scholarly journals Hydroxypyridinone-Diamine Hybrids as Potential Neuroprotective Agents in the PC12 Cell-Line Model of Alzheimer's Disease

2019 ◽  
Vol 12 (4) ◽  
pp. 162
Author(s):  
Lohou ◽  
Sasaki ◽  
Boullier ◽  
Duplantier ◽  
Sonnet
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Advanced Glycation Endproducts ◽  
Carbonyl Stress ◽  
Glycation Endproducts ◽  
New Therapeutic Approaches ◽  
Reactive Carbonyl Species ◽  
Model Of Alzheimer’S Disease ◽  
Induced Apoptosis

There is an urgent need to propose effective treatments for Alzheimer’s disease (AD). Although the origin of the disease is poorly understood, several therapeutic options have been proposed. The new therapeutic approaches targeting biometal-mediated neurodegenerative pathways appear to be interesting ones. As a continuation of our preceding studies, two novel series of advanced glycation endproducts (AGE)/advanced lipid peroxidation endproducts (ALE) inhibitors have been developed as multifunctional scavengers. This extended work allowed us to highlight the new hydroxypyridinone-diamine hybrid IIa-3 bearing a C4 alkyl linker between the two pharmacophores. This derivative exhibited preserved potent capacities to trap reactive carbonyl species (vicinal diamine function) as well as reactive oxygen species and transition metals (hydroxypyridinone moiety) in comparison with previously described lead compound 1. In addition, its good predicted absorption, distribution, metabolism and excretion (ADME) properties were correlated with a better efficacy to inhibit in vitro methylglyoxal-induced apoptosis in neuronal-like PC12 cells. This new promising agent revealed improved druglikeness and ability to prevent biometal-mediated oxidative and carbonyl stress amplification involved in AD pathogenesis.

scholarly journals Caffeine consumption during pregnancy accelerates the development of cognitive deficits in offspring in a model of tauopathy

2019 ◽  
Author(s):  
Stefania Zappettini ◽  
Emilie Faivre ◽  
Antoine Ghestem ◽  
Sébastien Carrier ◽  
Luc Buée ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Life ◽  
Pyramidal Cells ◽  
Tau Pathology ◽  
Caffeine Consumption ◽  
Early Life Exposure ◽  
Model Of Alzheimer’S Disease ◽  
Electrophysiological Recordings

AbstractPsychoactive drugs used during pregnancy can affect the development of the brain of offspring, directly triggering neurological disorders or increasing the risk for their occurrence. Caffeine is the most widely consumed psychoactive drug, including during pregnancy. In Wild type mice, early life exposure to caffeine renders offspring more susceptible to seizures. Here, we tested the long-term consequences of early life exposure to caffeine in THY-Tau22 transgenic mice, a model of Alzheimer’s disease-like Tau pathology. Caffeine exposed mutant offspring developed cognitive earlier than water treated mutants. Electrophysiological recordings of hippocampal CA1 pyramidal cells in vitro revealed that early life exposure to caffeine changed the way the glutamatergic and GABAergic drives were modified by the Tau pathology. We conclude that early-life exposure to caffeine affects the Tau phenotype and we suggest that caffeine exposure during pregnancy may constitute a risk-factor for early onset of Alzheimer’s disease-like pathology.

scholarly journals Red Ginseng Attenuates Aβ-Induced Mitochondrial Dysfunction and Aβ-mediated Pathology in an Animal Model of Alzheimer’s Disease

2019 ◽  
Vol 20 (12) ◽  
pp. 3030 ◽  
Author(s):  
Soo Jung Shin ◽  
Seong Gak Jeon ◽  
Jin-il Kim ◽  
Yu-on Jeong ◽  
Sujin Kim ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hippocampal Formation ◽  
Experimental Models ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Red Ginseng ◽  
Model Of Alzheimer’S Disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease and is characterized by neurodegeneration and cognitive deficits. Amyloid beta (Aβ) peptide is known to be a major cause of AD pathogenesis. However, recent studies have clarified that mitochondrial deficiency is also a mediator or trigger for AD development. Interestingly, red ginseng (RG) has been demonstrated to have beneficial effects on AD pathology. However, there is no evidence showing whether RG extract (RGE) can inhibit the mitochondrial deficit-mediated pathology in the experimental models of AD. The effects of RGE on Aβ-mediated mitochondrial deficiency were investigated in both HT22 mouse hippocampal neuronal cells and the brains of 5XFAD Aβ-overexpressing transgenic mice. To examine whether RGE can affect mitochondria-related pathology, we used immunohistostaining to study the effects of RGE on Aβ accumulation, neuroinflammation, neurodegeneration, and impaired adult hippocampal neurogenesis in hippocampal formation of 5XFAD mice. In vitro and in vivo findings indicated that RGE significantly improves Aβ-induced mitochondrial pathology. In addition, RGE significantly ameliorated AD-related pathology, such as Aβ deposition, gliosis, and neuronal loss, and deficits in adult hippocampal neurogenesis in brains with AD. Our results suggest that RGE may be a mitochondria-targeting agent for the treatment of AD.

scholarly journals Increased levels of Stress-inducible phosphoprotein-1 accelerates amyloid-β deposition in a mouse model of Alzheimer’s disease

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Rachel E. Lackie ◽  
Jose Marques-Lopes ◽  
Valeriy G. Ostapchenko ◽  
Sarah Good ◽  
Wing-Yiu Choy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Protein Quality ◽  
Amyloid Β ◽  
Amyloid Burden ◽  
C Elegans ◽  
Model Of Alzheimer’S Disease

Abstract Molecular chaperones and co-chaperones, which are part of the protein quality control machinery, have been shown to regulate distinct aspects of Alzheimer’s Disease (AD) pathology in multiple ways. Notably, the co-chaperone STI1, which presents increased levels in AD, can protect mammalian neurons from amyloid-β toxicity in vitro and reduced STI1 levels worsen Aβ toxicity in C. elegans. However, whether increased STI1 levels can protect neurons in vivo remains unknown. We determined that overexpression of STI1 and/or Hsp90 protected C. elegans expressing Aβ(3–42) against Aβ-mediated paralysis. Mammalian neurons were also protected by elevated levels of endogenous STI1 in vitro, and this effect was mainly due to extracellular STI1. Surprisingly, in the 5xFAD mouse model of AD, by overexpressing STI1, we find increased amyloid burden, which amplifies neurotoxicity and worsens spatial memory deficits in these mutants. Increased levels of STI1 disturbed the expression of Aβ-regulating enzymes (BACE1 and MMP-2), suggesting potential mechanisms by which amyloid burden is increased in mice. Notably, we observed that STI1 accumulates in dense-core AD plaques in both 5xFAD mice and human brain tissue. Our findings suggest that elevated levels of STI1 contribute to Aβ accumulation, and that STI1 is deposited in AD plaques in mice and humans. We conclude that despite the protective effects of STI1 in C. elegans and in mammalian cultured neurons, in vivo, the predominant effect of elevated STI1 is deleterious in AD.

Netrin-1 Interrupts Amyloid-β Amplification, Increases sAβPPα in vitro and in vivo, and Improves Cognition in a Mouse Model of Alzheimer’s Disease

2016 ◽  
Vol 52 (1) ◽  
pp. 223-242 ◽  
Author(s):  
Patricia R. Spilman ◽  
Veronique Corset ◽  
Olivia Gorostiza ◽  
Karen S. Poksay ◽  
Veronica Galvan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Amyloid Β ◽  
Model Of Alzheimer’S Disease

scholarly journals Modulatory Effects of Alpha- and Gamma-Tocopherol on the Mitochondrial Respiratory Capacity and Membrane Potential in an In Vitro Model of Alzheimer’s Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Aslina Pahrudin Arrozi ◽  
Wan Zurinah Wan Ngah ◽  
Hanafi Ahmad Damanhuri ◽  
Suzana Makpol
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Membrane Potential ◽  
Mitochondrial Function ◽  
Oxidative Metabolism ◽  
Respiratory Capacity ◽  
Gamma Tocopherol ◽  
Model Of Alzheimer’S Disease ◽  
Mitochondrial Oxidative Metabolism

Increased amyloid-beta (Aβ) and amyloid precursor protein (APP) in the brains of Alzheimer’s disease (AD) patients are common pathological hallmarks mediating the disease progression. Growing evidence also suggests that mitochondrial abnormalities are an early feature in the pathogenesis of AD. Intervention with antioxidants has received great interest as a molecular strategy for the manipulation of mitochondrial function. Our previous preliminary study using in vitro cell models expressing different types of APP demonstrated that treatment with alpha-tocopherol (ATF) or gamma-tocopherol (GTF) modulates mitochondrial function by reducing mitochondrial reactive oxygen species (ROS), increasing the production of ATP and preventing apoptosis events, especially in cells expressing the mutant APP form. Thus, we hypothesized that ATF or GTF treatment might also alter mitochondrial metabolic pathways such as oxidative phosphorylation. The present study aimed to investigate the role of ATF and GTF in modulating mitochondrial oxidative metabolism using high-resolution respirometry. Our results showed that both ATF and GTF increased the respiratory capacity and membrane potential in the ROUTINE and OXPHOSCI-LINKED states as well as complex IV enzyme activity in wild-type and mutant APP-overexpressing SH-SY5Y cells. Although preliminary, these findings indicate that ATF and GTF modulate mitochondrial oxidative metabolism in APP-overexpressing cells and, in part, may contribute to the planning of strategies for utilizing vitamin E isomers against mitochondrial-related diseases such as AD.

Sign in / Sign up

Export Citation Format

Share Document