Inflammasome NLRP3 Potentially Links Obesity-Associated Low-Grade Systemic Inflammation and Insulin Resistance with Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the most common form of neurodegenerative dementia. Metabolic disorders including obesity and type 2 diabetes mellitus (T2DM) may stimulate amyloid β (Aβ) aggregate formation. AD, obesity, and T2DM share similar features such as chronic inflammation, increased oxidative stress, insulin resistance, and impaired energy metabolism. Adiposity is associated with the pro-inflammatory phenotype. Adiposity-related inflammatory factors lead to the formation of inflammasome complexes, which are responsible for the activation, maturation, and release of the pro-inflammatory cytokines including interleukin-1β (IL-1β) and interleukin-18 (IL-18). Activation of the inflammasome complex, particularly NLRP3, has a crucial role in obesity-induced inflammation, insulin resistance, and T2DM. The abnormal activation of the NLRP3 signaling pathway influences neuroinflammatory processes. NLRP3/IL-1β signaling could underlie the association between adiposity and cognitive impairment in humans. The review includes a broadened approach to the role of obesity-related diseases (obesity, low-grade chronic inflammation, type 2 diabetes, insulin resistance, and enhanced NLRP3 activity) in AD. Moreover, we also discuss the mechanisms by which the NLRP3 activation potentially links inflammation, peripheral and central insulin resistance, and metabolic changes with AD.

Activation of the NLRP3 Inflammasome Increases the IL-1β Level and Decreases GLUT4 Translocation in Skeletal Muscle during Insulin Resistance

“…The cytoplasmic nucleotide-binding oligomerization domain-like receptor family (NOD-like) pyrin domain containing 3 (NLRP3) inflammasome has been implicated in the development of inflammation and insulin resistance in diverse tissues [ 9 ]. The NLRP3 inflammasome is a multi-protein complex that recruits pro-caspase-1 via ASC proteins and directly activates caspase-1, the enzyme responsible for the transformation of pro-IL-1β into mature IL-1β [ 9 , 10 ]. Activation of the NLRP3 inflammasome has been extensively studied in macrophages [ 11 ], and its function requires two steps, known as priming and activation [ 9 ].…”

Visceral Adipose Tissue Molecular Networks and Regulatory microRNA in Pediatric Obesity: An In Silico Approach

“…M2 macrophages can help efficiently clear these apoptotic cells to reduce the burden of inflammation and long-term complications. Adiposity-related inflammatory factors also form inflammasome complexes, which activate and release pro-inflammatory cytokines, including IL-18, one of the crucial cytokines involved in the development of IR [ 29 ]. Recently, the role of the complement system has also emerged in obesity-associated metabolic disorders and adipocyte inflammation.…”

Chronic refined carbohydrate consumption measured by glycemic load and variation in cognitive performance in healthy people

“…Finally, insulin resistance could promote inflammation. It has been shown that a high GL diet was associated with a higher concentration of CRP (C-reactive protein), a marker of systemic inflammation (Liu et al, 2002), and that chronic hyperglycemia, induced by a high GL diet, led to an increase in the plasma concentration of free fatty acids, which, in turn, stimulated the secretion of proinflammatory cytokines (Butterfield et al, 2014;Litwiniuk et al, 2021).…”