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Alpha-2 macroglobulin in Alzheimer's disease: a marker of neuronal injury through the RCAN1 pathway
- Source :
- Molecular psychiatry. 22(1)
- Publication Year :
- 2016
-
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.
- Subjects :
- 0301 basic medicine
Male
Proteomics
Pathology
Apolipoprotein E4
Muscle Proteins
Disease
Systemic inflammation
Pathogenesis
Cohort Studies
0302 clinical medicine
Cognition
Longitudinal Studies
Cognitive decline
Phosphorylation
Neurons
Calcineurin
Intracellular Signaling Peptides and Proteins
Brain
Middle Aged
Macroglobulin
DNA-Binding Proteins
Psychiatry and Mental health
Disease Progression
Female
medicine.symptom
medicine.medical_specialty
Inflammation
Neuroimaging
tau Proteins
03 medical and health sciences
Cellular and Molecular Neuroscience
Alzheimer Disease
medicine
Dementia
Humans
alpha-Macroglobulins
Molecular Biology
Aged
Amyloid beta-Peptides
business.industry
medicine.disease
Immunity, Innate
030104 developmental biology
Gene Expression Regulation
Immunology
business
Cognition Disorders
030217 neurology & neurosurgery
Biomarkers
Subjects
Details
- ISSN :
- 14765578
- Volume :
- 22
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Molecular psychiatry
- Accession number :
- edsair.doi.dedup.....c0d0b4835898d3e51b5ed645cd46d77c