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    Topic review

    NLRP3, Insulin, and Alzheimer’s Disease

    Subjects: Neurosciences
    View times: 19
    (This entry belongs to Entry Collection "Solid Tumors ")

    Definition

    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. 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. 

    1. Overview

    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 (nucleotide-binding oligomerization domain (NOD)-like receptor protein 3), 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. Herein, we present the role of obesity-related diseases (obesity, low-grade chronic inflammation, T2DM, 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. 

    2. Background

    AD, believed to contribute to 60–70% of neurodegenerative dementia cases, is a complex disorder that develops gradually and progressively with symptom progression over time, from mild forgetfulness to severe mental impairment. According to the World Alzheimer Report, it is estimated that 50 million people worldwide have dementia, and the number of people with dementia is projected to increase to 82 million by 2030 and to 152 million by 2050 [1].
    Although aging is the leading risk factor for the development of Alzheimer’s disease, growing evidence, also from animal models, indicates that metabolic dysfunctions may have a crucial role in the etiology of AD [2][3]. Obesity and T2DM are reported to be related to AD [3][4]. It has been hypothesized that central nervous system (CNS) inflammation takes part in the progression of chronic neurodegenerative diseases, but the mechanisms are still unclear. It is also possible that T2DM, or even prediabetes, can modulate the expression of brain pro-inflammatory cytokines in AD [5]. Additionally, both prediabetes and T2DM promote microglia activation in the mice AD model, thus confirming that the inflammatory process may serve as a link between AD and T2DM [6].
    Obesity, characterized by hypertrophy and hyperplasia of adipocytes, is accompanied by chronic local inflammation [7]. Excessive accumulation of fat leads to enhanced expression and release of pro-inflammatory cytokines including tumor necrosis factor α (TNFα), interleukin-6 (IL-6), adipokines, and monocyte chemoattractant protein-1 (MCP-1), which further recruit immune cells to intensify inflammation in adipose tissue [8][9]. Additionally, adipose tissue also contains numerous immune cells, and its total number increases dramatically with the grade of obesity. The downregulation of M2 macrophages with anti-inflammatory phenotype and the activation of M1 macrophages with pro-inflammatory phenotype can exaggerate inflammation and insulin resistance in adipocytes [10]. Innate immune cells such as macrophages can induce inflammatory reactions through detection of pathogen- or danger-associated molecular patterns (PAMPs or DAMPs) using a wide range of pattern-recognition receptors (PRRs) [11][12]. Adiposity-related inflammatory factors lead to the formation of inflammasome complexes. Inflammasomes are cytosolic multiprotein complexes that recognize both PAMPs and DAMPs. These high-molecular-weight factors are responsible for the activation, maturation, and release processes of the pro-inflammatory cytokines IL-1β and IL-18. Moreover, obesity-related factors are important activators of inflammasome-derived cytokines [13][14].

    There are two types of signaling pathways that activate one of the inflammasomes, the NLRP3 inflammasome: the canonical and noncanonical signaling pathways [15]. The canonical pathway depends on caspase-1 and involves inflammasome complexes detecting pattern PRR proteins and inducing recruitment of procaspase-1. The noncanonical signal pathway is mainly dependent on mouse caspase-11 or human caspase-4 and caspase-5. The noncanonical inflammasome is activated by lipopolysaccharide (LPS) [16].

    Recent advances have highlighted that various pathways could be regulators of the pathological features in Alzheimer’s disease. We present current knowledge of the metabolic dysregulations, including the NLRP3 inflammasome activation, and their contribution to AD pathology. 

    3. Alzheimer's Disease

    From the clinical point of view, AD is accompanied by a progressive decline in memory and executive functions, as well as impairment of daily living activities [17]. The first, early symptoms of AD have been associated with the loss of episodic memory and difficulties in learning new information. When AD progresses, there is greater memory loss, cognitive impairment, and behavioral change, along with dysfunction of language and speech [18][19].
    Neuropathological lesions in AD are associated with multiple changes at the cellular level. The typical histopathological features include Aβ formation and accumulation, mitochondrial damage, loss of synapses, activation of microglia (gliosis) and astrocytes (astrocytosis), phosphorylation of tau, and neurofibrillary tangles formation (NFT) [20]. All of these pathological processes lead to neuronal death, which is observed in the brains of AD patients.
    The metabolic dysfunction may stimulate the Aβ aggregate formation [4][21]. Furthermore, AD, obesity, and T2DM share similar risk factors and some clinical and biochemical features. These particular features are associated with chronic inflammation, increased oxidative stress, and impairment in insulin signaling and energy metabolism [22][23]. Additionally, due to the potential multifactorial role of obesity in pathological processes seen in AD, obesity could serve as a risk factor for this disease [24]

    4. Inflammasome NLRP3 and AD

    Although the inflammasome signaling in the CNS is mainly attributed to microglia, the key innate immune cells of the brain, expression of inflammasome components have also been found in other cell types of the CNS including neurons, astrocytes, perivascular CNS macrophages, oligodendrocytes, and endothelial cells [25][26][27][28]. Inappropriate NLRP3 signaling pathway has implications in neuroinflammatory processes [29][30].
    Data from both animal models and clinical studies indicate that activation of NLRP3 is linked to pathogenic mechanisms in AD. High levels of IL-1β in the brain induce tau protein hyperphosphorylation and neuronal damage [31]. In turn, accumulation and deposition of Aβ, as well as NFT formation, cause the release of mature IL-1β via activation of NLRP3 in microglia [32][33][34]. Therefore, overexpression of IL-1β may aggravate the central chronic inflammatory response. In AD microglial excessive NLRP3 activation and elevated IL-1β concentration can exacerbate tau hyperphosphorylation, neurofibrillary tangles formation, and synaptic dysfunction induced by a detrimental chronic inflammation [35]. NLRP3 activated by Aβ can induce enhanced production of IL-1β, promote microglial synthesis, and release proinflammatory cytokines and neurotoxic factors [36].
    Nlrp3-null mutation protects against cognitive deficits in aged mice and mouse models of AD [36][37]. Administration of NLRP3 or caspase-1 inhibitors resultes in a significant increase of microglia ability to clear Aβ deposits, as well as in reduced Aβ deposition, and improvement in cognitive impairment and hyperactive behavior [36][38].
    To sum up, it could be stated that the interrelation between NLRP3 and AD pathology is a vicious cycle.

    5. Conclusions

    The above evidence clearly shows that obesity-related inflammation initially located in adipose tissue may finally have systemic effects on other organs and systems, including the CNS. As it has been shown, inflammasomes can act as a link between obesity, insulin resistance, and the development of neuroinflammation in neurodegenerative diseases, including AD. Although the adiposity-related mechanism of inflammasome activation is still unclear, inflammasomes may be a therapeutic target in the treatment of obesity. Further studies on inflammasomes could result in the development of innovative precision medicine approaches for the management of obesity and its complications, including those of neurodegenerative origin. The problem that should be considered when discussing inflammasome-targeted treatment is the multitude of stimulant compounds and, in addition, many physiological as well as pathological results of NLRP3 activity. The inhibition of NLRP3 should be balanced to avoid any other side effects. Unfortunately, to date, there is no NLRP3 inflammasome-targeted drug admitted to treatment. However, it should be highlighted that prevention and proper treatment of obesity and obesity-related diseases might lower the risk of AD. Finally, exercise and a low caloric/low-fat diet are a must for all overweight/obese patients. 

    The entry is from 10.3390/ijms22115603

    References

    1. Wimo, A.; Ali, G.-C.; Guerchet, M.; Prince, M.; Prina, M.; Wu, Y.-T.; World Alzheimer Report 2015. The Global Impact of Dementia. An Analysis of Prevalence, Incidence, Cost and Trends. Available online: (accessed on 30 January 2021).
    2. de Bem, A.F.; Krolow, R.; Farias, H.R.; de Rezende, V.L.; Gelain, D.P.; Moreira, J.C.F.; Duarte, J.M. das N.; de Oliveira, J. Animal Models of Metabolic Disorders in the Study of Neurodegenerative Diseases: An Overview. Front. Neurosci. 2021, 14.
    3. Sun, Y.; Ma, C.; Sun, H.; Wang, H.; Peng, W.; Zhou, Z.; Wang, H.; Pi, C.; Shi, Y.; He, X. Metabolism: A Novel Shared Link between Diabetes Mellitus and Alzheimer’s Disease. J. Diabetes Res. 2020, 2020, 1–12.
    4. Bharadwaj, P.; Wijesekara, N.; Liyanapathirana, M.; Newsholme, P.; Ittner, L.; Fraser, P.; Verdile, G. The Link between Type 2 Diabetes and Neurodegeneration: Roles for Amyloid-β, Amylin, and Tau Proteins. J. Alzheimer’s Dis. 2017, 59, 421–432.
    5. Laiteerapong, N.; Ham, S.A.; Gao, Y.; Moffet, H.H.; Liu, J.Y.; Huang, E.S.; Karter, A.J. The Legacy Effect in Type 2 Diabetes: Impact of Early Glycemic Control on Future Complications (The Diabetes & Aging Study). Diabetes Care 2018, 42, 416–426.
    6. Carranza-Naval, M.J.; Vargas-Soria, M.; Hierro-Bujalance, C.; Baena-Nieto, G.; Garcia-Alloza, M.; Infante-Garcia, C.; del Marco, A. Alzheimer’s Disease and Diabetes: Role of Diet, Microbiota and Inflammation in Preclinical Models. Biomolecules 2021, 11, 262.
    7. Klöting, N.; Blüher, M. Adipocyte dysfunction, inflammation and metabolic syndrome. Rev. Endocr. Metab. Disord. 2014, 15, 277–287.
    8. Wang, B.; Trayhurn, P. Acute and prolonged effects of TNF-α on the expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture. Pflügers Arch. Eur. J. Physiol. 2006, 452, 418–427.
    9. Chang, Y.-C.; Chang, T.-J.; Lee, W.-J.; Chuang, L.-M. The relationship of visfatin/pre–B-cell colony-enhancing factor/nicotinamide phosphoribosyltransferase in adipose tissue with inflammation, insulin resistance, and plasma lipids. Metabolism 2010, 59, 93–99.
    10. Lee, J. Adipose tissue macrophages in the development of obesity-induced inflammation, insulin resistance and type 2 Diabetes. Arch. Pharmacal Res. 2013, 36, 208–222.
    11. Pedra, J.H.; Cassel, S.L.; Sutterwala, F.S. Sensing pathogens and danger signals by the inflammasome. Curr. Opin. Immunol. 2009, 21, 10–16.
    12. Amarante-Mendes, G.P.; Adjemian, S.; Branco, L.M.; Zanetti, L.C.; Weinlich, R.; Bortoluci, K.R. Pattern Recognition Receptors and the Host Cell Death Molecular Machinery. Front. Immunol. 2018, 9, 2379.
    13. Zheng, D.; Liwinski, T.; Elinav, E. Inflammasome activation and regulation: Toward a better understanding of complex mechanisms. Cell Discov. 2020, 6, 1–22.
    14. Lukens, J.R.; Dixit, V.D.; Kanneganti, T.-D. Inflammasome activation in obesity-related inflammatory diseases and autoimmunity. Discov. Med. 2011, 12, 65–74.
    15. Huiling Xiang; Feng Zhu; Zhifeng Xu; Jing Xiong; Role of Inflammasomes in Kidney Diseases via Both Canonical and Non-canonical Pathways. Frontiers in Cell and Developmental Biology 2020, 8, 106, 10.3389/fcell.2020.00106.
    16. Yadi Guan; Fang Han; Key Mechanisms and Potential Targets of the NLRP3 Inflammasome in Neurodegenerative Diseases. Frontiers in Integrative Neuroscience 2020, 14, 37, 10.3389/fnint.2020.00037.
    17. Scheltens, P.; Blennow, K.; Breteler, M.M.B.; de Strooper, B.; Frisoni, G.B.; Salloway, S.; van der Flier, W. Alzheimer’s disease. Lancet 2016, 388, 505–517.
    18. Tarawneh, R.; Holtzman, D.M. The Clinical Problem of Symptomatic Alzheimer Disease and Mild Cognitive Impairment. Cold Spring Harb. Perspect. Med. 2012, 2, a006148.
    19. Montenegro, J.M.F.; Villarini, B.; Angelopoulou, A.; Kapetanios, E.; Garcia-Rodriguez, J.; Argyriou, V. A Survey of Alzheimer’s Disease Early Diagnosis Methods for Cognitive Assessment. Sensors 2020, 20, 7292.
    20. Selkoe, D.J.; Hardy, J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol. Med. 2016, 8, 595–608.
    21. De La Monte, S.M.; Wands, J.R. Alzheimer’s Disease is Type 3 Diabetes—Evidence Reviewed. J. Diabetes Sci. Technol. 2008, 2, 1101–1113.
    22. Pugazhenthi, S.; Qin, L.; Reddy, P.H. Common neurodegenerative pathways in obesity, diabetes, and Alzheimer’s disease. Biochim. et Biophys. Acta (BBA) Mol. Basis Dis. 2017, 1863, 1037–1045.
    23. Walker, J.M.; Harrison, F.E. Shared Neuropathological Characteristics of Obesity, Type 2 Diabetes and Alzheimer’s Disease: Impacts on Cognitive Decline. Nutrition 2015, 7, 7332–7357.
    24. Tabassum, S.; Misrani, A.; Yang, L. Exploiting Common Aspects of Obesity and Alzheimer’s Disease. Front. Hum. Neurosci. 2020, 14, 14.
    25. Varsha Kaushal; Rebecca Dye; P. Pakavathkumar; Benedicte Foveau; J C Flores; Bradley T Hyman; Bernardino Ghetti; Beverly H Koller; Andrea C Leblanc; Neuronal NLRP1 inflammasome activation of Caspase-1 coordinately regulates inflammatory interleukin-1-beta production and axonal degeneration-associated Caspase-6 activation. Cell Death & Differentiation 2015, 22, 1676-1686, 10.1038/cdd.2015.16.
    26. Leslie Freeman; Haitao Guo; Clément N. David; W. June Brickey; Sushmita Jha; Jenny P.-Y. Ting; NLR members NLRC4 and NLRP3 mediate sterile inflammasome activation in microglia and astrocytes. Journal of Experimental Medicine 2017, 214, 1351-1370, 10.1084/jem.20150237.
    27. Zhe Gong; Jingrui Pan; Qingyu Shen; Mei Li; Ying Peng; Mitochondrial dysfunction induces NLRP3 inflammasome activation during cerebral ischemia/reperfusion injury. Journal of Neuroinflammation 2018, 15, 1-17, 10.1186/s12974-018-1282-6.
    28. Brienne A. McKenzie; Manmeet K. Mamik; Leina B. Saito; Roobina Boghozian; Maria Chiara Monaco; Eugene O. Major; Jian-Qiang Lu; William G. Branton; Christopher Power; Caspase-1 inhibition prevents glial inflammasome activation and pyroptosis in models of multiple sclerosis. Proceedings of the National Academy of Sciences 2018, 115, E6065-E6074, 10.1073/pnas.1722041115.
    29. Haitao Guo; Justin B. Callaway; Jenny P.-Y. Ting; Inflammasomes: mechanism of action, role in disease, and therapeutics. Nature Medicine 2015, 21, 677-687, 10.1038/nm.3893.
    30. Limin Song; Lei Pei; Shanglong Yao; Yan Wu; You Shang; NLRP3 Inflammasome in Neurological Diseases, from Functions to Therapies. Frontiers in Cellular Neuroscience 2017, 11, 63, 10.3389/fncel.2017.00063.
    31. W Sue T Griffin; Ling Liu; Yuekui Li; Robert E Mrak; Steven W Barger; Interleukin-1 mediates Alzheimer and Lewy body pathologies. Journal of Neuroinflammation 2006, 3, 5-5, 10.1186/1742-2094-3-5.
    32. Christina Ising; Carmen Venegas; Shuangshuang Zhang; Hannah Scheiblich; Susanne V. Schmidt; Ana Vieira-Saecker; Stephanie Schwartz; Shadi Albasset; Róisín McManus; Dario Tejera; et al. NLRP3 inflammasome activation drives tau pathology. Nature 2019, 575, 669-673, 10.1038/s41586-019-1769-z.
    33. Bidur Parajuli; Yoshifumi Sonobe; Hideki Horiuchi; H Takeuchi; Tetsuya Mizuno; Akio Suzumura; Oligomeric amyloid β induces IL-1β processing via production of ROS: implication in Alzheimer’s disease. Cell Death & Disease 2013, 4, e975-e975, 10.1038/cddis.2013.503.
    34. Carmen Venegas; Sathish Kumar; Bernardo S. Franklin; Tobias Dierkes; Rebecca Brinkschulte; Dario Tejera; Ana Vieira-Saecker; Stephanie Schwartz; Francesco Santarelli; Markus P. Kummer; et al. Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease. Nature 2017, 552, 355-361, 10.1038/nature25158.
    35. Jun Lee; Hong Kim; Jong Kim; Tae Yook; Kyeong Kim; Joo Lee; Gabsik Yang; A Novel Treatment Strategy by Natural Products in NLRP3 Inflammasome-Mediated Neuroinflammation in Alzheimer’s and Parkinson’s Disease. International Journal of Molecular Sciences 2021, 22, 1324, 10.3390/ijms22031324.
    36. Michael T. Heneka; Markus P. Kummer; Andrea Stutz; Andrea Delekate; Stephanie Schwartz; Ana Vieira-Saecker; Angelika Griep; Daisy Axt; Anita Remus; Te-Chen Tzeng; et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 2012, 493, 674-678, 10.1038/nature11729.
    37. Yun-Hee Youm; Ryan Grant; Laura R. McCabe; Diana C. Albarado; Kim Yen Nguyen; Anthony Ravussin; Paul Pistell; Susan Newman; Renee Carter; Amanda Laque; et al. Canonical Nlrp3 Inflammasome Links Systemic Low-Grade Inflammation to Functional Decline in Aging. Cell Metabolism 2013, 18, 519-532, 10.1016/j.cmet.2013.09.010.
    38. C. Dempsey; Ana Rubio-Araiz; K.J. Bryson; O. Finucane; C. Larkin; E.L. Mills; Avril Robertson; Matthew Cooper; L.A.J. O'neill; M.A. Lynch; et al. Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice. Brain, Behavior, and Immunity 2017, 61, 306-316, 10.1016/j.bbi.2016.12.014.
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