Inflammasome-mediated neurodegeneration following heart disease

Background: Myocardial infarction (MI) has been suggested as a critical predisposing factor for Alzheimer's disease (AD); however, the underlying mechanisms remain unknown. PYD domains-containing protein 3 (NLRP3) is a key factor to mediate inflammasome formation. Previous studies have shown that NLRP3 activation in brain microglia is required for AD; however, its possible role in MI-induced future development of neurodegeneration is not yet understood. These questions were addressed in the current study. Methods: We generated microglia-specific NLRP3 mutation mice in the AD-prone APP/PS1 background (APP/PS1/NLRP3MKO), and studied the neurodegeneration in these mice after MI compared to the control wild-type C57/BL6J or APP/PS1 mice. NLRP3, IL-1 beta and caspase-1 levels were determined by Enzyme linked immunoassay (ELISA). The heart function was determined by the slope of end systolic pressure volume relationship, left ventricular end diastolic pressure, the positive maximal pressure derivative as well as the degree of fibrosis by Masson's trichrome staining. Mouse behavior measurement includes Morris water maze test and motor assessment. Results: We found that compared with the control wild-type C57/BL6J or APP/PS1 mice, the effects of MI on the subsequent development of defected spatial reference memory and motor activity were all attenuated in APP/PS1/NLRP3MKO mice, likely resulting from the reduced formation of amyloid-beta peptide aggregates (A beta) plaques. Conclusions: NLRP3 may play a non-redundant role in the MI-induced future development of AD.