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

Molecular Psychiatry volume 19, pages 1243–1250 (2014)Cite this article

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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.

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Acknowledgements

Funding for this study was provided by the Litwin Zucker Alzheimer’s Disease Center (CCG, TEG, JJG, TBB, SC, PD) and GCAPP, IRP, NIMH (TMH, JEK, MH). Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott, AstraZeneca AB, Bayer Schering Pharma AG, Bristol-Myers Squibb, Eisai Global Clinical Development, Elan Corporation, Genentech, GE Healthcare, GlaxoSmithKline, Innogenetics, Johnson and Johnson, Eli Lilly, Medpace, Merck, Novartis AG, Pfizer, F. Hoffman-La Roche, Schering-Plough, Synarc, as well as non-profit partners like the Alzheimer’s Association and Alzheimer's Drug Discovery Foundation, with participation from the US Food and Drug Administration. Private sector contributions to ADNI are facilitated by the Foundation for the National Institutes of Health (http://www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Disease Cooperative Study at the University of California, San Diego, CA, USA. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles, CA, USA. This research was also supported by NIH grants P30 AG010129, K01 AG030514, and the Dana Foundation.The ADNI investigators contributed to the design of ADNI, diagnoses, and data collection of biomarkers, but not to the analyses and writing of this report.

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  1. J J Gomar and T Bobes-Bascaran: These authors contributed equally to this work.

Authors and Affiliations

  1. Litwin Zucker Center for the Study of Alzheimer’s Disease, Feinstein Institute, Hofstra North Shore-LIJ School of Medicine, Manhasset, NY, USA

    C Conejero-Goldberg, J J Gomar, T Bobes-Bascaran, S Chen, P Davies & T E Goldberg

  2. FIDMAG, Hermanas Hospitalarias, Sant Boi de Llobregat, Spain

    J J Gomar

  3. Neuropathology Section, Lieber Institute for Brain Development, Baltimore, MD, USA

    T M Hyde & J E Kleinman

  4. Section on Neuropathology, Clinical Brain Disorders Branch, GCAPP, IRP, National Institute of Mental Health, NIH, Bethesda, MD, USA

    M M Herman

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  1. C Conejero-Goldberg
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Correspondence to T E Goldberg.

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Competing interests

TG has consulted for Neurocog Trials. He receives royalties for use of a cognitive test battery in clinical trials, the BACS. PD has received research support from and served as a consultant to Applied Neurosolutions. The remaining authors declare no conflict of interest.

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Conejero-Goldberg, C., Gomar, J., Bobes-Bascaran, T. et al. APOE2 enhances neuroprotection against Alzheimer’s disease through multiple molecular mechanisms. Mol Psychiatry 19, 1243–1250 (2014). https://doi.org/10.1038/mp.2013.194

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