Increased expression of inflammasome signaling genes and proteins in selective brain regions in the intermediate stage of Alzheimer's disease

Abstract

Neuritic plaques (NP) are a key component of Alzheimer disease (AD) pathology composed of dystrophic neurites that form neurofibrillary tangles (NFTs) and amyloid-β (Aβ) proteins. NP accumulation is one fundamental feature seen in the intermediate stage of AD neuropathological pathology change. NPs are sites for cellular degeneration and can induce the upregulation of inflammatory signals including the inflammasome complex. We analyzed 758 genes using multiplex genomics in samples from the hippocampal, temporal and frontal brain regions that had intermediate AD neuropathological changes and aged-matched controls. In addition, we analyzed NP formation using phosphorylated tau at threonine 217 (pTau217) and Aβ antibodies along with inflammasome sensors using NOD-like receptor protein (NLRP) antibodies, apoptosis-associated speck like protein containing a caspase recruitment domain (ASC) and absent in melanoma-like receptor 2 (AIM2). Finally, we investigated if cell death is occurring cells by pyroptosis using Gasdermin D (GSDMD) antibody to detect pore formation on the membrane. Analyses show that inflammasome signaling genes and proteins are significantly increased in the hippocampus rather than the temporal and frontal lobe at the intermediate stage of AD. NPs are more prevalent in the hippocampus and temporal lobe in cases with intermediate AD pathology. ASC (1C100) immunostaining is colocalized with NLRP1, NLRP3 and AIM2. GSDMD immunostaining detected pericellular pores forming around the membrane of NFTs and in NPs. Messenger RNA and protein analyses demonstrate that inflammasome signaling molecules are elevated in AD suggesting that neuronal death occurs by the induction of pyroptosis.