scholarly journals A Novel Inhibitor Targeting NLRP3 Inflammasome Reduces Neuropathology and Improves Cognitive Function in Alzheimer’s Disease Transgenic Mice

2021 ◽  
pp. 1-15
Author(s):  
Ram Kuwar ◽  
Andrew Rolfe ◽  
Long Di ◽  
Hallie Blevins ◽  
Yiming Xu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecule ◽  
Cognitive Functions ◽  
Nlrp3 Inflammasome ◽  
Small Molecule Inhibitors ◽  
Critical Role ◽  
Hippocampal Neurogenesis ◽  
Synaptic Proteins ◽  
Essential Components

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, and the most common type of dementia. A growing body of evidence has implicated neuroinflammation as an essential player in the etiology of AD. Inflammasomes are intracellular multiprotein complexes and essential components of innate immunity in response to pathogen- and danger-associated molecular patterns. Among the known inflammasomes, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a critical role in the pathogenesis of AD. Objective: We recently developed a novel class of small molecule inhibitors that selectively target the NLRP3 inflammasome. One of the lead compounds, JC124, has shown therapeutic efficacy in a transgenic animal model of AD. In this study we will test the preventative efficacy of JC124 in another strain of transgenic AD mice. Methods: In this study, 5-month-old female APP/PS1 and matched wild type mice were treated orally with JC124 for 3 months. After completion of treatment, cognitive functions and AD pathologies, as well as protein expression levels of synaptic proteins, were assessed. Results: We found that inhibition of NLRP3 inflammasome with JC124 significantly decreased multiple AD pathologies in APP/PS1 mice, including amyloid-β (Aβ) load, neuroinflammation, and neuronal cell cycle re-entry, accompanied by preserved synaptic plasticity with higher expression of pre- and post-synaptic proteins, increased hippocampal neurogenesis, and improved cognitive functions. Conclusion: Our study demonstrates the importance of the NLRP3 inflammasome in AD pathological development, and pharmacological inhibition of NLRP3 inflammasome with small molecule inhibitors represents a potential therapy for AD.

scholarly journals Restored glial glutamate transporter EAAT2 function as a potential therapeutic approach for Alzheimer’s disease

2015 ◽  
Vol 212 (3) ◽  
pp. 319-332 ◽  
Author(s):  
Kou Takahashi ◽  
Qiongman Kong ◽  
Yuchen Lin ◽  
Nathan Stouffer ◽  
Delanie A. Schulte ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Functions ◽  
Protein Function ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Glutamate Transporter ◽  
Glial Glutamate Transporter ◽  
Disease Modifier ◽  
And Function

Glutamatergic systems play a critical role in cognitive functions and are known to be defective in Alzheimer’s disease (AD) patients. Previous literature has indicated that glial glutamate transporter EAAT2 plays an essential role in cognitive functions and that loss of EAAT2 protein is a common phenomenon observed in AD patients and animal models. In the current study, we investigated whether restored EAAT2 protein and function could benefit cognitive functions and pathology in APPSw,Ind mice, an animal model of AD. A transgenic mouse approach via crossing EAAT2 transgenic mice with APPSw,Ind. mice and a pharmacological approach using a novel EAAT2 translational activator, LDN/OSU-0212320, were conducted. Findings from both approaches demonstrated that restored EAAT2 protein function significantly improved cognitive functions, restored synaptic integrity, and reduced amyloid plaques. Importantly, the observed benefits were sustained one month after compound treatment cessation, suggesting that EAAT2 is a potential disease modifier with therapeutic potential for AD.

The Development of Small Molecule Inhibitors of Glutaminyl Cyclase and Isoglutaminyl Cyclase for Alzheimer's Disease

2019 ◽  
Vol 4 (35) ◽  
pp. 10591-10600 ◽  
Author(s):  
Ana Xu ◽  
Feng He ◽  
Chenggong Yu ◽  
Ying Qu ◽  
Qiuqiong Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Glutaminyl Cyclase

Inhibition of microRNA-155 Alleviates Cognitive Impairment in Alzheimer’s Disease and Involvement of Neuroinflammation

2019 ◽  
Vol 16 (6) ◽  
pp. 473-482 ◽  
Author(s):  
Dandan Liu ◽  
Dandan Zhao ◽  
Yingkai Zhao ◽  
Yan Wang ◽  
Yong Zhao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Functions ◽  
Spatial Working Memory ◽  
Critical Role ◽  
Learning Performance ◽  
Intracerebroventricular Infusion ◽  
Tnf Α ◽  
Current Report

Background: Neuroinflammation has important effects on cognitive functions in the pathophysiological process of Alzheimer’s Disease (AD). In the current report, we determined the effects of microRNA-155 (miR-155) on the levels of IL-1β, IL-6 and TNF-α, and their respective receptors in the hippocampus using a rat model of AD. Methods: Real-time RT-PCR, ELISA and western blot analysis were used to examine the miR-155, PICs and PIC receptors. The Morris water maze and spatial working memory tests were used to assess cognitive functions. Results: miR-155 was increased in the hippocampus of AD rats, accompanied by amplification of IL-1β, IL-6 and TNF-α. Intracerebroventricular infusion of miR-155 inhibitor, but not its scramble attenuated the increases of IL-1β, IL-6 and TNF-α and upregulation of their receptors. MiR-155 inhibitor also attenuated upregulation of apoptotic Caspase-3 in the hippocampus of AD rats. Notably, inhibition of miR- 155 or PIC receptors largely recovered the impaired learning performance in AD rat. Conclusion: We showed the critical role of miR-155 in regulating the memory impairment in AD rats likely via engagement of neuroinflammatory mechanisms, suggesting that miR-155 and its signaling molecules may present prospects in preventing and/or improving the development of the impaired cognitive functions in AD.

scholarly journals Porphyromonas gingivalisin Alzheimer’s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors

2019 ◽  
Vol 5 (1) ◽  
pp. eaau3333 ◽  
Author(s):  
Stephen S. Dominy ◽  
Casey Lynch ◽  
Florian Ermini ◽  
Malgorzata Benedyk ◽  
Agata Marczyk ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Bacterial Load ◽  
Brain Infection ◽  
Disease Causation ◽  
The Brain

Porphyromonas gingivalis, the keystone pathogen in chronic periodontitis, was identified in the brain of Alzheimer’s disease patients. Toxic proteases from the bacterium called gingipains were also identified in the brain of Alzheimer’s patients, and levels correlated with tau and ubiquitin pathology. OralP. gingivalisinfection in mice resulted in brain colonization and increased production of Aβ1–42, a component of amyloid plaques. Further, gingipains were neurotoxic in vivo and in vitro, exerting detrimental effects on tau, a protein needed for normal neuronal function. To block this neurotoxicity, we designed and synthesized small-molecule inhibitors targeting gingipains. Gingipain inhibition reduced the bacterial load of an establishedP. gingivalisbrain infection, blocked Aβ1–42production, reduced neuroinflammation, and rescued neurons in the hippocampus. These data suggest that gingipain inhibitors could be valuable for treatingP. gingivalisbrain colonization and neurodegeneration in Alzheimer’s disease.

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