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.

scholarly journals Astrocytic transporters in Alzheimer's disease

2017 ◽  
Vol 474 (3) ◽  
pp. 333-355 ◽  
Author(s):  
Chris Ugbode ◽  
Yuhan Hu ◽  
Benjamin Whalley ◽  
Chris Peers ◽  
Marcus Rattray ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Stage ◽  
Neurological Diseases ◽  
Current Evidence ◽  
Specific Targeting ◽  
Disease Modifying Therapies ◽  
The Central Nervous System ◽  
Disease Modifying ◽  
And Function

Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at an early stage in neurological diseases, including Alzheimer's disease (AD). These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease-modifying therapies for AD, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of AD. A small number of the 400 transporter superfamilies are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in AD. Here, we review the current evidence for six astrocytic transporter subfamilies involved in AD, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling 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 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.

Acetylcholinesterase Enzyme Inhibitor Molecules with Therapeutic Potential for Alzheimer's Disease

2021 ◽  
Vol 20 ◽  
Author(s):  
Bhuvaneswari Siwaraman ◽  
Vijaykumar R. ◽  
Bala Aakash Velmurugan ◽  
Ramalakshmi Natarajan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Enzyme Inhibitor ◽  
Therapeutic Potential ◽  
Psychological Symptoms ◽  
Heteroaromatic Compounds ◽  
The Central Nervous System ◽  
The Many ◽  
Acetylcholinesterase Enzyme ◽  
Ellman’S Method

: Acetylcholinesterase (AchE), hydrolase enzyme, regulates the hydrolysis of acetylcholine neurotransmitter in the neurons. AchE is found majorly in the central nervous system at the site of cholinergic neurotransmission. It is involved in the pathophysiology of Alzheimer’s disease-causing dementia, cognitive impairment, behavioral and psychological symptoms. Recent findings involved the inhibition of AchE that could aid in the treatment of Alzheimer's. Many drugs of different classes being analyzed in the clinical trials and examined for their potency. Drugs that are used in the treatment of Alzheimer’s disease are donepezil, galantamine, tacrine, rivastigmine shows major adverse effects. To overcome this, researchers work on novel drugs to elicit inhibition. This review comprises the many hybrids and non-hybrid forms of heteroaromatic and non-heteroaromatic compounds that were designed and evaluated for AchE inhibition by Ellman’s method of assay. These novel compounds may assist the future perspectives in the discovery of novel moieties against Alzheimer’s disease by the inhibition of AchE.

scholarly journals Neuroinflammation in Alzheimer’s Disease

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 524
Author(s):  
Isaac G. Onyango ◽  
Gretsen V. Jauregui ◽  
Mária Čarná ◽  
James P. Bennett ◽  
Gorazd B. Stokin
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Defense Mechanisms ◽  
Low Grade ◽  
Neurodegenerative Process ◽  
The Central Nervous System ◽  
Peripheral Immune Cells ◽  
The Relationship ◽  
The Brain ◽  
Gut Microbiota Dysbiosis

Alzheimer’s disease (AD) is a neurodegenerative disease associated with human aging. Ten percent of individuals over 65 years have AD and its prevalence continues to rise with increasing age. There are currently no effective disease modifying treatments for AD, resulting in increasingly large socioeconomic and personal costs. Increasing age is associated with an increase in low-grade chronic inflammation (inflammaging) that may contribute to the neurodegenerative process in AD. Although the exact mechanisms remain unclear, aberrant elevation of reactive oxygen and nitrogen species (RONS) levels from several endogenous and exogenous processes in the brain may not only affect cell signaling, but also trigger cellular senescence, inflammation, and pyroptosis. Moreover, a compromised immune privilege of the brain that allows the infiltration of peripheral immune cells and infectious agents may play a role. Additionally, meta-inflammation as well as gut microbiota dysbiosis may drive the neuroinflammatory process. Considering that inflammatory/immune pathways are dysregulated in parallel with cognitive dysfunction in AD, elucidating the relationship between the central nervous system and the immune system may facilitate the development of a safe and effective therapy for AD. We discuss some current ideas on processes in inflammaging that appear to drive the neurodegenerative process in AD and summarize details on a few immunomodulatory strategies being developed to selectively target the detrimental aspects of neuroinflammation without affecting defense mechanisms against pathogens and tissue damage.

scholarly journals Iron Homeostasis Disorder and Alzheimer’s Disease

2021 ◽  
Vol 22 (22) ◽  
pp. 12442
Author(s):  
Yu Peng ◽  
Xuejiao Chang ◽  
Minglin Lang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Body ◽  
Iron Homeostasis ◽  
Regulation Mechanism ◽  
The Central Nervous System ◽  
Strict Regulation ◽  
Genetic And Environmental Factors ◽  
Almost All ◽  
The Relationship

Iron is an essential trace metal for almost all organisms, including human; however, oxidative stress can easily be caused when iron is in excess, producing toxicity to the human body due to its capability to be both an electron donor and an electron acceptor. Although there is a strict regulation mechanism for iron homeostasis in the human body and brain, it is usually inevitably disturbed by genetic and environmental factors, or disordered with aging, which leads to iron metabolism diseases, including many neurodegenerative diseases such as Alzheimer’s disease (AD). AD is one of the most common degenerative diseases of the central nervous system (CNS) threatening human health. However, the precise pathogenesis of AD is still unclear, which seriously restricts the design of interventions and treatment drugs based on the pathogenesis of AD. Many studies have observed abnormal iron accumulation in different regions of the AD brain, resulting in cognitive, memory, motor and other nerve damages. Understanding the metabolic balance mechanism of iron in the brain is crucial for the treatment of AD, which would provide new cures for the disease. This paper reviews the recent progress in the relationship between iron and AD from the aspects of iron absorption in intestinal cells, storage and regulation of iron in cells and organs, especially for the regulation of iron homeostasis in the human brain and prospects the future directions for AD treatments.

scholarly journals CORRELATION BETWEEN COGNITION AND FUNCTION ACROSS THE SPECTRUM OF ALZHEIMER’S DISEASE

2016 ◽  
pp. 1-7
Author(s):  
H. Liu-Seifert ◽  
E. Siemers ◽  
K. Selzler ◽  
K. Sundell ◽  
P. Aisen ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Disease Progression ◽  
Mmse Score ◽  
Disease Stage ◽  
Two Phase ◽  
Identity Studies ◽  
Moderate Dementia ◽  
And Function ◽  
The Relationship

Background: Both cognitive and functional deterioration are characteristic of the clinical progression of Alzheimer’s disease (AD). Objectives: To systematically assess correlations between widely used measures of cognition and function across the spectrum of AD. Design: Spearman rank correlations were calculated for cognitive and functional measures across datasets from various AD patient populations. Setting: Post-hoc analysis from existing databases. Participants: Pooled data from placebo-treated patients with mild (MMSE score ≥20 and ≤26) and moderate (MMSE score ≥16 and ≤19) AD dementia from two Phase 3 solanezumab (EXPEDITION/2) and two semagecesatat (IDENTITY/2) studies and normal, late mild cognitive impairment (LMCI) and mild AD patients from the Alzheimer’s Disease Neuroimaging Initiative 2-Grand Opportunity (ADNI-2/GO). Intervention (if any): Placebo (EXPEDITION/2 and IDENTITY/2 subjects) Measurements: Cognitive and functional abilities were measured in all datasets. Data were collected at baseline and every three months for 18 months in EXPEDITION and IDENTITY studies; and at baseline, 6, 12, and 24 months in the ADNI dataset. Results: The relationship of cognition and function became stronger over time as AD patients progressed from preclinical to moderate dementia disease stages, with the magnitude of correlations dependent on disease stage and the complexity of functional task. The correlations were minimal in the normal control population, but became stronger with disease progression. Conclusions: This analysis found that measures of cognition and function become more strongly correlated with disease progression from preclinical to moderate dementia across multiple datasets. These findings improve the understanding of the relationship between cognitive and functional clinical measures during the course of AD progression and how cognition and function measures relate to each other in AD clinical trials.

CD200-, CX3CL1-, and TREM2-mediated neuron-microglia interactions and their involvements in Alzheimer’s disease

2018 ◽  
Vol 29 (8) ◽  
pp. 837-848 ◽  
Author(s):  
Lihang Zhang ◽  
Juan Xu ◽  
Jinchao Gao ◽  
Yuncheng Wu ◽  
Ming Yin ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Central Nervous System ◽  
Dependent Manner ◽  
Independent Manner ◽  
Physiological Conditions ◽  
The Central Nervous System ◽  
And Function ◽  
Cluster Of Differentiation ◽  
The Brain

Abstract Neurons and microglia are two major components in the central nervous system (CNS). The interactions between them play important roles in maintaining homeostasis of the brain. In recent years, substantial studies have focused on the interactions between neurons and microglia, revealing that microglia become reactive when the interactions are pathophysiologically interfered, usually accompanying neuronal injury, which is a common feature for Alzheimer’s disease (AD). Many molecules and factors participate in these physiological and pathological processes, either in a contact-dependent or a contact-independent manner. Accumulating studies have revealed that in the CNS, cluster of differentiation-200 (CD200) and fractalkine (CX3CL1) expressed mainly on neurons and triggering receptor expressed on myeloid cells 2 (TREM2) expressed mainly on microglia. These molecules can mediate neuron-microglia interactions in a contact-dependent manner and contribute to the pathogenesis of AD. Here, we review the expression, distribution, and function of CD200, CX3CL1, and TREM2 in regulating neuron-microglia interactions under physiological conditions as well as in AD.

scholarly journals TNF-α-mediated reduction in inhibitory neurotransmission precedes sporadic Alzheimer’s disease pathology in young Trem2R47H rats

2020 ◽  
pp. jbc.RA120.016395
Author(s):  
Siqiang Ren ◽  
Lionel Breuillaud ◽  
Wen Yao ◽  
Tao Yin ◽  
Kelly A Norris ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Potential ◽  
Long Term Potentiation ◽  
Glutamate Excitotoxicity ◽  
Inhibitory Neurotransmitter ◽  
Term Potentiation ◽  
Tnf Α ◽  
Neurodegenerative Dementia ◽  
The Central Nervous System

Alzheimer’s disease is a neurodegenerative dementia associated with deposition in the central nervous system (CNS) of amyloid plaques and neurofibrillary tangles, formed by Aβ peptides and phosphor-tau, respectively. ~2% of AD cases are due to familial mutations (FAD); ~98% of cases are sporadic (SAD). FAD animal models are commonly used to study SAD pathogenesis. Because mechanisms leading to FAD and SAD may be distinct, to study SAD pathogenesis we generated Trem2R47H knock-in rats, which carry the SAD risk factor p.R47H variant of the microglia gene Triggering Receptor Expressed on Myeloid Cells 2 (TREM2).  Trem2R47H rats produce human-Aβ from a humanized-App rat allele because human-Aβ is more toxic than rodent-Aβ and the pathogenic role of the p.R47H TREM2 variant has been linked to human-Aβ-clearing deficits. Using peri-adolescent Trem2R47H rats, we previously demonstrated that supraphysiological TNF-α boosts glutamatergic transmission, which is excitatory, and suppresses long-term potentiation (LTP), a surrogate of learning and memory. Here, we tested the effect of the p.R47H variant on the inhibitory neurotransmitter GABA. We report that GABAergic transmission is decreased in Trem2R47H/R47H rats. This decrease is due to acute and reversible action of TNF-α and is not associated with increased human-Aβ levels and AD-pathology. Thus, the p.R47H variant changes the excitatory/inhibitory balance, favoring excitation. This imbalance could potentiate glutamate excitotoxicity and contribute to neuronal dysfunction, enhanced neuronal death and neurodegeneration. Future studies will determine whether this imbalance represents an early, Aβ-independent pathway leading to dementia and may reveal the AD-modifying therapeutic potential of TNF-α inhibition in the CNS.

scholarly journals Neuroprotective Properties and Therapeutic Potential of Bone Marrow–Derived Microglia in Alzheimer’s Disease

2020 ◽  
Vol 35 ◽  
pp. 153331752092716 ◽  
Author(s):  
Chang Li ◽  
Yu-Hua Chen ◽  
Ke Zhang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Central Nervous System ◽  
Bone Marrow ◽  
Immune Cells ◽  
Therapeutic Potential ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Efficient Manner ◽  
The Central Nervous System

Alzheimer’s disease (AD) is the most common form of dementia, which is characterized by a progressive cognitive decline and senile plaques formed by amyloid β (Aβ). Microglia are the immune cells of the central nervous system (CNS). Studies have proposed 2 types of microglia, namely, the resident microglia and bone marrow–derived microglia (BMDM). Recent studies suggested that BMDM, not the resident microglia, can phagocytose Aβ, which has a great therapeutic potential in AD. Bone marrow–derived microglia can populate the CNS in an efficient manner and their functions can be regulated by some genes. Thus, methods that increase their recruitment and phagocytosis could be used as a new tool that clears Aβ and ameliorates cognitive impairment. Herein, we review the neuroprotective functions of BMDM and their therapeutic potential in AD.

Sign in / Sign up

Export Citation Format

Share Document