title: Alpha-2 macroglobulin in Alzheimer's disease: a marker of neuronal injury through the RCAN1 pathway.
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.
authors.affiliation: Clinical and Translational Neuroscience Unit, Laboratory of Behavioral Neuroscience, National Institute on Aging (NIA), National Institutes of Health (NIH), Baltimore, MD, USA.
authors.forename: V R
authors.initials: VR
authors.lastname: Varma
authors.affiliation: HiThru Analytics, Laurel, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Varma
authors.affiliation: Clinical and Translational Neuroscience Unit, Laboratory of Behavioral Neuroscience, National Institute on Aging (NIA), National Institutes of Health (NIH), Baltimore, MD, USA.
authors.forename: Y
authors.identifier: 0000-0002-3377-7014
authors.initials: Y
authors.lastname: An
authors.affiliation: Department of Neurology, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Hohman
authors.affiliation: Clinical and Translational Neuroscience Unit, Laboratory of Behavioral Neuroscience, National Institute on Aging (NIA), National Institutes of Health (NIH), Baltimore, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Seddighi
authors.affiliation: Department of Biostatistical Science, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: R
authors.initials: R
authors.lastname: Casanova
authors.affiliation: Laboratory of Informatics Development (BTRIS), National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Beri
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: E B
authors.initials: EB
authors.lastname: Dammer
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: N T
authors.initials: NT
authors.lastname: Seyfried
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: O
authors.initials: O
authors.lastname: Pletnikova
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Moghekar
authors.affiliation: School of Biological Sciences, University of Wollongong, Wollongong, NSW, Australia.
authors.forename: M R
authors.initials: MR
authors.lastname: Wilson
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Lah
authors.affiliation: Department of Neurology, Duke University School of Medicine, Durham, NC, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: O'Brien
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: A I
authors.initials: AI
authors.lastname: Levey
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Troncoso
authors.affiliation: Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: M S
authors.initials: MS
authors.lastname: Albert
authors.affiliation: Clinical and Translational Neuroscience Unit, Laboratory of Behavioral Neuroscience, National Institute on Aging (NIA), National Institutes of Health (NIH), Baltimore, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Thambisetty
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000235:genetics; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001921:Brain / Q000378:metabolism; D019703:Calcineurin; D003071:Cognition / Q000502:physiology; D003072:Cognition Disorders / Q000378:metabolism; D015331:Cohort Studies; D004268:DNA-Binding Proteins; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000134:cerebrospinal fluid; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000378:metabolism*; D059906:Neuroimaging; D009474:Neurons; D010766:Phosphorylation; D040901:Proteomics; D000511:alpha-Macroglobulins / Q000032:analysis / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D015415:Biomarkers; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C108612:RCAN1 protein, human; D000511:alpha-Macroglobulins; D016875:tau Proteins; D019703:Calcineurin