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.

scholarly journals Mesenchymal Stem Cell-Derived Extracellular Vesicle-Based Therapy for Alzheimer’s Disease: Progress and Opportunity

Membranes ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 796
Author(s):  
Yi-An Chen ◽  
Cheng-Hsiu Lu ◽  
Chien-Chih Ke ◽  
Ren-Shyan Liu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Extracellular Vesicle ◽  
Synaptic Loss ◽  
Molecular Machinery ◽  
And Function ◽  
Preclinical And Clinical Studies ◽  
Ad Therapy

Alzheimer’s disease (AD), as a neurodegenerative disorder, is characterized by mass neuronal and synaptic loss and, currently, there are no successful curative therapies. Extracellular vesicles (EVs) are an emerging approach to intercellular communication via transferring cellular materials such as proteins, lipids, mRNAs, and miRNAs from parental cells to recipient cells, leading to the reprogramming of the molecular machinery. Numerous studies have suggested the therapeutic potential of EVs derived from mesenchymal stem cells (MSCs) in the treatment of AD, based on the neuroprotective, regenerative and immunomodulatory effects as effective as MSCs. In this review, we focus on the biology and function of EVs, the potential of MSC-derived EVs for AD therapy in preclinical and clinical studies, as well as the potent mechanisms of MSC-derived EVs actions. Finally, we highlight the modification strategies and diagnosis utilities in order to make advance in this field.

scholarly journals Soluble Prion Peptide 107–120 Protects Neuroblastoma SH-SY5Y Cells against Oligomers Associated with Alzheimer’s Disease

2020 ◽  
Vol 21 (19) ◽  
pp. 7273
Author(s):  
Elham Rezvani Boroujeni ◽  
Seyed Masoud Hosseini ◽  
Giulia Fani ◽  
Cristina Cecchi ◽  
Fabrizio Chiti
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Amyloid Β ◽  
Cellular Prion Protein ◽  
Ros Generation ◽  
Aβ Oligomers ◽  
Self Recognition ◽  
High Affinity Receptor

Alzheimer’s disease (AD) is the most prevalent form of dementia and soluble amyloid β (Aβ) oligomers are thought to play a critical role in AD pathogenesis. Cellular prion protein (PrPC) is a high-affinity receptor for Aβ oligomers and mediates some of their toxic effects. The N-terminal region of PrPC can interact with Aβ, particularly the region encompassing residues 95–110. In this study, we identified a soluble and unstructured prion-derived peptide (PrP107–120) that is external to this region of the sequence and was found to successfully reduce the mitochondrial impairment, intracellular ROS generation and cytosolic Ca2+ uptake induced by oligomeric Aβ42 ADDLs in neuroblastoma SH-SY5Y cells. PrP107–120 was also found to rescue SH-SY5Y cells from Aβ42 ADDL internalization. The peptide did not change the structure and aggregation pathway of Aβ42 ADDLs, did not show co-localization with Aβ42 ADDLs in the cells and showed a partial colocalization with the endogenous cellular PrPC. As a sequence region that is not involved in Aβ binding but in PrP self-recognition, the peptide was suggested to protect against the toxicity of Aβ42 oligomers by interfering with cellular PrPC and/or activating a signaling that protected the cells. These results strongly suggest that PrP107–120 has therapeutic potential for AD.

Peptidylarginine Deiminase and Alzheimer’s Disease

2021 ◽  
pp. 1-12
Author(s):  
Lai Wang ◽  
Hongyang Chen ◽  
Jing Tang ◽  
Zhengwei Guo ◽  
Yanming Wang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Drug Targets ◽  
Therapeutic Potential ◽  
Peptidylarginine Deiminase ◽  
Post Translational Modification ◽  
Rodent Brain ◽  
The Central Nervous System ◽  
And Function ◽  
The Relationship

Peptidylarginine deiminases (PADs) are indispensable enzymes for post-translational modification of proteins, which can convert Arg residues on the surface of proteins to citrulline residues. The PAD family has five isozymes, PAD1, 2, 3, 4, and 6, which have been found in multiple tissues and organs. PAD2 and PAD4 were detected in cerebral cortex and hippocampus from human and rodent brain. In the central nervous system, abnormal expression and activation of PADs are involved in the pathological changes and pathogenesis of Alzheimer’s disease (AD). This article reviews the classification, distribution, and function of PADs, with an emphasis on the relationship between the abnormal activation of PADs and AD pathogenesis, diagnosis, and the therapeutic potential of PADs as drug targets for AD.

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 A Perfect sTORm: The Role of the Mammalian Target of Rapamycin (mTOR) in Cerebrovascular Dysfunction of Alzheimer's Disease: A Mini-Review

Gerontology ◽  
2018 ◽  
Vol 64 (3) ◽  
pp. 205-211 ◽  
Author(s):  
Candice E. Van Skike ◽  
Veronica Galvan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
Critical Role ◽  
Mammalian Target Of Rapamycin ◽  
Cerebrovascular Reactivity ◽  
Target Of Rapamycin ◽  
Cerebrovascular Function ◽  
Cerebrovascular Dysfunction

Cerebrovascular dysfunction is detected prior to the onset of cognitive and histopathological changes in Alzheimer's disease (AD). Increasing evidence indicates a critical role of cerebrovascular dysfunction in the initiation and progression of AD. Recent studies identified the mechanistic/mammalian target of rapamycin (mTOR) as a critical effector of cerebrovascular dysfunction in AD. mTOR has a key role in the regulation of metabolism, but some mTOR-dependent mechanisms are uniquely specific to the regulation of cerebrovascular function. These include the regulation of cerebral blood flow, blood-brain barrier integrity and maintenance, neurovascular coupling, and cerebrovascular reactivity. This article examines the available evidence for a role of mTOR-driven cerebrovascular dysfunction in the pathogenesis of AD and of vascular cognitive impairment and dementia (VCID) and highlights the therapeutic potential of targeting mTOR and/or specific downstream effectors for vasculoprotection in AD, VCID, and other age-associated neurological diseases with cerebrovascular etiology.

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.

The glial glutamate transporter, GLT-1, is oxidatively modified by 4-hydroxy-2-nonenal in the Alzheimer's disease brain: the role of Aβ1-42

2001 ◽  
Vol 78 (2) ◽  
pp. 413-416 ◽  
Author(s):  
Christopher M. Lauderback ◽  
Janna M. Hackett ◽  
Feng F. Huang ◽  
Jeffrey N. Keller ◽  
Luke I. Szweda ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glutamate Transporter ◽  
Glial Glutamate Transporter ◽  
Oxidatively Modified
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