scholarly journals Toll-Like Receptor 2 and NLRP3 Cooperate To Recognize a Functional Bacterial Amyloid, Curli

2014 ◽  
Vol 83 (2) ◽  
pp. 693-701 ◽  
Author(s):  
Glenn J. Rapsinski ◽  
Meghan A. Wynosky-Dolfi ◽  
Gertrude O. Oppong ◽  
Sarah A. Tursi ◽  
R. Paul Wilson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nlrp3 Inflammasome ◽  
Amyloid Β ◽  
Underlying Mechanism ◽  
Secondary Amyloidosis ◽  
Toll Like Receptor ◽  
Content Type ◽  
Caspase 1 ◽  
Toll Like Receptor 2

Amyloids are proteins with cross-β-sheet structure that contribute to pathology and inflammation in complex human diseases, including Alzheimer's disease, Parkinson's disease, type II diabetes, and secondary amyloidosis. Bacteria also produce amyloids as a component of their extracellular matrix during biofilm formation. Recently, several human amyloids were shown to activate the NLRP3 inflammasome, leading to the activation of caspase 1 and production of interleukin 1β (IL-1β). In this study, we investigated the activation of the NLRP3 inflammasome by bacterial amyloids using curli fibers, produced bySalmonella entericaserovar Typhimurium andEscherichia coli. Here, we show that curli fibers activate the NLRP3 inflammasome, leading to the production of IL-1β via caspase 1 activation. Investigation of the underlying mechanism revealed that activation of Toll-like receptor 2 (TLR2) by curli fibers is critical in the generation of IL-1β. Interestingly, activation of the NLRP3 inflammasome by curli fibers or by amyloid β of Alzheimer's disease does not cause cell death in macrophages. Overall, these data identify a cross talk between TLR2 and NLRP3 in response to the bacterial amyloid curli and generation of IL-1β as a product of this interaction.

scholarly journals NLRP3 Inflammasome: A Starring Role in Amyloid-β- and Tau-Driven Pathological Events in Alzheimer’s Disease

2021 ◽  
pp. 1-22
Author(s):  
Mariana Van Zeller ◽  
Diogo M. Dias ◽  
Ana M. Sebastião ◽  
Cláudia A. Valente
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glial Cells ◽  
Neurofibrillary Tangles ◽  
Nlrp3 Inflammasome ◽  
Neuronal Death ◽  
Inflammatory Responses ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Wide Range

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease commonly diagnosed among the elderly population. AD is characterized by the loss of synaptic connections, neuronal death, and progressive cognitive impairment, attributed to the extracellular accumulation of senile plaques, composed by insoluble aggregates of amyloid-β (Aβ) peptides, and to the intraneuronal formation of neurofibrillary tangles shaped by hyperphosphorylated filaments of the microtubule-associated protein tau. However, evidence showed that chronic inflammatory responses, with long-lasting exacerbated release of proinflammatory cytokines by reactive glial cells, contribute to the pathophysiology of the disease. NLRP3 inflammasome (NLRP3), a cytosolic multiprotein complex sensor of a wide range of stimuli, was implicated in multiple neurological diseases, including AD. Herein, we review the most recent findings regarding the involvement of NLRP3 in the pathogenesis of AD. We address the mechanisms of NLRP3 priming and activation in glial cells by Aβ species and the potential role of neurofibrillary tangles and extracellular vesicles in disease progression. Neuronal death by NLRP3-mediated pyroptosis, driven by the interneuronal tau propagation, is also discussed. We present considerable evidence to claim that NLRP3 inhibition, is undoubtfully a potential therapeutic strategy for AD.

scholarly journals Amyloid-beta uptake by blood monocytes is reduced with ageing and Alzheimer’s disease

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Si-Han Chen ◽  
Ding-Yuan Tian ◽  
Ying-Ying Shen ◽  
Yuan Cheng ◽  
Dong-Yu Fan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Blood Levels ◽  
Amyloid Β Protein ◽  
Blood Monocytes ◽  
Cognitively Normal ◽  
Β Protein ◽  
Toll Like Receptor 2 ◽  
Age And Sex

AbstractDeficits in the clearance of amyloid β-protein (Aβ) play a pivotal role in the pathogenesis of sporadic Alzheimer’s disease (AD). The roles of blood monocytes in the development of AD remain unclear. In this study, we sought to investigate the alterations in the Aβ phagocytosis function of peripheral monocytes during ageing and in AD patients. A total of 104 cognitively normal participants aged 22–89 years, 24 AD patients, 25 age- and sex-matched cognitively normal (CN) subjects, 15 Parkinson’s disease patients (PD), and 15 age- and sex-matched CN subjects were recruited. The Aβ uptake by blood monocytes was measured and its alteration during ageing and in AD patients were investigated. Aβ1-42 uptake by monocytes decreased during ageing and further decreased in AD but not in PD patients. Aβ1-42 uptake by monocytes was associated with Aβ1-42 levels in the blood. Among the Aβ uptake-related receptors and enzymes, the expression of Toll-like receptor 2 (TLR2) was reduced in monocytes from AD patients. Our findings suggest that monocytes regulate the blood levels of Aβ and might be involved in the development of AD. The recovery of the Aβ uptake function by blood monocytes represents a potential therapeutic strategy for AD.

scholarly journals GPCR19 regulates P2X7R-mediated NLRP3 inflammasomal activation of microglia by Amyloid β in Alzheimer’s diseases

2020 ◽  
Author(s):  
Jahirul Islam ◽  
Jung-Ah Cho ◽  
Ju-yong Kim ◽  
Kyung-Sun Park ◽  
Young-Jae koh ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nlrp3 Inflammasome ◽  
Memory Function ◽  
Scavenger Receptor ◽  
Amyloid Β ◽  
Neuronal Loss ◽  
Priming Phase ◽  
5Xfad Mice ◽  
The Brain

Abstract Amyloid β (Aβ) and/or ATP activates NLRP3 inflammasome (N3I) by P2 × 7R ion channel of microglia, which is crucial in neuroinflammation shown in Alzheimer’s disease (AD). Due to polymorphisms, subtypes, and ubiquitous expression of P2 × 7R, inhibition of P2 × 7R has not been effective for AD. We first report that GPCR19 is a prerequisite for P2 × 7R-mediated N3I activation and Taurodeoxycholate (TDCA), a GPCR19 ligand, inhibited the priming phase of N3I activation, suppressed P2 × 7R expression and P2 × 7R-mediated Ca++ mobilization, and N3I oligomerization which is essential for production of IL-1β/IL-18. Further, TDCA increased expression of scavenger receptor (SR) A, enhanced phagocytosis of Aβ, and decreased Aβ plaque numbers in the brain of 5x Familial Alzheimer’s disease (5xFAD) mice. TDCA also reduced microgliosis, prevented neuronal loss, and improved memory function of 5xFAD mice. The pleiotropic roles of GPCR19 in P2 × 7-mediated N3I activation suggest that targeting GPCR19 might resolve neuroinflammation in AD patients.

scholarly journals Amyloid-beta Uptake by Peripheral Blood Monocytes is Reduced by Ageing and Alzheimer’s Disease

2020 ◽  
Author(s):  
Si-Han Chen ◽  
Ding-Yuan Tian ◽  
Ying-Ying Shen ◽  
Yuan Cheng ◽  
Dong-Yu Fan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Blood Levels ◽  
Amyloid Β Protein ◽  
Blood Monocytes ◽  
Cognitively Normal ◽  
Β Protein ◽  
Toll Like Receptor 2 ◽  
Age And Sex

Abstract BackgroundDeficits in the clearance of amyloid β-protein (Aβ) play a pivotal role in the pathogenesis of sporadic Alzheimer’s disease (AD). The roles of blood monocytes, the counterpartsof microglia in the periphery, in the development of AD remain unclear. In this study, we sought to investigate the alterations in the Aβ phagocytosis function of peripheral monocytes during ageing and in AD patients. Methods:A total of104 cognitively normal participants aged 22 to 89 years old, 22 AD patients, 22 age- and sex-matched cognitively normal (CN) subjects, 15 Parkinson’s disease patients (PD) and 15 age- and sex-matched CN subjects were recruited. The Aβ uptake by blood monocytes were measured and its alteration during ageing and in AD were investigated. ResultsAβ1-42 uptake by monocytes was associated with Aβ1-42 levels in the blood. Aβ1-42 uptake by monocytes decreased during ageing, and further decreased in AD but not in PD patients. Among the Aβ uptake-related receptors and enzymes, the expression of Toll‑like receptor 2 (TLR2) was reduced in monocytes from AD patients.ConclusionOur findings suggest that monocytes regulate the blood levels of Aβ and might be involved in the development of AD. The recovery of the Aβ clearance function by blood monocytes represents a potential therapeutic strategy for AD.

scholarly journals Microglia Activated with the Toll-Like Receptor 9 Ligand CpG Attenuate Oligomeric Amyloid β Neurotoxicity in in Vitro and in Vivo Models of Alzheimer’s Disease

2009 ◽  
Vol 175 (5) ◽  
pp. 2121-2132 ◽  
Author(s):  
Yukiko Doi ◽  
Tetsuya Mizuno ◽  
Yuki Maki ◽  
Shijie Jin ◽  
Hiroyuki Mizoguchi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Toll Like Receptor ◽  
In Vivo Models

Amyloid-β oligomers as a template for secondary amyloidosis in Alzheimer's disease

2014 ◽  
Vol 71 ◽  
pp. 14-23 ◽  
Author(s):  
Marcos J. Guerrero-Muñoz ◽  
Diana L. Castillo-Carranza ◽  
Shashirekha Krishnamurthy ◽  
Adriana A. Paulucci-Holthauzen ◽  
Urmi Sengupta ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Secondary Amyloidosis

scholarly journals 4,4′-Diaminodiphenyl Sulfone (DDS) as an Inflammasome Competitor

2020 ◽  
Vol 21 (17) ◽  
pp. 5953
Author(s):  
Jong-hoon Lee ◽  
Ha Kyeu An ◽  
Mun-Gi Sohn ◽  
Paul Kivela ◽  
Sangsuk Oh
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Nlrp3 Inflammasome ◽  
Prion Diseases ◽  
Lepromatous Leprosy ◽  
Molecular Regulation ◽  
Toll Like Receptor ◽  
Diaminodiphenyl Sulfone ◽  
Preventive Effects

The aim of this study is to examine the use of an inflammasome competitor as a preventative agent. Coronaviruses have zoonotic potential due to the adaptability of their S protein to bind receptors of other species, most notably demonstrated by SARS-CoV. The binding of SARS-CoV-2 to TLR (Toll-like receptor) causes the release of pro-IL-1β, which is cleaved by caspase-1, followed by the formation and activation of the inflammasome, which is a mediator of lung inflammation, fever, and fibrosis. The NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome is implicated in a variety of human diseases including Alzheimer’s disease (AD), prion diseases, type 2 diabetes, and numerous infectious diseases. By examining the use of 4,4′-diaminodiphenyl sulfone (DDS) in the treatment of patients with Hansen’s disease, also diagnosed as Alzheimer’s disease, this study demonstrates the diverse mechanisms involved in the activation of inflammasomes. TLRs, due to genetic polymorphisms, can alter the immune response to a wide variety of microbial ligands, including viruses. In particular, TLR2Arg677Trp was reported to be exclusively present in Korean patients with lepromatous leprosy (LL). Previously, mutation of the intracellular domain of TLR2 has demonstrated its role in determining the susceptibility to LL, though LL was successfully treated using a combination of DDS with rifampicin and clofazimine. Of the three tested antibiotics, DDS was effective in the molecular regulation of NLRP3 inflammasome activators that are important in mild cognitive impairment (MCI), Parkinson’s disease (PD), and AD. The specific targeting of NLRP3 itself or up-/downstream factors of the NLRP3 inflammasome by DDS may be responsible for its observed preventive effects, functioning as a competitor.

No association of toll-like receptor 2 polymorphisms with Alzheimer's disease in Han Chinese

2011 ◽  
Vol 32 (10) ◽  
pp. 1924.e1-1924.e3 ◽  
Author(s):  
Jin-Tai Yu ◽  
Yan-Ping Sun ◽  
Jiang-Rong Ou ◽  
Wei-Zhen Cui ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Han Chinese ◽  
Toll Like Receptor ◽  
Toll Like Receptor 2
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