APOE2 enhances neuroprotection against Alzheimer's disease through multiple molecular mechanisms

C. Conejero-Goldberg, J. J. Gomar, T. Bobes-Bascaran, Thomas Hyde, Joel Kleinman, M. M. Herman, S. Chen, P. Davies, T. E. Goldberg

Research output: Contribution to journalArticle

Abstract

The common APOE2 gene variant is neuroprotective against Alzheimer's disease (AD) and reduces risk by nearly 50%. However, the mechanisms by which APOE2 confers neuroprotection are largely unknown. Here we showed that ApoE protein abundance in human postmortem cortex follows an isoform-dependent pattern (E2>E3>E4). We also identified a unique downstream transcriptional profile determined by microarray and characterized by downregulation of long-term potentiation (LTP) related transcripts and upregulation of extracellular matrix (ECM)/integrin-related transcripts in E2 cases and corroborated this finding at the protein level by demonstrating increases in ECM collagens and laminins. In vivo studies of healthy older individuals demonstrated a unique and advantageous biomarker signature in E2 carriers. APOE2 also reduced the risk of mild cognitive impairment to AD conversion by half. Our findings suggest that ApoE2 protein abundance, coupled with its inability to bind to LDLRs, may act to increase amyloid-beta (Ab) clearance. In addition, increased ECM and reduced LTP-related expression results in diminished activity-dependent Ab secretion and/or excitotoxicity, and thus also promotes neuroprotection.

Original languageEnglish (US)
Pages (from-to)1243-1250
Number of pages8
JournalMolecular Psychiatry
Volume19
Issue number11
DOIs
StatePublished - Nov 1 2014

Fingerprint

Extracellular Matrix
Alzheimer Disease
Long-Term Potentiation
Amyloid
Apolipoprotein E2
Proteins
Apolipoproteins E
Laminin
Integrins
Protein Isoforms
Up-Regulation
Collagen
Down-Regulation
Biomarkers
Genes
Neuroprotection
Cognitive Dysfunction

ASJC Scopus subject areas

  • Molecular Biology
  • Cellular and Molecular Neuroscience
  • Psychiatry and Mental health

Cite this

Conejero-Goldberg, C., Gomar, J. J., Bobes-Bascaran, T., Hyde, T., Kleinman, J., Herman, M. M., ... Goldberg, T. E. (2014). APOE2 enhances neuroprotection against Alzheimer's disease through multiple molecular mechanisms. Molecular Psychiatry, 19(11), 1243-1250. https://doi.org/10.1038/mp.2013.194

APOE2 enhances neuroprotection against Alzheimer's disease through multiple molecular mechanisms. / Conejero-Goldberg, C.; Gomar, J. J.; Bobes-Bascaran, T.; Hyde, Thomas; Kleinman, Joel; Herman, M. M.; Chen, S.; Davies, P.; Goldberg, T. E.

In: Molecular Psychiatry, Vol. 19, No. 11, 01.11.2014, p. 1243-1250.

Research output: Contribution to journalArticle

Conejero-Goldberg, C, Gomar, JJ, Bobes-Bascaran, T, Hyde, T, Kleinman, J, Herman, MM, Chen, S, Davies, P & Goldberg, TE 2014, 'APOE2 enhances neuroprotection against Alzheimer's disease through multiple molecular mechanisms', Molecular Psychiatry, vol. 19, no. 11, pp. 1243-1250. https://doi.org/10.1038/mp.2013.194
Conejero-Goldberg, C. ; Gomar, J. J. ; Bobes-Bascaran, T. ; Hyde, Thomas ; Kleinman, Joel ; Herman, M. M. ; Chen, S. ; Davies, P. ; Goldberg, T. E. / APOE2 enhances neuroprotection against Alzheimer's disease through multiple molecular mechanisms. In: Molecular Psychiatry. 2014 ; Vol. 19, No. 11. pp. 1243-1250.
@article{fd7391438ed74dae9faca1ded9282899,
title = "APOE2 enhances neuroprotection against Alzheimer's disease through multiple molecular mechanisms",
abstract = "The common APOE2 gene variant is neuroprotective against Alzheimer's disease (AD) and reduces risk by nearly 50{\%}. However, the mechanisms by which APOE2 confers neuroprotection are largely unknown. Here we showed that ApoE protein abundance in human postmortem cortex follows an isoform-dependent pattern (E2>E3>E4). We also identified a unique downstream transcriptional profile determined by microarray and characterized by downregulation of long-term potentiation (LTP) related transcripts and upregulation of extracellular matrix (ECM)/integrin-related transcripts in E2 cases and corroborated this finding at the protein level by demonstrating increases in ECM collagens and laminins. In vivo studies of healthy older individuals demonstrated a unique and advantageous biomarker signature in E2 carriers. APOE2 also reduced the risk of mild cognitive impairment to AD conversion by half. Our findings suggest that ApoE2 protein abundance, coupled with its inability to bind to LDLRs, may act to increase amyloid-beta (Ab) clearance. In addition, increased ECM and reduced LTP-related expression results in diminished activity-dependent Ab secretion and/or excitotoxicity, and thus also promotes neuroprotection.",
author = "C. Conejero-Goldberg and Gomar, {J. J.} and T. Bobes-Bascaran and Thomas Hyde and Joel Kleinman and Herman, {M. M.} and S. Chen and P. Davies and Goldberg, {T. E.}",
year = "2014",
month = "11",
day = "1",
doi = "10.1038/mp.2013.194",
language = "English (US)",
volume = "19",
pages = "1243--1250",
journal = "Molecular Psychiatry",
issn = "1359-4184",
publisher = "Nature Publishing Group",
number = "11",

}

TY - JOUR

T1 - APOE2 enhances neuroprotection against Alzheimer's disease through multiple molecular mechanisms

AU - Conejero-Goldberg, C.

AU - Gomar, J. J.

AU - Bobes-Bascaran, T.

AU - Hyde, Thomas

AU - Kleinman, Joel

AU - Herman, M. M.

AU - Chen, S.

AU - Davies, P.

AU - Goldberg, T. E.

PY - 2014/11/1

Y1 - 2014/11/1

N2 - The common APOE2 gene variant is neuroprotective against Alzheimer's disease (AD) and reduces risk by nearly 50%. However, the mechanisms by which APOE2 confers neuroprotection are largely unknown. Here we showed that ApoE protein abundance in human postmortem cortex follows an isoform-dependent pattern (E2>E3>E4). We also identified a unique downstream transcriptional profile determined by microarray and characterized by downregulation of long-term potentiation (LTP) related transcripts and upregulation of extracellular matrix (ECM)/integrin-related transcripts in E2 cases and corroborated this finding at the protein level by demonstrating increases in ECM collagens and laminins. In vivo studies of healthy older individuals demonstrated a unique and advantageous biomarker signature in E2 carriers. APOE2 also reduced the risk of mild cognitive impairment to AD conversion by half. Our findings suggest that ApoE2 protein abundance, coupled with its inability to bind to LDLRs, may act to increase amyloid-beta (Ab) clearance. In addition, increased ECM and reduced LTP-related expression results in diminished activity-dependent Ab secretion and/or excitotoxicity, and thus also promotes neuroprotection.

AB - The common APOE2 gene variant is neuroprotective against Alzheimer's disease (AD) and reduces risk by nearly 50%. However, the mechanisms by which APOE2 confers neuroprotection are largely unknown. Here we showed that ApoE protein abundance in human postmortem cortex follows an isoform-dependent pattern (E2>E3>E4). We also identified a unique downstream transcriptional profile determined by microarray and characterized by downregulation of long-term potentiation (LTP) related transcripts and upregulation of extracellular matrix (ECM)/integrin-related transcripts in E2 cases and corroborated this finding at the protein level by demonstrating increases in ECM collagens and laminins. In vivo studies of healthy older individuals demonstrated a unique and advantageous biomarker signature in E2 carriers. APOE2 also reduced the risk of mild cognitive impairment to AD conversion by half. Our findings suggest that ApoE2 protein abundance, coupled with its inability to bind to LDLRs, may act to increase amyloid-beta (Ab) clearance. In addition, increased ECM and reduced LTP-related expression results in diminished activity-dependent Ab secretion and/or excitotoxicity, and thus also promotes neuroprotection.

UR - http://www.scopus.com/inward/record.url?scp=84926254510&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84926254510&partnerID=8YFLogxK

U2 - 10.1038/mp.2013.194

DO - 10.1038/mp.2013.194

M3 - Article

C2 - 24492349

AN - SCOPUS:84926254510

VL - 19

SP - 1243

EP - 1250

JO - Molecular Psychiatry

JF - Molecular Psychiatry

SN - 1359-4184

IS - 11

ER -