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Cited by 31Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchCholesterol and Lipid Metabolism

The DOI matches its Crossref record; 55 of the 55 references it cites were found in a registry or an index; none of the 72 sources its claims cite is checked for support yet.

ApoB100/LDLR-/- Hypercholesterolaemic Mice as a Model for Mild Cognitive Impairment and Neuronal Damage

Open access
Ramírez, Carlos, Sierra, Saleta, Tercero, Inmaculada, Vázquez, Jose Antonio, Pineda, Antonia, Manrique, Tatiana, Burgos, Javier S.·2011·PLoS ONE
DOI 10.1371/journal.pone.0022712PMC PMC3144244
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Abstract

Recent clinical findings support the notion that the progressive deterioration of cholesterol homeostasis is a central player in Alzheimer's disease (AD). Epidemiological studies suggest that high midlife plasma total cholesterol levels are associated with an increased risk of AD. This paper reports the plasma cholesterol concentrations, cognitive performance, locomotor activity and neuropathological signs in a murine model (transgenic mice expressing apoB100 but knockout for the LDL receptor [LDLR]) of human familial hypercholesterolaemia (FH). From birth, these animals have markedly elevated LDL-cholesterol and apolipoprotein B100 (apoB100) levels. These transgenic mice were confirmed to have higher plasma cholesterol concentrations than wild-type mice, an effect potentiated by aging. Further, 3-month-old transgenic mice showed cholesterol (total and fractions) concentrations considerably higher than those of 18-month-old wild-type mice. The hypercholesterolaemia of the transgenic mice was associated with a clear locomotor deficit (as determined by rotarod, grip strength and open field testing) and impairment of the episodic-like memory (determined by the integrated memory test). This decline in locomotor activity and cognitive status was associated with neuritic dystrophy and/or the disorganization of the neuronal microtubule network, plus an increase in astrogliosis and lipid peroxidation in the brain regions associated with AD, such as the motor and lateral entorhinal cortex, the amygdaloid basal nucleus, and the hippocampus. Aortic atherosclerotic lesions were positively correlated with age, although potentiated by the transgenic genotype, while cerebral β-amyloidosis was positively correlated with genetic background rather than with age. These findings confirm hypercholesterolaemia as a key biomarker for monitoring mild cognitive impairment, and shows these transgenic mice can be used as a model for cognitive and psycho-motor decline.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

ApoB100/LDLR-/- mice, a model of human familial hypercholesterolaemia, show early and severe hypercholesterolaemia accompanied by locomotor deficits, temporal-memory impairment, neuritic dystrophy, oxidative damage, astrogliosis, and cerebrovascular β-amyloidosis. The authors propose these mice as a model for mild cognitive impairment and psychomotor decline associated with hypercholesterolaemia.

Key findings

  • Transgenic mice had significantly higher plasma total cholesterol, free and esterified cholesterol, LDL-cholesterol, apoB, and triglycerides, and lower HDL-cholesterol, at both 3 and 18 months; 3-month-old transgenic mice had higher total cholesterol, free and esterified cholesterol, LDL, and apoB than 18-month-old wild-type mice.
  • Behaviourally, aged transgenic mice had shorter rotarod fall latencies than aged wild-type mice (p<0.05); 3-month-old transgenic mice had reduced grip strength versus young wild-type mice (p<0.05); and transgenic mice showed reduced vertical activity and increased immobility in the open field, with immobility increasing with age (p<0.05).
  • In the integrated memory test, 3- and 18-month-old transgenic mice had significantly lower temporal-memory ratios than wild-type mice of the same ages (p<0.05), while 18-month-old transgenic mice had poorer spatial memory than 3-month-old transgenic mice (p<0.05).
  • Neuropathologically, transgenic mice showed reduced MAP2 staining in the lateral entorhinal cortex and amygdaloid basal nucleus, stronger HNE staining in hippocampus and amygdala at 18 versus 3 months, increased GFAP-positive activated astrocytes, and early cerebrovascular β-amyloid deposits; aortic atherosclerosis scores were 1.5±0.3 in 18-month transgenic, 0.6±0.2 in 3-month transgenic, 0.9±0.3 in 18-month wild-type, and 0.0±0.0 in 3-month wild-type mice.

Methods

  • Male homozygous apoB100/LDLR-/- transgenic mice and male wild-type C57Bl/6 mice were studied at 3 and 18 months of age; mice were housed under a 12L/12D photoperiod with free access to food and water.
  • Plasma total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, and apoB were measured spectrophotometrically; free and esterified cholesterol were measured fluorometrically.
  • Behaviour was assessed with grip strength, accelerating rotarod, open field, and an integrated memory test for temporal and spatial order memory; brain and aorta were analysed by immunohistochemistry for MAP2, HNE, and GFAP, by Congo red and 4G8 for β-amyloid, and by Van Gieson staining for aortic atherosclerosis scored 0–3 by two blinded investigators.
  • Statistical analysis used one-way ANOVA with Newman-Keuls post-hoc tests, two-tailed t tests against a preset ratio of 1, and one-tailed t tests between genotype/age groups, with significance at p<0.05.

Limitations

  • The paper does not state a dedicated limitations section.
  • Evident from the text: only male mice were used, selected because they show higher total and LDL-cholesterol than females, so sex-specific effects are not addressed.
  • Evident from the text: group sizes were small (n=6–8 per group in behavioural tests), and the transgenic mice received no pharmacological treatment or hypercholesterolaemic diet, so the findings are limited to this untreated genetic model.

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

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0022712

Cites

55 of 55 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 72 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In the young transgenic mice, Aβ deposits were detected in the vessel walls similar to those found in the aged wild-type mice.

    “However, in the young transgenic mice, Aβ deposits were detected in the vessel walls similar to those found in the aged wild-type mice.”
    Quote in the paperSubstantial claim
  • Findingown data

    Aged transgenic mice showed significantly shorter fall latencies than aged wild-type mice in the rotarod test.

    “In the rotarod test, the aged transgenic mice showed significantly shorter fall latencies than the aged wild-type mice (p<0.05) (Fig. 2).”
    Quote in the paperSubstantial claim
  • Findingown data

    Young transgenic mouse aortas showed a marked alteration of the classical structure (mean score 0.6±0.2).

    “The young transgenic mouse aortas showed a marked alteration of the classical structure (overall mean score 0.6±0.2)”
    Quote in the paperNot a substantial claim
  • Findingown data

    The dentate gyrus of the hippocampus of 18-month-old wild-type mice showed a strong reduction in dendrite but not axon MAP2 staining compared to young wild-type mice.

    “However, the dentate gyrus of the hippocampus of the 18-month-old wild-type mice showed a strong reduction in dendrite – but not axon - MAP2 staining compared to the young wild-type mice.”
    Quote in the paperNot a substantial claim
  • Findingown data

    The hypercholesterolaemia of the transgenic mice was associated with a clear locomotor deficit.

    “The hypercholesterolaemia of the transgenic mice was associated with a clear locomotor deficit (as determined by rotarod, grip strength and open field testing)”
    Quote in the paperSubstantial claim
  • The quote only partly states this claim. 1
  • It may state two separate claims as one. 20
  • Probably not a substantial claim. 25

  • The quote only partly states this claim.

    Findingown data

    The decline in locomotor activity and cognitive status was associated with an increase in astrogliosis and lipid peroxidation in brain regions associated with Alzheimer's disease.

    “plus an increase in astrogliosis and lipid peroxidation in the brain regions associated with AD, such as the motor and lateral entorhinal cortex, the amygdaloid basal nucleus, and the hippocampus.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Aortic atherosclerotic lesions were positively correlated with age, although potentiated by the transgenic genotype.

    “Aortic atherosclerotic lesions were positively correlated with age, although potentiated by the transgenic genotype”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    No loss of MAP2 stain was observed in 3- or 18-month-old wild-type mice, whose microtubule networks showed dense and uniform labelling.

    “No loss of the MAP2 stain was observed in the 3-month-old or 18-month-old wild-type mice, whose microtubule networks showed dense and uniform labelling.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Congo red staining revealed age-dependent cerebral β-amyloidosis in wild-type mice: no Aβ immunoreactive deposits were detected in the young mice, but were detected in the aged mice, mainly in the hypothalamus and occasionally in cortical areas.

    “Congo red staining revealed age-dependent cerebral β-amyloidosis in wild-type mice: no Aβ immunoreactive deposits were detected in the young mice, but were detected in the aged mice, mainly in the hypothalamus and occasionally in cortical areas (Fig. 7).”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    The transgenic mice were confirmed to have higher plasma cholesterol concentrations than wild-type mice, an effect potentiated by aging.

    “These transgenic mice were confirmed to have higher plasma cholesterol concentrations than wild-type mice, an effect potentiated by aging.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    Both the young and old transgenic mice showed longer periods of immobility and fewer rearings than wild-type mice in the open field test.

    “Moreover both the young and old transgenic mice showed longer periods of immobility and fewer rearings than wild-type mice in the open field test.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Findingown data

    The present transgenic mice showed early cerebrovascular β-amyloidosis that was exacerbated with age.

    “Interestingly, the present transgenic mice showed early cerebrovascular β-amyloidosis that was exacerbated with age, in the same way that, in human mutant APP mouse models, a close relationship is seen between high plasma cholesterol and brain vessel amyloidosis [49], [50].”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    An inverse relationship has been reported between plasma HDL-cholesterol and cerebral β-amyloid load in Tg2576 mice fed an atherogenic diet.

    “An inverse relationship has been reported between plasma HDL-cholesterol and cerebral β-amyloid load in Tg2576 mice fed an atherogenic diet [10], and it has been shown that HDL-cholesterol increases the degradation of Aβ by microglia in vitro [29].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] FS Shie, 2002, Diet-induced hypercholesterolemia enhances brain A beta accumulation in transgenic mice., Neuroreport source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Both Tg2576 and LDLR-deficient Tg2576 mice show impaired learning after Aβ deposition, with the latter showing greater spatial learning deficits.

    “However, both Tg2576 and LDLR-deficient Tg2576 mice showed impaired learning after Aβ deposition, although the latter showed greater spatial learning deficits.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] D Cao, 2006, Lack of LDL receptor aggravates learning deficits and amyloid deposits in Alzheimer transgenic mice., Neurobiol Aging source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    Transgenic LDLR-deficient Tg2576 mice develop high-level hypercholesterolaemia and age-dependent cerebral β-amyloidosis.

    “Other authors report transgenic LDLR-deficient Tg2576 mice to develop high-level hypercholesterolaemia and age-dependent cerebral β-amyloidosis [12].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [12] D Cao, 2006, Lack of LDL receptor aggravates learning deficits and amyloid deposits in Alzheimer transgenic mice., Neurobiol Aging source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Familial hypercholesterolaemia is caused by inherited genetic abnormalities that directly or indirectly affect LDL receptor function.

    “FH is caused by inherited genetic abnormalities that directly or indirectly affect the function of the LDL receptors (LDLRs) [5].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] F Civeira, 2004, Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia., Atherosclerosis source

  • It may state two separate claims as one.

    Premisecitation

    In AD patients, LDL-cholesterol and apoB concentrations are increased, and correlate with brain Aβ concentrations.

    “In AD patients, LDL-cholesterol and apoB concentrations are increased, and correlate with brain Aβ concentrations [31], [32], [33].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [31] YM Kuo, 1998, Elevated low-density lipoprotein in Alzheimer's disease correlates with brain abeta 1-42 levels., Biochem Biophys Res Commun source
    • cites [32] P Caramelli, 1999, Increased apolipoprotein B serum concentration in Alzheimer's disease., Acta Neurol Scand source
    • cites [33] L Thirumangalakudi, 2008, High cholesterol-induced neuroinflammation and amyloid precursor protein processing correlate with loss of working memory in mice., J Neurochem source

  • It may state two separate claims as one.

    Premisecitation

    The transgenic mice have markedly elevated LDL cholesterol and apoB100 levels, providing a model of human FH, and develop extensive atherosclerosis when fed a chow diet.

    “This results in markedly elevated LDL cholesterol and apoB100 levels (thus providing a model of human FH) that develop extensive atherosclerosis when fed a chow diet [13].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] L Powell-Braxton, 1998, A mouse model of human familial hypercholesterolemia: markedly elevated low density lipoprotein cholesterol levels and severe atherosclerosis on a low-fat chow diet., Nat Med source

  • It may state two separate claims as one.

    Premisecitation

    Little attention has been paid to neurodegeneration in hypercholesterolaemic mice; most studies have focused on the accumulation of amyloid plaques.

    “However, while much attention has been focused on the effect of cholesterol in murine AD models, little attention has been paid to neurodegeneration in hypercholesterolaemic mice; most studies have focused on the accumulation of amyloid plaques [7], [8], [9].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [7] DL Sparks, 1994, Induction of Alzheimer-like beta-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol., Exp Neurol source
    • cites [8] O Ghribi, 2006, Deposition of iron and beta-amyloid plaques is associated with cortical cellular damage in rabbits fed with long-term cholesterol-enriched diets., J Neurochem source
    • cites [9] LM Refolo, 2000, Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model., Neurobiol Dis source

  • Probably not a substantial claim. The paper may give no reason why it holds.

    Interpretationreasoning

    The severe atherosclerotic process might be associated with poor brain irrigation, leading to impaired cognitive function.

    “The severe atherosclerotic process underway might be associated with poor brain irrigation, leading to impaired cognitive function.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductnone given

    All experiments were approved by the ethical committees of NEURON BPh and the University of Granada.

    “All experiments were undertaken in accordance with the guidelines of the European Union, took place under the supervision of veterinary staff, and were approved by the ethical committees of NEURON BPh (“Comité Ético de Bienestar Animal” or CEBA) and the University of Granada (“Comité Ético de Experimentación Animal” or CEEA).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    Grip strength measurements were made by an investigator blinded to genotype.

    “The strength measurements of young transgenic mice (n = 6), young wild type mice (n = 6), aged transgenic mice (n = 8) and aged wild type mice (n = 8), were measured five times (in succession) by an investigator blinded to genotype.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    HDL-cholesterol increases the degradation of Aβ by microglia in vitro.

    “An inverse relationship has been reported between plasma HDL-cholesterol and cerebral β-amyloid load in Tg2576 mice fed an atherogenic diet [10], and it has been shown that HDL-cholesterol increases the degradation of Aβ by microglia in vitro [29].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] GM Cole, 1999, Lipoprotein effects on Abeta accumulation and degradation by microglia in vitro., J Neurosci Res source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The grip strength test determines muscular strength and neuromuscular integration relating to the grasping reflex in the forepaws.

    “The grip strength test determines the muscular strength and neuromuscular integration relating to the grasping reflex in the forepaws [15].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] A Zadrozniak, 2009, Characterization of acute adverse-effect profiles of selected antiepileptic drugs in the grip-strength test in mice., Pharmacol Rep source

  • Probably not a substantial claim.

    Study design and conductcitation

    MAP2 monoclonal antibodies were used to determine the degree of neuritic dystrophy as a marker of neuronal damage.

    “MAP2 monoclonal antibodies were used to determine the degree of neuritic dystrophy as a marker of neuronal damage (Fig. 4).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] M Gottlieb, 2006, Neuroprotection by two polyphenols following excitotoxicity and experimental ischemia., Neurobiol Dis source

  • Probably not a substantial claim.

    Premisecitation

    Hypercholesterolaemia accelerates cerebral Aβ deposition in APP-transgenic mice.

    “and the acceleration of cerebral Aβ deposition in APP-transgenic mice [9], [10].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] LM Refolo, 2000, Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model., Neurobiol Dis source
    • cites [10] FS Shie, 2002, Diet-induced hypercholesterolemia enhances brain A beta accumulation in transgenic mice., Neuroreport source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Hypercholesterolaemia is linked to the appearance of Aβ deposits in the brains of rabbits.

    “reporting it linked to the appearance of Aβ deposits in the brains of rabbits [7], [8]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [7] DL Sparks, 1994, Induction of Alzheimer-like beta-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol., Exp Neurol source
    • cites [8] O Ghribi, 2006, Deposition of iron and beta-amyloid plaques is associated with cortical cellular damage in rabbits fed with long-term cholesterol-enriched diets., J Neurochem source

  • Probably not a substantial claim. The authors may not put it forward as true. The paper’s conclusions may not depend on it.

    Premisecitation

    Absence of LDL receptors in 6-month-old mice leads to impaired spatial memory.

    “Some authors have reported the absence of LDLRs in 6 month-old mice to lead to impaired spatial memory [11], although no aging studies nor cholesterol determinations were undertaken.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] M Mulder, 2004, Low-density lipoprotein receptor-knockout mice display impaired spatial memory associated with a decreased synaptic density in the hippocampus., Neurobiol Dis source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    High HDL-cholesterol levels in elderly individuals are associated with a reduced risk of AD.

    “In general, elevated TC, LDL and TG characterise the lipid profiles of AD subjects, while high HDL-cholesterol levels in elderly individuals are associated with a reduced risk of the disease [34], [35], [36], [37].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [34] C Reitz, 2010, Association of higher levels of high-density lipoprotein cholesterol in elderly individuals and lower risk of late-onset Alzheimer disease., Arch Neurol source
    • cites [35] M Sabbagh, 2004, Is there a characteristic lipid profile in Alzheimer's disease?, J Alzheimers Dis source
    • cites [36] M Cankurtaran, 2005, Are serum lipid and lipoprotein levels related to dementia?, Arch Gerontol Geriatr source

  • It may state two separate claims as one.

    Premisecitation

    This model is superior to previous hypercholesterolaemic models in which mice were only deficient in LDLRs, that had only mildly elevated LDL cholesterol levels and little atherosclerosis, or that were based exclusively on the overexpression of apoB100 and no alteration in plasma total cholesterol.

    “This model is superior to previous hypercholesterolaemic models in which mice were only deficient in LDLRs, that had only mildly elevated LDL cholesterol levels and little atherosclerosis [27], or that were based exclusively on the overexpression of apoB100 and no alteration in plasma total cholesterol [28].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] S Ishibashi, 1993, Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery., J Clin Invest source
    • cites [28] E Bereczki, 2008, Overexpression of human apolipoprotein B-100 induces severe neurodegeneration in transgenic mice., J Proteome Res source

  • It may state two separate claims as one.

    Premisecitation

    The transgenic mice used in the present study are characterized by their deficiency in LDLRs and in their inability to splice apoB mRNA.

    “The transgenic mice used in the present study are characterized by their deficiency in LDLRs and in their inability to splice apoB mRNA.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] L Powell-Braxton, 1998, A mouse model of human familial hypercholesterolemia: markedly elevated low density lipoprotein cholesterol levels and severe atherosclerosis on a low-fat chow diet., Nat Med source

  • It may state two separate claims as one.

    Interpretationown data

    The hypercholesterolaemia of the young transgenic mice simulates accelerated aging and induces cognitive and psychomotor impairment.

    “With respect to most of the variables analysed, the young mice showed profiles similar to those of aged normal old mice, indicating that the hypercholesterolaemia of the former simulates accelerated aging and induces cognitive and psychomotor impairment.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Study design and conductcitation

    The integrated memory test has been validated in a KA-induced neurodegeneration mouse model.

    “Memory status was analysed using the integrated memory test, following a procedure adapted from a previously described experiment [18] that has been validated in a KA-induced neurodegeneration mouse model [19].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] C Ramirez, 2011, Simvastatin is the Statin that Most Efficiently Protects Against Kainate-Induced Excitotoxicity and Memory Impairment., J Alzheimers Dis source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Study design and conductown data

    Aortic atherosclerosis sections were evaluated by two independent investigators blind to the study protocol.

    “Two independent investigators blind to the study protocol evaluated each section for different characteristics relating to the presence or absence of plaque and the deterioration of the elastic fibres in the media layer.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    The elevation of plasma TG precedes amyloid deposition in the murine Tg-CRND8, APP/PS1 and Tg-SwDI/B AD models.

    “Additionally, the elevation of plasma TG precedes amyloid deposition in the murine Tg-CRND8, APP/PS1 and Tg-SwDI/B AD models [30].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] BL Burgess, 2006, Elevated plasma triglyceride levels precede amyloid deposition in Alzheimer's disease mouse models with abundant A beta in plasma., Neurobiol Dis source

  • Probably not a substantial claim.

    Premisenone given

    It is not yet known whether increases in baseline lipid profiles in non-AD mouse models provoke behavioural deficits or neurodegeneration.

    “Although it is clear that dietary and pharmacological alterations of plasma lipid metabolism can influence cognitive impairment and Aβ deposition in AD transgenic animals, it is not yet known whether increases in baseline lipid profiles in non-AD mouse models provoke behavioural deficits or neurodegeneration.”
    Quote in the paperSubstantial claim

  • It may state two separate claims as one.

    Premisecitation

    Atherosclerosis has been associated with AD and cerebral angiopathy in humans.

    “Atherosclerosis has been associated with AD and cerebral angiopathy in humans [43], [44], and recent findings indicate that vascular risk factors and neurovascular dysfunction play integral roles in the pathogenesis of AD [45].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [43] A Hofman, 1997, Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study., Lancet source
    • cites [44] RJ Ellis, 1996, Cerebral amyloid angiopathy in the brains of patients with Alzheimer's disease: the CERAD experience, Part XV., Neurology source

  • It may state two separate claims as one.

    Interpretationown data

    Hypercholesterolaemia early in the life of the ApoB100/LDLR-/- mice is associated with neuritic dystrophy, oxidative damage, astrogliosis and vascular β-amyloidosis, leading to neuronal damage and eventually psychomotor and cognitive impairment.

    “In summary, hypercholesterolaemia early in the life of the ApoB100/LDLR-/- mice is associated with neuritic dystrophy, oxidative damage, astrogliosis and vascular β-amyloidosis, leading to neuronal damage and eventually psychomotor and cognitive impairment.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    A relationship is reported between aortic atherosclerosis and brain Aβ deposits and learning deficits in transgenic Tg2576 mice fed an atherogenic diet.

    “Moreover, a relationship is reported between aortic atherosclerosis and brain Aβ deposits and learning deficits in transgenic Tg2576 mice fed an atherogenic diet [41].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] L Li, 2003, Association of aortic atherosclerosis with cerebral beta-amyloidosis and learning deficits in a mouse model of Alzheimer's disease., Am J Pathol source

  • It may state two separate claims as one.

    Interpretationreasoning

    Changes in plasma lipid homeostasis precede cognitive and psychomotor decline, and potentiate the cerebral β-amyloidosis that occurs with aging.

    “The present results suggest that changes in plasma lipid homeostasis precede cognitive and psychomotor decline, and potentiate the cerebral β-amyloidosis that occurs with aging.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    The overexpression of APP alone causes no Aβ deposition in most mouse lines, and mouse app does not generate amyloid plaques.

    “Indeed, many of the mouse models for genetic AD that harbour different human APP mutations have also been shown to exhibit CAA [49], [50], although the overexpression of APP alone causes no Aβ deposition in most mouse lines [51], and mouse app does not generate amyloid plaques.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] C Duyckaerts, 2008, Alzheimer disease models and human neuropathology: similarities and differences., Acta Neuropathol source

  • It may state two separate claims as one.

    Premisecitation

    Vascular risk factors and neurovascular dysfunction play integral roles in the pathogenesis of AD.

    “Atherosclerosis has been associated with AD and cerebral angiopathy in humans [43], [44], and recent findings indicate that vascular risk factors and neurovascular dysfunction play integral roles in the pathogenesis of AD [45].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] DL Dickstein, 2010, Role of vascular risk factors and vascular dysfunction in Alzheimer's disease., Mt Sinai J Med source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.

    Premisecitation

    In humans, Aβ peptide accumulates in the core of senile plaques and in blood vessel walls.

    “In humans, Aβ peptide accumulates in the core of senile plaques and in blood vessel walls; in fact, >90% of human amyloid plaques are in direct contact with capillaries [47].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] M Kawai, 1990, The relationship of amyloid plaques to cerebral capillaries in Alzheimer's disease., Am J Pathol

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Cholesterol may affect β-amyloidosis by modulating the proteolytic processing of APP and/or subsequent amyloid formation and deposition.

    “Cholesterol may affect β-amyloidosis by modulating the proteolytic processing of APP and/or subsequent amyloid formation and deposition [9], [46].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] LM Refolo, 2000, Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model., Neurobiol Dis source
    • cites [46] S Bodovitz, 1996, Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein., J Biol Chem source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Cerebral amyloid angiopathy (CAA) caused by Aβ deposition has a pathogenic role in dementia.

    “Moreover, it has been shown that cerebral amyloid angiopathy (CAA) caused by Aβ deposition has a pathogenic role in dementia (reviewed in [48]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] KA Jellinger, 2007, The enigma of vascular cognitive disorder and vascular dementia., Acta Neuropathol source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    Many of the mouse models for genetic AD that harbour different human APP mutations have also been shown to exhibit CAA.

    “Indeed, many of the mouse models for genetic AD that harbour different human APP mutations have also been shown to exhibit CAA [49], [50], although the overexpression of APP alone causes no Aβ deposition in most mouse lines [51], and mouse app does not generate amyloid plaques.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [49] JL Breslow, 1996, Mouse models of atherosclerosis., Science source
    • cites [50] DJ Selkoe, 1987, Conservation of brain amyloid proteins in aged mammals and humans with Alzheimer's disease., Science source

  • Probably not a substantial claim. The paper’s conclusions may not depend on it.

    Premisecitation

    More than 90% of human amyloid plaques are in direct contact with capillaries.

    “In humans, Aβ peptide accumulates in the core of senile plaques and in blood vessel walls; in fact, >90% of human amyloid plaques are in direct contact with capillaries [47].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] M Kawai, 1990, The relationship of amyloid plaques to cerebral capillaries in Alzheimer's disease., Am J Pathol
42 of 42

  • The paper relies on this without support.

    Reduction in MAP2 signal indicates neuritic dystrophy/neuronal damage.

    “MAP2 monoclonal antibodies were used to determine the degree of neuritic dystrophy as a marker of neuronal damage (Fig. 4).”
    “Compared to the wild type mice of the same age, the dendrites and axons in the lateral entorhinal cortex and amygdaloidal basal nucleus of the 3-month-old and 18-month-old transgenic mice showed a clear reduction in the MAP2 signal.”

  • The paper relies on this without support.

    The behavioural and cognitive deficits observed in apoB100/LDLR-/- mice correspond to human mild cognitive impairment.

    “These findings confirm hypercholesterolaemia as a key biomarker for monitoring mild cognitive impairment, and shows these transgenic mice can be used as a model for cognitive and psycho-motor decline.”

  • The paper relies on this without support.

    The brain regions examined (motor and lateral entorhinal cortex, amygdaloid basal nucleus, hippocampus) are associated with Alzheimer's disease.

    “plus an increase in astrogliosis and lipid peroxidation in the brain regions associated with AD, such as the motor and lateral entorhinal cortex, the amygdaloid basal nucleus, and the hippocampus.”
3 of 3

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?

  • Astrogliosis, classically characterized by increased GFAP immunoreactivity, is a prominent feature of hypercholesterolemic animal models and frequently co-localizes with regions of BBB disruption.

    “Consistent with this role, astrogliosis, classically characterized by increased glial fibrillary acid protein (GFAP) immunoreactivity, is a prominent feature of hypercholesterolemic animal models and frequently co‐localizes with regions of BBB disruption (Ramírez et al. 2011; de Oliveira et al. 2014; de Oliveira, Engel, de Paula, Dos Santos, et al. 2020).”

    From LDL Cholesterol Modulates Astrocyte Metabolism, Lipid Handling, and Morphology: Evidence From In Vitro and In Vivo Models (2026) · cites this paper as Ramírez et al. 2011

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.

  • Age dependence of cerebral β-amyloidosis is stated inconsistently

    Minor

    The abstract says cerebral β-amyloidosis is associated with genotype rather than age, but the results explicitly say it depends on both genotype and age.

1 of 1

Cited works that were retracted

Works this paper cites that were later retracted, from the retraction notices publishers deposit. Major when the notice came out before this paper was published.

  • Cites a retracted work: 10.1111/j.1471-4159.2006.04079.x

    Info

    The cited work was retracted on 2023-03-07 (notice 10.1111/jnc.15791), not before this paper was published (2011-07-26).

    Cited work 10.1111/j.1471-4159.2006.04079.x · retracted 2023-03-07 · notice 10.1111/jnc.15791 · this paper published 2011-07-26

1 of 1

Citations

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1 retracted

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Metadata

Authors
Ramírez, C., Sierra, S., Tercero, I., Vázquez, J. A., Pineda, A., Manrique, T., & Burgos, J. S.
Affiliations
Neuron BioPharma (Spain) (ES)
Corresponding author
Burgos, Javier S.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2011-07-26
Volume
6
Issue
7
Pages
e22712
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0022712
PMC
PMC3144244
OpenAlex
W1983805020
Cited by
31
References
54
Citations by year
2026: 2 · 2025: 1 · 2022: 3 · 2021: 1 · 2020: 1 · 2019: 6 · 2018: 1 · 2017: 1 · 2016: 2 · 2015: 3 · 2014: 2 · 2013: 5 · 2012: 3
FWCI
1.15
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Centro para el Desarrollo Tecnológico Industrial
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
Keywords
familial hypercholesterolemia, hypercholesterolemia, Alzheimer's disease, mild cognitive impairment, episodic-like memory, locomotor deficits, neuritic dystrophy, astrocyte activation, lipid peroxidation, beta-amyloidosis, atherosclerosis, serum cholesterol, cholesterol homeostasis, transgenic mouse model
MeSH terms
Amyloidosis, Animals, Aortic Diseases, Behavior, Animal, Cells, Cultured, Cholesterol, Disease Models, Animal, Homozygote, Hypercholesterolemia, Immunoenzyme Techniques, Male, Mice, Inbred C57BL, Mice, Transgenic, Neurons, Receptors, LDL, Mice, Knockout, Atherosclerosis, Mice, Apolipoprotein B-100, Cognitive Dysfunction

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.

A language model drew the claims from the paper on 2026-11-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).

A second model labelled each claim on 2026-11-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).

Statistics and arithmetic are recomputed, not judged.

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

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