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Cited by 11Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index; 1 of the 21 sources its claims cite were checked for support.

Alzheimer's amyloid‐β and tau protein accumulation is associated with decreased expression of the LDL receptor‐associated protein in human brain tissue

Open access
Shepherd, Claire E., Affleck, Andrew J., Bahar, Anita Y., Carew‐Jones, Francine, Gregory, Gillian, Small, David H., Halliday, Glenda M.·2020·Brain and Behavior
DOI 10.1002/brb3.1672PMC PMC7375106
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Abstract

Introduction: One of the major neuropathological features of Alzheimer's disease (AD) is the accumulation of amyloid‐β (Aβ) protein in the brain. Evidence suggests that the low‐density lipoprotein receptor‐associated protein (RAP) binds strongly to Aβ and enhances its cellular uptake and that decreased RAP expression correlates with increased Aβ production in animal models of AD. Methods: The current study examined whether RAP levels change in AD human brain tissue and whether they are related to the amount of AD pathology. RAP and NeuN levels were determined by Western blot, while low‐density lipoprotein receptor‐related protein 1 (LRP1), tau and Aβ levels were determined by ELISA in the temporal cortex of 17 AD and 16 control cases. Results: An increase in total Aβ and insoluble and soluble tau protein was observed in AD brain tissue. In contrast, RAP levels were significantly decreased in AD brain tissue compared to controls. Correlation analysis revealed that levels of RAP correlated with both total Aβ and soluble and insoluble tau levels. Neither LRP1 nor NeuN levels were significantly altered in AD brain tissue homogenates and did not correlate with Aβ or tau protein levels. Conclusion: Reduction in RAP may contribute to the accumulation and aggregation of Aβ in the AD brain.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

In human inferior temporal cortex, RAP protein levels were significantly lower in Alzheimer’s disease cases than controls and inversely correlated with total Aβ and soluble/insoluble tau, whereas LRP1 and NeuN did not differ significantly. The authors conclude that reduced RAP may contribute to Aβ accumulation and aggregation in AD, possibly via an LRP1-independent mechanism.

Key findings

  • RAP was significantly decreased in AD temporal cortex versus controls (p < .0001; estimated means 30.8 ± 6.3 vs. 63.6 ± 6.2 AIU).
  • AD cases had higher total Aβ (152.0 ± 27.6 vs. 55.9 ± 27.7 ng/ml), soluble tau (6.6 ± 0.8 vs. 0.1 ± 0.8 ng/ml), and insoluble tau (31.6 ± 5.2 vs. 4.8 ± 5.4 ng/ml), all p < .0001.
  • RAP correlated negatively with total Aβ (R = −.426, p = .021), soluble tau (R = −.582, p = .001), and insoluble tau (R = −.566, p = .002). LRP1 and NeuN did not differ significantly between groups (p = .45 and p = .59), and LRP1 did not correlate with Aβ or tau (p > .05).
  • Aβ correlated positively with soluble tau (R = .775, p < .001) and insoluble tau (R = .407, p = .028).

Methods

  • Fresh-frozen inferior temporal cortex from the Sydney Brain Bank: 17 AD and 16 pathological/disease-free control cases; mean age at death 78 ± 10 vs. 74 ± 8 years, postmortem interval 27 ± 24 vs. 31 ± 17 hr, and AD disease duration 7 ± 3 years.
  • RAP and NeuN levels were measured by Western blot; LRP1, Aβ, and soluble/insoluble tau were measured by ELISA.
  • Differences between groups used a multilevel mixed model with age and postmortem delay as covariates; Pearson correlations assessed relationships; p < .05 was significant. Age and postmortem delay showed no significant effects (p > .08 and p > .07).

Limitations

  • Stated: accurate measurement of neuronal cell loss requires knowledge of atrophy, which is difficult using isolated tissue samples of similar volumes; NeuN showed only a nonsignificant trend toward reduction in AD.
  • Stated: the RAP–tau relationship is unclear because no previous studies have investigated it in vitro or in vivo, and the authors suggest any tau relationship may be indirect; RAP was not significantly decreased in FTLD-tau versus control (p = .144).
  • Evident: the sample is small (17 AD/16 controls, with some assays using fewer cases, e.g., LRP1 12 controls/15 AD), the design is cross-sectional and correlational so causality cannot be established, and findings are restricted to the inferior temporal cortex.

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

Integrity signals

Registry

Crossref · 10.1002/brb3.1672

Cites

38 of 38 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

1 of 21 cited sources checked · 1 supported · 0 flagged

  • Premisecitation

    Previous studies of LRP1 levels in AD brain tissue have yielded conflicting results.

    “studies assessing AD brain tissue levels have yielded conflicting results (Kang et al., 2000; Matsui et al., 2007)”
    • Also stated in: § DISCUSSION · plain
      “previous studies have failed to report consistent changes in LRP1 in AD brain tissue, with some showing no change (Causevic, Ramoz, Haroutunian, Davis, & Buxbaum, 2003; Provias & Jeynes, 2014) and others showing increases (Matsui et al., 2007; Qiu, Strickland, Hyman, & Rebeck, 2001) or decreases (Kang et al., 2000) compared to controls.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites Kang et al., 2000 source
    • cites Matsui et al., 2007 source
  • Findingown data

    Total Aβ levels were significantly higher in AD temporal cortex compared to controls.

    “An increase in total Aβ and insoluble and soluble tau protein was observed in AD brain tissue.”
    • Also stated in: § Relationships between brain protein levels · plain
      “the levels of total Aβ (p < .0001, Figure 2a), soluble tau (p < .0001, Figure 2b), and insoluble tau (p < .0001, Figure 2c) were significantly higher in AD cases”
    • Also stated in: § Levels of RAP and LRP1 in the AD brain · plain
      “Aβ (ng/ml) | 55.9 ± 27.7 | 152.0 ± 27.6*”
    Quote in the paperSubstantial claim
  • Findingown data

    RAP levels correlated negatively with insoluble tau in AD brain tissue.

    “Correlation analysis revealed that levels of RAP correlated with both total Aβ and soluble and insoluble tau levels.”
    • Also stated in: § Relationships between brain protein levels · plain
      “insoluble tau (R = −.566, p = .002, Figure 3c)”
    • Also stated in: § Relationships between brain protein levels · plain
      “insoluble tau (c, R = −.566, p = .002)”
    Quote in the paperSubstantial claim
  • Findingown data

    LRP1 levels did not correlate with tau protein levels in AD brain tissue.

    “Neither LRP1 nor NeuN levels were significantly altered in AD brain tissue homogenates and did not correlate with Aβ or tau protein levels.”
    • Also stated in: § Relationships between brain protein levels · plain
      “In contrast, LRP1 levels did not show any relationship with total Aβ or tau (p > .05).”
    Quote in the paperNot a substantial claim
  • Findingown data

    RAP protein expression is not decreased in FTLD-tau compared to controls.

    “a lack of decrease in RAP protein expression in tauopathies such as frontotemporal lobar degeneration with tau deposition (FTLD‐tau vs. control RAP protein p = .144; see Figure S1)”
    Quote in the paperSubstantial claim
  • The quote only partly states this claim. 2
  • Probably not a substantial claim. 15
  • It may state two separate claims as one. 3

  • The quote only partly states this claim.

    Findingown data

    AD cases had significantly lower RAP protein levels in the temporal cortex compared to controls.

    “In contrast, RAP levels were significantly decreased in AD brain tissue compared to controls.”
    • Also stated in: § Levels of RAP and LRP1 in the AD brain · plain
      “Alzheimer's disease cases had significantly lower RAP levels compared to controls (p < .0001, Figure 1a)”
    • Also stated in: § Levels of RAP and LRP1 in the AD brain · plain
      “RAP (AIU) | 63.6 ± 6.2 | 30.8 ± 6.3*”
    Quote in the paperSubstantial claim

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

    Findingown data

    There was a nonsignificant trend toward reduced NeuN in the AD group compared to controls.

    “The findings in the present study were of a nonsignificant trend toward reduced NeuN in the same tissue volumes measured from the AD group compared to controls.”
    Quote in the paperNot a substantial claim

  • It may state two separate claims as one.

    Findingown data

    LRP1 levels were not associated with age at onset or age at death in this cohort.

    “we did not observe any association between LRP1 and age at onset (p = .541) or age at death (p = .196)”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.

    Interpretationown data

    The nonsignificant trend toward reduced NeuN is consistent with overall neuronal loss in a region with tissue atrophy in AD.

    “This would be consistent with an overall neuronal loss in a region with tissue atrophy in AD.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Neuronal cell loss is a feature of the AD brain.

  • It may state two separate claims as one.

    Premisecitation

    LRP1 plays an important role in Aβ degradation and transport across the blood-brain barrier.

    “the low‐density lipoprotein receptor‐related protein 1 (LRP1) plays an important role in Aβ degradation and transport across the blood–brain barrier (Kanekiyo et al., 2011, 2013; Liu et al., 2017; Ma et al., 2018; Shibata et al., 2000; Storck et al., 2016)”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Kanekiyo et al., 2011, 2013

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

    • cites Liu et al., 2017 source
    • cites Ma et al., 2018

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

  • Probably not a substantial claim. It may state two separate claims as one.

    Premisecitation

    RAP inhibits Aβ aggregation and toxicity.

    “inhibiting its aggregation and toxicity (Kerr et al., 2010)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Kerr et al., 2010

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

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

    Premisecitation

    RAP binds to Aβ and forms a complex on cell membranes.

    “our previous studies demonstrating that RAP binds to Aβ and forms a complex (not necessarily colocalized with LRP1) on cell membranes (Kerr et al., 2010)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kerr et al., 2010

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

  • Probably not a substantial claim.

    Interpretationcitation

    RAP possesses an ability to affect Aβ independently of LRP1.

    “suggesting that either a relatively modest change in LRP1 may be significant enough to cause changes in Aβ deposition or RAP possesses an ability to affect Aβ independently of LRP1 (Xu et al., 2008)”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Xu et al., 2008

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

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

    Premisecitation

    RAP may enhance reuptake of Aβ in neuronal and glial cell cultures via an LRP1-independent mechanism.

    “may be capable of enhancing the reuptake of Aβ in neuronal and glial cell cultures via an LRP1‐independent mechanism (Kanekiyo & Bu, 2009)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kanekiyo & Bu, 2009 source

  • Probably not a substantial claim.

    Study design and conductown data

    Preliminary studies showed NeuN, RAP, and LRP1 were located in the SDS fraction.

    “Our preliminary studies showed that NeuN, RAP, and LRP1 were located in the SDS fraction, so protein levels were analyzed in these fractions.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Extracellular RAP does not inhibit the degradation of Aβ by neurons.

    “extracellular RAP does not inhibit the degradation of Aβ by neurons (by utilizing its affinity for LRP1), further indicating an LRP1‐independent mechanism of action (Narita, Holtzman, Schwartz, & Bu, 1997)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Narita, Holtzman, Schwartz, & Bu, 1997 source

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

    Premisecitation

    RAP is used as an effective LRP1 antagonist.

    “RAP is also used as an effective LRP1 antagonist (Yamauchi et al., 2013)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Yamauchi et al., 2013 source

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

    Study design and conductown data

    Protein levels were standardized to GAPDH as a loading control.

    “The intensity of each protein band was quantified and expressed as arbitrary units standardized to GAPDH.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    RAP is responsible for ensuring LRP1's effective transport to the cell surface.

    “As a chaperone protein, RAP is responsible for ensuring LRP1's effective transport to the cell surface (Bu & Schwartz, 1998)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bu & Schwartz, 1998 source

  • Probably not a substantial claim.

    Study design and conductnone given

    Disease-free controls were cases without neurological or neuropsychiatric disorders and without significant neuropathology.

    “Disease‐free controls were cases without neurological or neuropsychiatric disorders and without significant neuropathology.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Study design and conductnone given

    Cases with head injury, significant cerebrovascular disease, or other specified conditions were excluded.

    “Cases with head injury, significant cerebrovascular disease including stroke, and nontau intracellular inclusions or substantive neurodegeneration in the absence of intracellular inclusions were excluded.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim.

    Study design and conductcitation

    Neuropathology was confirmed using systematic assessments.

    “Neuropathology was confirmed using systematic assessments, as previously described (Shepherd, McCann, Thiel, & Halliday, 2002).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Shepherd, McCann, Thiel, & Halliday, 2002 source

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

    Study design and conductown data

    Age and postmortem delay were included as covariates in the mixed model.

    “Age and postmortem delay were included as covariates.”
    Quote in the paperNot a substantial claim
18 of 18

  • The paper relies on this without support.

    The observed cross-sectional association between lower RAP and higher Aβ/tau reflects RAP influencing Aβ/tau pathology rather than reverse causation or a common cause.

    “Reduction in RAP may contribute to the accumulation and aggregation of Aβ in the AD brain.”
    “our observation that RAP is reduced in the AD brain and is significantly associated with increased Aβ pathology suggests that RAP plays an important role in the accumulation and aggregation of Aβ in AD, possibly via an LRP1‐independent mechanism.”

  • The paper relies on this without support.

    Neuronal cell loss is a feature of the AD brain.

    “Neuronal cell loss is a widely accepted feature of the AD brain.”
2 of 2

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Metadata

Authors
Shepherd, C. E., Affleck, A. J., Bahar, A. Y., Carew‐Jones, F., Gregory, G., Small, D. H., & Halliday, G. M.
Affiliations
  • UNSW Sydney (AU)
  • Neuroscience Research Australia (AU)
  • University of Tasmania (AU)
  • The University of Sydney (AU)
Corresponding author
Shepherd, Claire E.
ORCID
Venue
Brain and Behavior
Publisher
Wiley
Published
2020-06-02
Volume
10
Issue
7
Pages
e01672-e01672
ISSN
  • 2157-9032 (ISSN-L)
  • 2162-3279
DOI
10.1002/brb3.1672
PMC
PMC7375106
OpenAlex
W3030980062
Cited by
11
References
38
Citations by year
2025: 2 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 5
FWCI
0.66
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain and Behavior (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UTAS Research Repository (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • National Health and Medical Research Council of Australia (1079679, 1095127, 605530)
  • Rebecca Cooper Foundation
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 › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, amyloid-beta, tau protein, rap, LRP1, amyloid-beta uptake, temporal cortex, neuropathology
MeSH terms
Alzheimer Disease, Animals, Brain, Humans, Amyloid beta-Peptides, tau Proteins, LDL-Receptor Related Protein-Associated Protein

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