Association of region‐specific hippocampal reduction of neurogranin with inflammasome proteins in post mortem brains of Alzheimer's disease

Abstract

INTRODUCTIONNeurogranin (Ng) is considered a biomarker for synaptic dysfunction in Alzheimer's disease (AD). In contrast, the inflammasome complex has been shown to exacerbate AD pathology.METHODSWe investigated the protein expression, morphological differences of Ng, and correlated Ng to hyperphosphorylated tau in the post mortem brains of 17 AD cases and 17 age‐ and sex‐matched controls. In addition, we correlated the Ng expression with two different epitopes of apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC).RESULTSWe show a reduction of Ng immunopositive neurons and morphological differences in AD compared to controls. Ng immunostaining was negatively correlated with neurofibrillary tangles, humanized anti‐ASC (IC100) positive neurons and anti‐ASC positive microglia, in AD.DISCUSSIONThe finding of a negative correlation between Ng and ASC speck protein expression in post mortem brains of AD suggests that the activation of inflammasome/ASC speck pathway may play an important role in synaptic degeneration in AD.Highlights We show the role that neurogranin plays on post‐synaptic signaling in specific hippocampal regions. We demonstrate that there could be clinical implications of using neurogranin as a biomarker for dementia. We describe the loss of plasticity and neuronal scaffolding proteins in the present of AD pathology. We show the response of neuroinflammation when tau proteins phosphorylate in hippocampal neurons. We show that there is a potential therapeutic target for the inflammasome, and future studies may show that IC100, a humanized monoclonal antibody directed against ASC, may slow the progression of neurodegeneration.