P2-182: DEFECTIVE MIRNA-223-MEDIATED REGULATION OF NLRP3 INFLAMMASOME ACTIVATION IN ALZHEIMER'S DISEASE

Abstract Alzheimer’s disease (AD) is a progressive, late-onset dementia with no effective treatment available. Recent studies suggest that AD pathology is driven by age-related changes in metabolism. Alterations in metabolism, such as placing patients on a ketogenic diet, can alter cognition by an unknown mechanism. One of the ketone bodies produced as a result of ketogenesis, β-hydroxybutyrate (BHB), is known to inhibit NLRP3 inflammasome activation. Therefore, we tested if BHB inhibition of the NLRP3 inflammasome reduces overall AD pathology in the 5XFAD mouse model of AD. Here, we find BHB levels are lower in red blood cells and brain parenchyma of AD patients when compared with non-AD controls. Furthermore, exogenous BHB administration reduced plaque formation, microgliosis, apoptosis-associated speck-like protein containing a caspase recruitment domain (Asc) speck formation, and caspase-1 activation in the 5XFAD mouse model of AD. Taken together, our findings demonstrate that BHB reduces AD pathology by inhibiting NLRP3 inflammasome activation. Additionally, our data suggest dietary or pharmacological approaches to increase BHB levels as promising therapeutic strategies for AD.

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TXNIP regulates age-associated neuroinflammation: Implication in Alzheimer’s disease

10.21203/rs.3.rs-25794/v1 ◽

2020 ◽

Author(s):

Saifudeen Ismael ◽

Sanaz Nasoohi ◽

Arum Yoo ◽

Lexiao Li ◽

Khurram Aslam ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Decline ◽

Nlrp3 Inflammasome ◽

Experimental Studies ◽

Inflammasome Activation ◽

Control Analysis ◽

Age Related ◽

Nlrp3 Inflammasome Activation ◽

Thioredoxin System

Abstract Background Immune system hypersensitivity with aging is believed to contribute to mental frailty in elderlies. This is postulated to arise from accumulation of oxidative molecular patterns. Solid evidences delineates thioredoxin interacting protein (TXNIP), an inducible protein involved in oxidative stress, is essential for NOD-like receptor pyrin domain containing-3 (NLRP3)-inflammasome activation which intimately connects “inflammaging” to senile cognitive decline. This study aims to fundamentally explore the plausible involvement of TXNIP/NLRP3 inflammasome pathway in senile dementia and the typical Alzhemier’s disease. Methods In experimental studies cerebral samples from gender-matched mice were compared for TXNIP/NLRP3 inflammasome activation and klotho depletion, through immunoblotting and immunostaining in different life span points. In aged males, genetic or pharmacological ablation of TXNIP were then used to determine effects on cognitive decline and sensorimotor frailty in morris water maze, novel object recognition test and gait control analysis. Immunoblotting/staining experiments were also performed on human postmortem aged hippocampal specimens and 5XFAD transgenic mice, to ultimately address Alzheimer’s disease (AD) as the most age related dementia. Results According to our preclinical studies, cerebral TXNIP was significantly upregulated in aged animals, paralleled by the NLRP3-inflammasome over-activity in both sexes, and closely associated klotho depletion in aged males. TXNIP knock-out reversed age-related NLRP3-hyperactivity and enhanced thioredoxin (TRX) levels in aged brains. Further, pharmacological TXNIP inhibition replicated the TXNIP/NLRP3-inflammasome downregulation in aged animals, with FOXO-1 and mTOR upregulation. These alterations concurred with substantial improvements in both cognitive and sensorimotor abilities. Moreover, our immunostaining shows a significant increase of TXNIP in transgenic 5XFAD mice brain and TXNIP/NLRP3-inflammasome activity in AD human postmortem hippocampal specimens, in proximity of p-tau tangles and β-amyloid plaques. Conclusion Together, these findings substantiate the pivotal role of TXNIP to drive inflammging in parallel with klotho depletion and functional decline. TXNIP co-localization with hallmarks of AD pathology is further supportive of potential mechanistic links between TXNIP and AD. Unraveling new information on upstream pathways, these data support modulating thioredoxin system as a potential approach to decelerate senile frailty.

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Mechanisms of NLRP3 Inflammasome Activation: Its Role in the Treatment of Alzheimer’s Disease

Neurochemical Research ◽

10.1007/s11064-020-03121-z ◽

2020 ◽

Vol 45 (11) ◽

pp. 2560-2572 ◽

Cited By ~ 3

Author(s):

Yidan Zhang ◽

Yuan Zhao ◽

Jian Zhang ◽

Guofeng Yang

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation

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ER stress associated TXNIP-NLRP3 inflammasome activation in hippocampus of human Alzheimer's disease

Neurochemistry International ◽

10.1016/j.neuint.2021.105104 ◽

2021 ◽

pp. 105104

Author(s):

Saifudeen Ismael ◽

Wajidunnisa ◽

Kazuko Sakata ◽

Michael P. McDonald ◽

Francesca-Fang Liao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Er Stress ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation

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Alterations in the Gut-Microbial-Inflammasome-Brain Axis in a Mouse Model of Alzheimer’s Disease

Cells ◽

10.3390/cells10040779 ◽

2021 ◽

Vol 10 (4) ◽

pp. 779

Author(s):

Pradeep K. Shukla ◽

David F. Delotterie ◽

Jianfeng Xiao ◽

Joseph F. Pierre ◽

RadhaKrishna Rao ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Model ◽

Gut Microbiota ◽

Transgenic Mice ◽

Nlrp3 Inflammasome ◽

Inflammasome Activation ◽

Gut Barrier Function ◽

Elevated Expression ◽

5Xfad Mice

Alzheimer’s disease (AD), a progressive neurodegenerative disorder characterized by memory loss and cognitive decline, is a major cause of death and disability among the older population. Despite decades of scientific research, the underlying etiological triggers are unknown. Recent studies suggested that gut microbiota can influence AD progression; however, potential mechanisms linking the gut microbiota with AD pathogenesis remain obscure. In the present study, we provided a potential mechanistic link between dysbiotic gut microbiota and neuroinflammation associated with AD progression. Using a mouse model of AD, we discovered that unfavorable gut microbiota are correlated with abnormally elevated expression of gut NLRP3 and lead to peripheral inflammasome activation, which in turn exacerbates AD-associated neuroinflammation. To this end, we observe significantly altered gut microbiota compositions in young and old 5xFAD mice compared to age-matched non-transgenic mice. Moreover, 5xFAD mice demonstrated compromised gut barrier function as evident from the loss of tight junction and adherens junction proteins compared to non-transgenic mice. Concurrently, we observed increased expression of NLRP3 inflammasome and IL-1β production in the 5xFAD gut. Consistent with our hypothesis, increased gut–microbial–inflammasome activation is positively correlated with enhanced astrogliosis and microglial activation, along with higher expression of NLRP3 inflammasome and IL-1β production in the brains of 5xFAD mice. These data indicate that the elevated expression of gut–microbial–inflammasome components may be an important trigger for subsequent downstream activation of inflammatory and potentially cytotoxic mediators, and gastrointestinal NLRP3 may promote NLRP3 inflammasome-mediated neuroinflammation. Thus, modulation of the gut microbiota may be a potential strategy for the treatment of AD-related neurological disorders in genetically susceptible hosts.

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Key Mechanisms and Potential Implications of Hericium erinaceus in NLRP3 Inflammasome Activation by Reactive Oxygen Species during Alzheimer’s Disease

Antioxidants ◽

10.3390/antiox10111664 ◽

2021 ◽

Vol 10 (11) ◽

pp. 1664

Author(s):

Marika Cordaro ◽

Angela Trovato Salinaro ◽

Rosalba Siracusa ◽

Ramona D’Amico ◽

Daniela Impellizzeri ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Nlrp3 Inflammasome ◽

Neuronal Degeneration ◽

Behavioral Changes ◽

Antioxidant Systems ◽

Inflammasome Activation ◽

Protective Effects ◽

Behavioral Alteration ◽

Hericium Erinaceus

Alzheimer’s disease (AD) is the principal cause of dementia, and its incidence increases with age. Altered antioxidant systems and inflammation have an important role in the etiology of neurodegenerative disorders. In this study, we evaluated the effects of Hericium erinaceus, a nutritional mushroom with important antioxidant effects, in a rat model of AD. Animals were injected with 70 mg/Kg of AlCl3 daily for 6 weeks, and Hericium erinaceus was administered daily by gavage. Before the experiment’s end date, behavioral test training was performed. At the end of the study, behavioral changes were assessed, and the animals were euthanized. Brain tissues were harvested for further analysis. AlCl3 mainly accumulates in the hippocampus, the principal region of the brain involved in memory functions and learning. Hericium erinaceus administration reduced behavioral changes and hippocampal neuronal degeneration. Additionally, it reduced phosphorylated Tau levels, aberrant APP overexpression, and β-amyloid accumulation. Moreover, Hericium erinaceus decreased the pro-oxidative and pro-inflammatory hippocampal alterations induced by AD. In particular, it reduced the activation of the NLRP3 inflammasome components, usually activated by increased oxidative stress during AD. Collectively, our results showed that Hericium erinaceus has protective effects on behavioral alteration and histological modification associated with AD due to the modulation of the oxidative and inflammatory pathways, as well as regulating cellular brain stress.

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Microglial and Astrocyte priming in the APP/PS1 model of Alzheimer’s Disease: increased vulnerability to acute inflammation and cognitive deficits

10.1101/344218 ◽

2018 ◽

Cited By ~ 5

Author(s):

Ana Belen Lopez-Rodriguez ◽

Edel Hennessy ◽

Carol Murray ◽

Anouchka Lewis ◽

Niamh de Barra ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cognitive Deficits ◽

Inflammasome Activation ◽

Nuclear Localisation ◽

Amyloid Pathology ◽

Model Of Alzheimer’S Disease ◽

Nlrp3 Inflammasome Activation ◽

Β Amyloid ◽

Secondary Stimulation

AbstractAlzheimer’s disease (AD) causes devastating cognitive decline and has no disease-modifying therapies. Neuroinflammation is a significant contributor to disease progression but its precise contribution remains unclear. An emerging literature indicates that secondary inflammatory insults including acute trauma and infection alter the trajectory of chronic neurodegenerative diseases and the roles of microglia and astrocytes require elucidation. The current study, using the APP/PS1 mouse model of AD, demonstrates that microglia are primed by β-amyloid pathology to induce exaggerated IL-1β responses to acute stimulation with LPS or IL-1β. Despite disease-associated NLRP3 inflammasome activation, evidenced by ASC speck formation, APP/PS1 microglial cells show neither IL-1β induction nor NFκB p65 nuclear localisation. Upon secondary stimulation with LPS or IL-1β, NFκB-p65 nuclear localisation and exaggerated pro-IL-1 induction occur. Microglial priming was also unmasked by secondary stimulation with systemic LPS leading to significant cognitive impairment in APP/PS1 mice compared to WT LPS-treated mice. Astrocytes have also recently emerged as displaying significant phenotypic heterogeneity. Here, by-passing microglial priming, and acutely challenging mice with intra-hippocampal IL-1β we demonstrate that astrocytes proximal to Aβ-plaques are also primed to produce exaggerated CCL2, CXCL1 and CXCL10 responses. Many astrocytosis-associated genes in APP/PS1 mice share these exaggerated responses to IL-1β, while others are equally induced in both strains. Collectively the data show that the amyloid-laden brain shows multiple vulnerabilities to secondary inflammatory challenge: both microglia and astrocytes are primed to produce exaggerated secondary inflammation and systemic LPS is sufficient to cause cognitive impairments relevant to delirium, selectively in animals with prior amyloid pathology.

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Pharmacological and Epigenetic Regulators of NLRP3 Inflammasome Activation in Alzheimer’s Disease

Pharmaceuticals ◽

10.3390/ph14111187 ◽

2021 ◽

Vol 14 (11) ◽

pp. 1187

Author(s):

Francesca La Rosa ◽

Roberta Mancuso ◽

Simone Agostini ◽

Federica Piancone ◽

Ivana Marventano ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Nlrp3 Inflammasome ◽

Mononuclear Cells ◽

Cytokine Production ◽

Protein Translation ◽

Inflammasome Activation ◽

Peripheral Blood Mononuclear ◽

Caspase 1 ◽

Inflammatory Status

Activation of the NLRP3 inflammasome complex results in the production of IL-18, Caspase-1 and IL-1β. These cytokines have a beneficial role in promoting inflammation, but an excessive activation of the inflammasome and the consequent constitutive inflammatory status is a negative factor in human pathologies including Alzheimer’s Disease (AD). MicroRNAs (miR-NAs) target the 3′UTR region of NLRP3, preventing the activation of the inflammasome and inhibiting cytokine production. Because Stavudine (D4T), an antiretroviral drug, was recently shown to reduce inflammasome activation, we verified whether its effect is mediated by miR-7-5p, miR-22-3p, miR-30e-5p and miR-223-3p: miRNAs that bind the NLRP3-mRNA-UTR region and interfere with protein translation, reducing NLRP3 activation. Peripheral blood mononuclear cells (PBMCs) of twenty AD patients and ten sex-matched Healthy Controls (HC) were stimulated with Lipopolysaccharides (LPS)+Amyloid-beta (Aβ42) in the absence/presence of D4T. Expression of genes within the inflammasome complex and of miRNAs was evaluated by RT-PCR; cytokines and caspase-1 production was measured by ELISA. Results have shown that: NLRP3, ASC, IL-1β and IL-18 expression, as well as IL-18, IL-1β and caspase-1 production, were significantly augmented (p < 0.05) in LPS+Aβ42-stimulated PBMCs of AD patients compared to HC. D4T reduced the expression of inflammasome genes and cytokine production (p < 0.005). miR-7-5p and miR-223-3p expression was significantly increased in LPS+Aβ42-stimulated PBMCs of AD patients (p < 0.05), and it was reduced by D4T in AD alone. In conclusion: miR-223-3p and mir-7-5p expression is increased in AD, but this does not result in down-regulation of NLRP3 inflammasome expression and of IL-1β and IL-18 production. D4T increased miRNA expression in HC but had an opposite effect in AD, suggesting that miRNA regulatory mechanisms are altered in AD.

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Oligodendroglial glycolytic stress triggers inflammasome activation and neuropathology in Alzheimer’s disease

Science Advances ◽

10.1126/sciadv.abb8680 ◽

2020 ◽

Vol 6 (49) ◽

pp. eabb8680

Author(s):

Xinwen Zhang ◽

Rihua Wang ◽

Di Hu ◽

Xiaoyan Sun ◽

Hisashi Fujioka ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

White Matter ◽

Mitochondrial Fission ◽

Underlying Mechanism ◽

Inflammasome Activation ◽

Pyrin Domain ◽

Nlrp3 Inflammasome Activation ◽

Signaling Axis ◽

Guanosine Triphosphatase

Myelin degeneration and white matter loss resulting from oligodendrocyte (OL) death are early events in Alzheimer’s disease (AD) that lead to cognitive deficits; however, the underlying mechanism remains unknown. Here, we find that mature OLs in both AD patients and an AD mouse model undergo NLR family pyrin domain containing 3 (NLRP3)–dependent Gasdermin D–associated inflammatory injury, concomitant with demyelination and axonal degeneration. The mature OL-specific knockdown of dynamin-related protein 1 (Drp1; a mitochondrial fission guanosine triphosphatase) abolishes NLRP3 inflammasome activation, corrects myelin loss, and improves cognitive ability in AD mice. Drp1 hyperactivation in mature OLs induces a glycolytic defect in AD models by inhibiting hexokinase 1 (HK1; a mitochondrial enzyme that initiates glycolysis), which triggers NLRP3-associated inflammation. These findings suggest that OL glycolytic deficiency plays a causal role in AD development. The Drp1-HK1-NLRP3 signaling axis may be a key mechanism and therapeutic target for white matter degeneration in AD.

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