The Role of Oxidative Stress-Induced Epigenetic Alterations in Amyloid-βProduction in Alzheimer’s Disease

An increasing number of studies have proposed a strong correlation between reactive oxygen species (ROS)-induced oxidative stress (OS) and the pathogenesis of Alzheimer’s disease (AD). With over five million people diagnosed in the United States alone, AD is the most common type of dementia worldwide. AD includes progressive neurodegeneration, followed by memory loss and reduced cognitive ability. Characterized by the formation of amyloid-beta (Aβ) plaques as a hallmark, the connection between ROS and AD is compelling. Analyzing the ROS response of essential proteins in the amyloidogenic pathway, such as amyloid-beta precursor protein (APP) and beta-secretase (BACE1), along with influential signaling programs of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and c-Jun N-terminal kinase (JNK), has helped visualize the path between OS and Aβoverproduction. In this review, attention will be paid to significant advances in the area of OS, epigenetics, and their influence on Aβplaque assembly. Additionally, we aim to discuss available treatment options for AD that include antioxidant supplements, Asian traditional medicines, metal-protein-attenuating compounds, and histone modifying inhibitors.

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Mis-expression of the Alzheimer’s disease associated gene Ankyrin causes memory loss and shortened lifespan in Drosophila

10.1101/423129 ◽

2018 ◽

Author(s):

James P Higham ◽

Bilal R Malik ◽

Edgar Buhl ◽

Jenny Dawson ◽

Anna S Ogier ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Beta ◽

Neuronal Excitability ◽

Therapeutic Potential ◽

Association Studies ◽

Treatment Options ◽

Memory Loss ◽

Normal Function ◽

Mutant Proteins

ABSTRACTAlzheimer’s disease (AD) is the most common form of dementia and is characterized by the accumulation of extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles of hyperphosphorylated Tau, including the 4R0N isoform. Recent epigenome-wide association studies (EWAS) of AD have identified a number of loci that are differentially methylated in AD cortex. Indeed, hypermethylation of the Ankyrin 1 (ANK1) gene in AD has been reported in the cortex in numerous different post-mortem brain cohorts. Little is known about the normal function of ANK1 in the healthy brain, nor the role it may play in AD. We have generated Drosophila models to allow us to functionally characterize Drosophila Ank2, the ortholog of human ANK1. These models have targeted reduction in the expression of Ank2 in neurons. We find that Drosophila with reduced neuronal Ank2 expression have shortened lifespan, reduced locomotion, reduced memory and reduced neuronal excitability similar to flies overexpressing either human mutant APP (that leads to Aβ42 production) and MAPT (that leads to 0N4R Tau). Therefore, we show that the mis-expression of Ank2 can drive disease relevant processes and phenocopy some features of AD and we propose targeting ANK1 may have therapeutic potential. This represents the first study to characterize a gene implicated in AD, which was nominated from EWAS.Author summaryThe majority (>95%) of Alzheimer’s disease (AD) cases are sporadic, with their incidence attributed to common genetic mutations, epigenetic variation, aging and the environment. There is no cure for AD and only limited treatment options which only treat the symptoms of AD and only work in some people. Recent epigenome-wide association studies (EWAS) in AD have highlighted hypermethylation of the Ankyrin1 (ANK1) gene in AD cortex. Little is known of the normal role of the gene in the brain. Here, we have demonstrated that Drosophila with reduced neuronal expression of the Drosophila ortholog of human ANK1 (Ank2), can drive AD relevant processes including locomotor difficulties, memory loss and shortened lifespan similar to expression of human amyloid-Beta or tau mutant proteins. Furthermore, increasing Ank2 expression reversed the memory loss caused by expression of human amyloid-Beta or tau mutant proteins, suggesting that targeting ANK1 may have therapeutic potential. This represents the first study to characterize a gene implicated in AD, which was nominated from EWAS.

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Oxidative Stress and Amyloid Beta Toxicity in Alzheimer’s Disease: Intervention in a Complex Relationship by Antioxidants

Current Medicinal Chemistry ◽

10.2174/09298673113209990152 ◽

2013 ◽

Vol 20 (37) ◽

pp. 4648-4664 ◽

Cited By ~ 35

Author(s):

S. Chakrabarti ◽

M. Sinha ◽

I. Thakurta ◽

P. Banerjee ◽

M. Chattopadhyay

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Beta ◽

Complex Relationship

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Oxidative Stress Targeting Amyloid Beta Accumulation and Clearance in Alzheimer’s Disease: Insight into Pathological Mechanisms and Therapeutic Strategies

Current Psychopharmacologye ◽

10.2174/2211556009666191231155927 ◽

2020 ◽

Vol 9 (1) ◽

pp. 22-42

Author(s):

Sunpreet Kaur ◽

Puneet Kumar ◽

Shamsher Singh

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Beta ◽

Neurodegenerative Disorder ◽

Acetylcholinesterase Inhibitors ◽

The Elderly ◽

Biochemical Alterations ◽

App Trafficking ◽

Copper Aluminum

Background: Alzheimer’s disease is the most common neurodegenerative disorder affecting the elderly population and emerges as a leading challenge for the scientific research community. The wide pathological aspects of AD made it a multifactorial disorder and even after long time it’s difficult to treat due to unexplored etiological factors. Methods: The etiogenesis of AD includes mitochondrial failure, gut dysbiosis, biochemical alterations but deposition of amyloid-beta plaques and neurofibrillary tangles are implicated as major hallmarks of neurodegeneration in AD. The aggregates of these proteins disrupt neuronal signaling, enhance oxidative stress and reduce activity of various cellular enzymes which lead to neurodegeneration in the cerebral cortex, neocortex and hippocampus. The metals like copper, aluminum are involved in APP trafficking and promote amyloidbeta aggregation. Similarly, disturbed ubiquitin proteasomal system, autophagy and amyloid- beta clearance mechanisms exert toxic insult in the brain. Result and conclusion : The current review explored the role of oxidative stress in disruption of amyloid homeostasis which further leads to amyloid-beta plaque formation and subsequent neurodegeneration in AD. Presently, management of AD relies on the use of acetylcholinesterase inhibitors, antioxidants and metal chelators but they are not specific measures. Therefore, in this review, we have widely cited the various pathological mechanisms of AD as well as possible therapeutic targets.

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Lipoprotein-Based Nanoparticles Rescue the Memory Loss of Mice with Alzheimer’s Disease by Accelerating the Clearance of Amyloid-Beta

ACS Nano ◽

10.1021/nn4058215 ◽

2014 ◽

Vol 8 (3) ◽

pp. 2345-2359 ◽

Cited By ~ 110

Author(s):

Qingxiang Song ◽

Meng Huang ◽

Lei Yao ◽

Xiaolin Wang ◽

Xiao Gu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Beta ◽

Memory Loss

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Ginkgo biloba and vitamin E for Alzheimer's disease

Mental Health Clinician ◽

10.9740/mhc.n107157 ◽

2012 ◽

Vol 1 (11) ◽

pp. 283-284

Author(s):

Chris Paxos

Keyword(s):

United States ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Vitamin E ◽

Drug Administration ◽

Ginkgo Biloba ◽

Food And Drug Administration ◽

Treatment Options ◽

The United States ◽

Additional Treatment

Alzheimer's disease affects an estimated 35 million people worldwide, with over 5 million affected in the United States. Few medications are currently approved by the Food and Drug Administration (FDA) for the treatment of Alzheimer's disease; subsequently, patients and caregivers often look for additional treatment options. This article reviews studies evaluating the use of Ginkgo biloba and vitamin E for the treatment of Alzheimer's disease.

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Protective Effect of Kaempferol on the Transgenic Drosophila Model of Alzheimer’s Disease

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527317666180508123050 ◽

2018 ◽

Vol 17 (6) ◽

pp. 421-429 ◽

Cited By ~ 23

Author(s):

Tanveer Beg ◽

Smita Jyoti ◽

Falaq Naz ◽

Rahul ◽

Fahad Ali ◽

...

Keyword(s):

Oxidative Stress ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Beta ◽

Neuronal Damage ◽

Natural Antioxidants ◽

Acetylcholinesterase Activity ◽

Model Of Alzheimer’S Disease ◽

Climbing Ability ◽

Transgenic Drosophila

Background: Alzheimer’s disease (AD) is characterized by the accumulation and deposition of β-amyloid peptides leading to a progressive neuronal damage and cell loss. Besides several hypotheses for explaining the neurodegenerative mechanisms, oxidative stress has been considered to be one of them. Till date, there is no cure for AD, but the pathogenesis of the disease could be delayed by the use of natural antioxidants. In this context, we decided to study the effect of kaempferol against the transgenic Drosophila expressing human amyloid beta-42. Method: The AD flies were allowed to feed on the diet having 10, 20, 30 and 40µM of kaempferol for 30 days. After 30 days of exposure, the amyloid beta flies were studied for their climbing ability and Aversive Phototaxis Suppression assay. Amyloid beta flies head homogenate was prepared for estimating the oxidative stress markers, Caspase and acetylcholinesterase activity. Results: The results of the present study reveal that the exposure of AD flies to kaempferol delayed the loss of climbing ability, memory, reduced the oxidative stress and acetylcholinesterase activity. Conclusion: Kaempferol could be used as a possible therapeutic agent against the progression of the Alzheimer’s disease.

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