Human apoE isoforms differentially regulate brain amyloid-β peptide clearance

Joseph M. Castellano, Jungsu Kim, Floy R. Stewart, Hong Jiang, Ronald B. DeMattos, Bruce W. Patterson, Anne M. Fagan, John C. Morris, Kwasi G. Mawuenyega, Carlos Cruchaga, Alison M. Goate, Kelly R. Bales, Steven M. Paul, Randall J. Bateman, David M. Holtzman

Research output: Contribution to journalArticle

Abstract

The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease (AD). The APOE ε4 allele markedly increases AD risk and decreases age of onset, likely through its strong effect on the accumulation of amyloid-β (Aβ) peptide. In contrast, the APOE ε2 allele appears to decrease AD risk. Most rare, early-onset forms of familial AD are caused by autosomal dominant mutations that often lead to overproduction of Aβ42 peptide. However, the mechanism by which APOE alleles differentially modulate Aβ accumulation in sporadic, late-onset AD is less clear. In a cohort of cognitively normal individuals, we report that reliable molecular and neuroimaging biomarkers of cerebral Aβ deposition vary in an apoE isoform-dependent manner. We hypothesized that human apoE isoforms differentially affect Aβ clearance or synthesis in vivo, resulting in an apoE isoform-dependent pattern of Aβ accumulation later in life. Performing in vivo microdialysis in a mouse model of Aβ-amyloidosis expressing human apoE isoforms (PDAPP/TRE), we find that the concentration and clearance of soluble Aβ in the brain interstitial fluid depends on the isoform of apoE expressed. This pattern parallels the extent of Aβ deposition observed in aged PDAPP/TRE mice. ApoE isoform-dependent differences in soluble Aβ metabolism are observed not only in aged but also in young PDAPP/TRE mice well before the onset of Aβ deposition in amyloid plaques in the brain. Additionally, amyloidogenic processing of amyloid precursor protein and Aβ synthesis, as assessed by in vivo stable isotopic labeling kinetics, do not vary according to apoE isoform in young PDAPP/TRE mice. Our results suggest that APOE alleles contribute to AD risk by differentially regulating clearance of Aβ from the brain, suggesting that Aβ clearance pathways may be useful therapeutic targets for AD prevention.

Original languageEnglish (US)
Article number89ra57
JournalScience translational medicine
Volume3
Issue number89
DOIs
StatePublished - Jun 29 2011

Fingerprint

Apolipoproteins E
Amyloid
Protein Isoforms
Peptides
Alzheimer Disease
Brain
Alleles
Apolipoprotein E4
Serum Amyloid A Protein
Apolipoprotein E2
Amyloid beta-Protein Precursor
Extracellular Fluid
Amyloid Plaques
Microdialysis
Amyloidosis
Age of Onset
Neuroimaging
Biomarkers
Mutation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Castellano, J. M., Kim, J., Stewart, F. R., Jiang, H., DeMattos, R. B., Patterson, B. W., ... Holtzman, D. M. (2011). Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Science translational medicine, 3(89), [89ra57]. https://doi.org/10.1126/scitranslmed.3002156

Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. / Castellano, Joseph M.; Kim, Jungsu; Stewart, Floy R.; Jiang, Hong; DeMattos, Ronald B.; Patterson, Bruce W.; Fagan, Anne M.; Morris, John C.; Mawuenyega, Kwasi G.; Cruchaga, Carlos; Goate, Alison M.; Bales, Kelly R.; Paul, Steven M.; Bateman, Randall J.; Holtzman, David M.

In: Science translational medicine, Vol. 3, No. 89, 89ra57, 29.06.2011.

Research output: Contribution to journalArticle

Castellano, JM, Kim, J, Stewart, FR, Jiang, H, DeMattos, RB, Patterson, BW, Fagan, AM, Morris, JC, Mawuenyega, KG, Cruchaga, C, Goate, AM, Bales, KR, Paul, SM, Bateman, RJ & Holtzman, DM 2011, 'Human apoE isoforms differentially regulate brain amyloid-β peptide clearance', Science translational medicine, vol. 3, no. 89, 89ra57. https://doi.org/10.1126/scitranslmed.3002156
Castellano, Joseph M. ; Kim, Jungsu ; Stewart, Floy R. ; Jiang, Hong ; DeMattos, Ronald B. ; Patterson, Bruce W. ; Fagan, Anne M. ; Morris, John C. ; Mawuenyega, Kwasi G. ; Cruchaga, Carlos ; Goate, Alison M. ; Bales, Kelly R. ; Paul, Steven M. ; Bateman, Randall J. ; Holtzman, David M. / Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. In: Science translational medicine. 2011 ; Vol. 3, No. 89.
@article{ca6f8b6a4756479a832da13597381b29,
title = "Human apoE isoforms differentially regulate brain amyloid-β peptide clearance",
abstract = "The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease (AD). The APOE ε4 allele markedly increases AD risk and decreases age of onset, likely through its strong effect on the accumulation of amyloid-β (Aβ) peptide. In contrast, the APOE ε2 allele appears to decrease AD risk. Most rare, early-onset forms of familial AD are caused by autosomal dominant mutations that often lead to overproduction of Aβ42 peptide. However, the mechanism by which APOE alleles differentially modulate Aβ accumulation in sporadic, late-onset AD is less clear. In a cohort of cognitively normal individuals, we report that reliable molecular and neuroimaging biomarkers of cerebral Aβ deposition vary in an apoE isoform-dependent manner. We hypothesized that human apoE isoforms differentially affect Aβ clearance or synthesis in vivo, resulting in an apoE isoform-dependent pattern of Aβ accumulation later in life. Performing in vivo microdialysis in a mouse model of Aβ-amyloidosis expressing human apoE isoforms (PDAPP/TRE), we find that the concentration and clearance of soluble Aβ in the brain interstitial fluid depends on the isoform of apoE expressed. This pattern parallels the extent of Aβ deposition observed in aged PDAPP/TRE mice. ApoE isoform-dependent differences in soluble Aβ metabolism are observed not only in aged but also in young PDAPP/TRE mice well before the onset of Aβ deposition in amyloid plaques in the brain. Additionally, amyloidogenic processing of amyloid precursor protein and Aβ synthesis, as assessed by in vivo stable isotopic labeling kinetics, do not vary according to apoE isoform in young PDAPP/TRE mice. Our results suggest that APOE alleles contribute to AD risk by differentially regulating clearance of Aβ from the brain, suggesting that Aβ clearance pathways may be useful therapeutic targets for AD prevention.",
author = "Castellano, {Joseph M.} and Jungsu Kim and Stewart, {Floy R.} and Hong Jiang and DeMattos, {Ronald B.} and Patterson, {Bruce W.} and Fagan, {Anne M.} and Morris, {John C.} and Mawuenyega, {Kwasi G.} and Carlos Cruchaga and Goate, {Alison M.} and Bales, {Kelly R.} and Paul, {Steven M.} and Bateman, {Randall J.} and Holtzman, {David M.}",
year = "2011",
month = "6",
day = "29",
doi = "10.1126/scitranslmed.3002156",
language = "English (US)",
volume = "3",
journal = "Science Translational Medicine",
issn = "1946-6234",
publisher = "American Association for the Advancement of Science",
number = "89",

}

TY - JOUR

T1 - Human apoE isoforms differentially regulate brain amyloid-β peptide clearance

AU - Castellano, Joseph M.

AU - Kim, Jungsu

AU - Stewart, Floy R.

AU - Jiang, Hong

AU - DeMattos, Ronald B.

AU - Patterson, Bruce W.

AU - Fagan, Anne M.

AU - Morris, John C.

AU - Mawuenyega, Kwasi G.

AU - Cruchaga, Carlos

AU - Goate, Alison M.

AU - Bales, Kelly R.

AU - Paul, Steven M.

AU - Bateman, Randall J.

AU - Holtzman, David M.

PY - 2011/6/29

Y1 - 2011/6/29

N2 - The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease (AD). The APOE ε4 allele markedly increases AD risk and decreases age of onset, likely through its strong effect on the accumulation of amyloid-β (Aβ) peptide. In contrast, the APOE ε2 allele appears to decrease AD risk. Most rare, early-onset forms of familial AD are caused by autosomal dominant mutations that often lead to overproduction of Aβ42 peptide. However, the mechanism by which APOE alleles differentially modulate Aβ accumulation in sporadic, late-onset AD is less clear. In a cohort of cognitively normal individuals, we report that reliable molecular and neuroimaging biomarkers of cerebral Aβ deposition vary in an apoE isoform-dependent manner. We hypothesized that human apoE isoforms differentially affect Aβ clearance or synthesis in vivo, resulting in an apoE isoform-dependent pattern of Aβ accumulation later in life. Performing in vivo microdialysis in a mouse model of Aβ-amyloidosis expressing human apoE isoforms (PDAPP/TRE), we find that the concentration and clearance of soluble Aβ in the brain interstitial fluid depends on the isoform of apoE expressed. This pattern parallels the extent of Aβ deposition observed in aged PDAPP/TRE mice. ApoE isoform-dependent differences in soluble Aβ metabolism are observed not only in aged but also in young PDAPP/TRE mice well before the onset of Aβ deposition in amyloid plaques in the brain. Additionally, amyloidogenic processing of amyloid precursor protein and Aβ synthesis, as assessed by in vivo stable isotopic labeling kinetics, do not vary according to apoE isoform in young PDAPP/TRE mice. Our results suggest that APOE alleles contribute to AD risk by differentially regulating clearance of Aβ from the brain, suggesting that Aβ clearance pathways may be useful therapeutic targets for AD prevention.

AB - The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset, sporadic Alzheimer's disease (AD). The APOE ε4 allele markedly increases AD risk and decreases age of onset, likely through its strong effect on the accumulation of amyloid-β (Aβ) peptide. In contrast, the APOE ε2 allele appears to decrease AD risk. Most rare, early-onset forms of familial AD are caused by autosomal dominant mutations that often lead to overproduction of Aβ42 peptide. However, the mechanism by which APOE alleles differentially modulate Aβ accumulation in sporadic, late-onset AD is less clear. In a cohort of cognitively normal individuals, we report that reliable molecular and neuroimaging biomarkers of cerebral Aβ deposition vary in an apoE isoform-dependent manner. We hypothesized that human apoE isoforms differentially affect Aβ clearance or synthesis in vivo, resulting in an apoE isoform-dependent pattern of Aβ accumulation later in life. Performing in vivo microdialysis in a mouse model of Aβ-amyloidosis expressing human apoE isoforms (PDAPP/TRE), we find that the concentration and clearance of soluble Aβ in the brain interstitial fluid depends on the isoform of apoE expressed. This pattern parallels the extent of Aβ deposition observed in aged PDAPP/TRE mice. ApoE isoform-dependent differences in soluble Aβ metabolism are observed not only in aged but also in young PDAPP/TRE mice well before the onset of Aβ deposition in amyloid plaques in the brain. Additionally, amyloidogenic processing of amyloid precursor protein and Aβ synthesis, as assessed by in vivo stable isotopic labeling kinetics, do not vary according to apoE isoform in young PDAPP/TRE mice. Our results suggest that APOE alleles contribute to AD risk by differentially regulating clearance of Aβ from the brain, suggesting that Aβ clearance pathways may be useful therapeutic targets for AD prevention.

UR - http://www.scopus.com/inward/record.url?scp=79959772357&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79959772357&partnerID=8YFLogxK

U2 - 10.1126/scitranslmed.3002156

DO - 10.1126/scitranslmed.3002156

M3 - Article

C2 - 21715678

AN - SCOPUS:79959772357

VL - 3

JO - Science Translational Medicine

JF - Science Translational Medicine

SN - 1946-6234

IS - 89

M1 - 89ra57

ER -