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

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.

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 Small molecule inhibitors of apolipoprotein E4‐catalyzed amyloid‐β fibrillization as novel therapeutics for Alzheimer’s disease

2020 ◽  
Vol 16 (S2) ◽  
Author(s):  
Noah R. Johnson ◽  
Athena Ching‐Jung Wang ◽  
Christina M. Coughlan ◽  
Esteban M. Lucero ◽  
Lisa Viltz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Amyloid Β ◽  
Apolipoprotein E4 ◽  
Novel Therapeutics
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