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

Nov 23, 2016Molecular psychiatry

Alpha-2 macroglobulin as a marker of brain cell damage in Alzheimer's disease through the RCAN1 pathway

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Abstract

Higher baseline serum alpha-2 macroglobulin (A2M) concentration is associated with an almost threefold greater risk of progression to clinical symptoms of Alzheimer's disease in men.

A2M concentration in blood shows a significant association with cerebrospinal fluid markers of neuronal injury, specifically tau and phosphorylated tau.
Increased blood A2M levels may reflect early neuronal injury during the preclinical stage of Alzheimer's disease.
A systems-level analysis identified an A2M gene network linked to calcineurin, a phosphatase involved in tau regulation.
A2M gene and protein expression in the brain correlate with calcineurin expression levels, suggesting a potential pathway for tau phosphorylation.

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

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