Alpha2-macroglobulin (A2M) is a marker of neuronal injury in Alzheimer's disease
Alpha2-macroglobulin (A2M) is a marker of neuronal injury in Alzheimer’s disease. Although systemic inflammation is known to be closely related to the pathogenesis of AD, the precise molecular mechanisms underlying this association are poorly understood. A detailed characterization of the biological pathways implicated in inflammation and their relationship to the onset of AD symptoms is critical in order to develop disease-modifying treatments targeting inflammation in AD. We have recently applied an integrated, systems-biology approach to study the role of the acute phase protein, A2M in AD pathogenesis. Combining population-level epidemiological analyses with multi-tissue gene expression and brain proteomics data, we show that higher A2M concentrations in serum are associated with a nearly three-fold greater risk of AD in males and with CSF concentrations of the neuronal injury markers, t-tau and p-tau. We also describe an A2M-gene network that includes Regulator of Calcineurin-1 (RCAN1), an inhibitor of the well characterized tau phosphatase, calcinerin. We find that brain A2M protein levels are negatively correlated with protein levels of calcineurin. We believe that these novel findings have several translational implications including those relevant to explaining sex-specific differences in AD risk as well as in the rational design of clinical trials targeting inflammation in AD.
Fig. 7 - Schematic representation of the study design. (A) Using the BIOCARD and ADNI study we explored associations between A2M and CSF measures of preclinical AD pathophysiology and risk of MCI/ AD. (B) Using publicly available gene expression data acquired from the GTEx project, we explored the association between blood and brain A2M gene expression. (C) Using publicly available gene expression data acquired from GEO we explored global gene networks driving A2M gene expression (C.I.) and brain specific gene expression correlations (C.II.). Protein expression data from autopsy samples in the BLSA was used to validate gene expression findings (C.III.).