampus, Inflammation, Male, Memory, Mice, Transgenic, Neurons, Neurotoxins, Olfactory Bulb, Receptors, LDL, Synapses, Tetrahydronaphthalenes, Biomarkers, Cytokines, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Glutamic Acid, Membrane Transport Proteins, Retinoid X Receptors, Plaque, Amyloid

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Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

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