Involvement of NLRC4 inflammasome through caspase-1 and IL-1β augments neuroinflammation and contributes to memory impairment in an experimental model of Alzheimer's like disease

Abstract

Inflammatory response through interleukin-1β (IL-1β) plays a key role in the pathogenesis of Alzheimer's disease (AD). However, the molecular mechanism of pro-IL-1β processing in AD is not clearly defined. The current study was designed to investigate which of the inflammasome complexes are critical for IL-1β production in AD. An experimental model for Alzheimer like disease was induced in male Wistar rats and Morris Water Maze was used to evaluate the function of learning and memory. The expression of genes involved in inflammasome complex including NLRP1, NLRP3, NLRC4, AIM2, ASC, IL18, IL-1β and caspase-1 was determined via Real-time PCR. Hematoxylin and Eosin (H&E) staining and Immunohistochemistry (IHC) for CD45 was applied to assess inflammatory cells infiltration. Furthermore, caspase-1, IL-1β and phosphorylated tau (p-Tau) protein expressing cells were investigated in the lesion area using immunofluorescence staining technique. The behavioral study revealed that streptozotocin (STZ) injection significantly impaired learning and memory function. In addition, the infiltration of inflammatory cells was confirmed in the hippocampus region of STZ-treated animals. Furthermore, a significant increase in the expression level of NLRC4 inflammasome, ASC and IL-1β was identified in STZ-treated animals. In contrast, no significant difference was observed in other inflammasome components including NLRP1, NLRP3, AIM2, IL-18 and caspase-1 in STZ-treated group compared with the control group. Moreover, the number of caspase-1, IL-1β and p-Tau protein positive cells were remarkably increased in STZ-treated animals. Based on the obtained results, it can be concluded that increased production of IL-1β, caspase-1 and p-Tau through association with NLRC4 inflammasome may be involved in neuroinflammation and memory impairment in AD, which creates a new horizon in this regard. Hence, strategies targeting NLRC4 inflammasome could be beneficial for the treatment of AD.

Keywords: Alzheimer; Caspase-1; Interleukin-1β; Memory impairment; NLRC4; Neuroinflammation.