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

Publication ,  Journal Article
Varma, VR; Varma, S; An, Y; Hohman, TJ; Seddighi, S; Casanova, R; Beri, A; Dammer, EB; Seyfried, NT; Pletnikova, O; Moghekar, A; Wilson, MR ...
Published in: Mol Psychiatry
January 2017

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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Published In

Mol Psychiatry

DOI

EISSN

1476-5578

Publication Date

January 2017

Volume

22

Issue

1

Start / End Page

13 / 23

Location

England

Related Subject Headings

  • tau Proteins
  • alpha-Macroglobulins
  • Psychiatry
  • Proteomics
  • Phosphorylation
  • Neurons
  • Neuroimaging
  • Muscle Proteins
  • Middle Aged
  • Male
 

Citation

APA
Chicago
ICMJE
MLA
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Varma, V. R., Varma, S., An, Y., Hohman, T. J., Seddighi, S., Casanova, R., … Thambisetty, M. (2017). Alpha-2 macroglobulin in Alzheimer's disease: a marker of neuronal injury through the RCAN1 pathway. Mol Psychiatry, 22(1), 13–23. https://doi.org/10.1038/mp.2016.206
Varma, V. R., S. Varma, Y. An, T. J. Hohman, S. Seddighi, R. Casanova, A. Beri, et al. “Alpha-2 macroglobulin in Alzheimer's disease: a marker of neuronal injury through the RCAN1 pathway.Mol Psychiatry 22, no. 1 (January 2017): 13–23. https://doi.org/10.1038/mp.2016.206.
Varma VR, Varma S, An Y, Hohman TJ, Seddighi S, Casanova R, et al. Alpha-2 macroglobulin in Alzheimer's disease: a marker of neuronal injury through the RCAN1 pathway. Mol Psychiatry. 2017 Jan;22(1):13–23.
Varma, V. R., et al. “Alpha-2 macroglobulin in Alzheimer's disease: a marker of neuronal injury through the RCAN1 pathway.Mol Psychiatry, vol. 22, no. 1, Jan. 2017, pp. 13–23. Pubmed, doi:10.1038/mp.2016.206.
Varma VR, Varma S, An Y, Hohman TJ, Seddighi S, Casanova R, Beri A, Dammer EB, Seyfried NT, Pletnikova O, Moghekar A, Wilson MR, Lah JJ, O’Brien RJ, Levey AI, Troncoso JC, Albert MS, Thambisetty M. Alpha-2 macroglobulin in Alzheimer's disease: a marker of neuronal injury through the RCAN1 pathway. Mol Psychiatry. 2017 Jan;22(1):13–23.

Published In

Mol Psychiatry

DOI

EISSN

1476-5578

Publication Date

January 2017

Volume

22

Issue

1

Start / End Page

13 / 23

Location

England

Related Subject Headings

  • tau Proteins
  • alpha-Macroglobulins
  • Psychiatry
  • Proteomics
  • Phosphorylation
  • Neurons
  • Neuroimaging
  • Muscle Proteins
  • Middle Aged
  • Male