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Alpha-2 macroglobulin in Alzheimer’s disease: a marker of neuronal injury through the RCAN1 pathway

Molecular Psychiatry volume 22, pages 13–23 (2017)Cite this article

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Abstract

Preclinical changes that precede the onset of symptoms and eventual diagnosis of Alzheimer’s disease (AD) are a target for potential preventive interventions. A large body of evidence suggests that inflammation is closely associated with AD pathogenesis and may be a promising target pathway for such interventions. However, little is known about the association between systemic inflammation and preclinical AD pathophysiology. We first examined whether the acute-phase protein, alpha-2 macroglobulin (A2M), a major component of the innate immune system, was associated with cerebrospinal fluid (CSF) markers of neuronal injury in preclinical AD and risk of incident AD in the predictors of cognitive decline among normal individuals (BIOCARD) cohort. We find that A2M concentration in blood is significantly associated with CSF concentrations of the neuronal injury markers, tau and phosphorylated tau, and that higher baseline serum A2M concentration is associated with an almost threefold greater risk of progression to clinical symptoms of AD in men. These findings were replicated in the Alzheimer’s Disease Neuroimaging (ADNI) study. Then, utilizing a systems level approach combining large multi-tissue gene expression datasets with mass spectrometry-based proteomic analyses of brain tissue, we identified an A2M gene network that includes regulator of calcineurin (RCAN1), an inhibitor of calcineurin, a well-characterized tau phosphatase. A2M gene and protein expression in the brain were significantly associated with gene and protein expression levels of calcineurin. Collectively these novel findings suggest that A2M is associated with preclinical AD, reflects early neuronal injury in the disease course and may be responsive to tau phosphorylation in the brain through the RCAN1-calcineurin pathway.

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Acknowledgements

The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI/SAIC-Frederick (SAIC-F) subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171) and Science Care (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to The Broad Institute Biorepository operations were funded through an SAIC-F subcontract to Van Andel Institute (10ST1035). Additional data repository and project management were provided by SAIC-F (HHSN261200800001E). The Brain Bank was supported by a supplements to University of Miami Grants DA006227 and DA033684 and to contract N01MH000028. Statistical Methods development grants were made to the University of Geneva (MH090941 and MH101814), the University of Chicago (MH090951, MH090937, MH101820, MH101825), the University of North Carolina—Chapel Hill (MH090936 and MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University St Louis (MH101810) and the University of Pennsylvania (MH101822). The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 01/18/2016. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica; Biogen; Bristol-Myers Squibb Company; CereSpir; Cogstate; Eisai; Elan Pharmaceuticals; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche and its affiliated company Genentech; Fujirebio; GE Healthcare; IXICO; Janssen Alzheimer Immunotherapy Research & Development; Johnson & Johnson Pharmaceutical Research & Development; Lumosity; Lundbeck; Merck; Meso Scale Diagnostics; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. We are grateful to participants in the Baltimore Longitudinal Study of Aging for their invaluable contribution. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging.

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  1. V R Varma, S Varma, Y An, T J Hohman, S Seddighi, R Casanova, A Beri, E B Dammer, N T Seyfried, O Pletnikova, A Moghekar, M R Wilson, J J Lah, R J O'Brien, A I Levey, J C Troncoso, M S Albert and M Thambisetty: Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (adni.loni.usc.edu). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: http://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf.

Authors and Affiliations

  1. Clinical and Translational Neuroscience Unit, Laboratory of Behavioral Neuroscience, National Institute on Aging (NIA), National Institutes of Health (NIH), Baltimore, MD, USA

    V R Varma, Y An, S Seddighi & M Thambisetty

  2. HiThru Analytics, Laurel, MD, USA

    S Varma

  3. Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN, USA

    T J Hohman

  4. Department of Biostatistical Science, Wake Forest School of Medicine, Winston-Salem, NC, USA

    R Casanova

  5. Laboratory of Informatics Development (BTRIS), National Institutes of Health (NIH), Bethesda, MD, USA

    A Beri

  6. Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA

    E B Dammer & N T Seyfried

  7. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    O Pletnikova & J C Troncoso

  8. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    A Moghekar & M S Albert

  9. School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia

    M R Wilson

  10. Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA

    J J Lah & A I Levey

  11. Department of Neurology, Duke University School of Medicine, Durham, NC, USA

    R J O'Brien

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Predictors of Cognitive Decline Among Normal Individuals (BIOCARD) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) studies

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Correspondence to M Thambisetty.

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Varma, V., Varma, S., An, Y. et al. Alpha-2 macroglobulin in Alzheimer’s disease: a marker of neuronal injury through the RCAN1 pathway. Mol Psychiatry 22, 13–23 (2017). https://doi.org/10.1038/mp.2016.206

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