Comparative Analysis of Aducanumab, Zagotenemab and Pioglitazone as Targeted Treatment Strategies for Alzheimer’s Disease

Abyadeh, Morteza; Gupta, Vivek Kumar; Gupta, Veer; Chitranshi, Nitin; Wu, Yunqi; Amirkhani, Ardeshir; Meyfour, Anna; Sheriff, S.; Shen, Ting; Dhiman, Kunal; Salekdeh, Ghasem Hosseini; Haynes, Paul A.; Graham, Stuart L.; Mirzaei, Mehdi

doi:10.14336/ad.2021.0719

Cited by 45 publications

(41 citation statements)

References 79 publications

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“…Alzheimer's disease (AD) is the leading cause of dementia, affecting between 70 to 80% of older adults with dementia [1]. Currently, over 50 million people are living with the disease worldwide, and this number is estimated to rise to 150 million in 2050, exacerbating an already constrained healthcare system unless preventive strategies are implemented [2,3].…”

Section: Introductionmentioning

confidence: 99%

“…Although results of clinical trials have been underwhelming for the past 25 years, recently an anti-amyloid β antibody, Aducanumab, received an accelerated FDA approval, requiring further clinical trials to confirm the estimated efficacy [1]. Repeated failure in clinical trials has challenged our understanding of this multifactorial disease, leading to recent studies concentrating on advancing our knowledge of the underlying mechanisms of AD pathogenesis to find druggable targets.…”

Section: Introductionmentioning

confidence: 99%

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Key Genes and Biochemical Networks in Various Brain Regions Affected in Alzheimer’s Disease

Abyadeh

Tofigh

Hosseinian

et al. 2022

Cells

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Alzheimer’s disease (AD) is one of the most complicated progressive neurodegenerative brain disorders, affecting millions of people around the world. Ageing remains one of the strongest risk factors associated with the disease and the increasing trend of the ageing population globally has significantly increased the pressure on healthcare systems worldwide. The pathogenesis of AD is being extensively investigated, yet several unknown key components remain. Therefore, we aimed to extract new knowledge from existing data. Ten gene expression datasets from different brain regions including the hippocampus, cerebellum, entorhinal, frontal and temporal cortices of 820 AD cases and 626 healthy controls were analyzed using the robust rank aggregation (RRA) method. Our results returned 1713 robust differentially expressed genes (DEGs) between five brain regions of AD cases and healthy controls. Subsequent analysis revealed pathways that were altered in each brain region, of which the GABAergic synapse pathway and the retrograde endocannabinoid signaling pathway were shared between all AD affected brain regions except the cerebellum, which is relatively less sensitive to the effects of AD. Furthermore, we obtained common robust DEGs between these two pathways and predicted three miRNAs as potential candidates targeting these genes; hsa-mir-17-5p, hsa-mir-106a-5p and hsa-mir-373-3p. Three transcription factors (TFs) were also identified as the potential upstream regulators of the robust DEGs; ELK-1, GATA1 and GATA2. Our results provide the foundation for further research investigating the role of these pathways in AD pathogenesis, and potential application of these miRNAs and TFs as therapeutic and diagnostic targets.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Key Genes and Biochemical Networks in Various Brain Regions Affected in Alzheimer’s Disease

Abyadeh

Tofigh

Hosseinian

et al. 2022

Cells

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“…Aducanumab was effective in the early stages of Alzheimer’s disease against a surrogate endpoint. AE of aducanumab are Alzheimer-related imaging abnormality, headache, superficial siderosis, falls, and diarrhea (Abyadeh et al 2021 ). Of note, the pivotal studies did not have a clinical primary endpoint, and the advisory committee of the FDA almost unanimously argued against the approval of aducanumab (Mullard 2021b ).…”

Section: Methodsmentioning

confidence: 99%

A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2021

Kaykı-Mutlu

Aksoyalp

Wojnowski

et al. 2022

Naunyn-Schmiedeberg's Arch Pharmacol

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The second year of the COVID-19 pandemic had no adverse effect on the number of new drug approvals by the US Food and Drug Administration (FDA). Quite the contrary, with a total of 50 new drugs, 2021 belongs to the most successful FDA years. We assign these new drugs to one of three levels of innovation: (1) first drug against a condition (“first-in-indication”), (2) first drug using a novel molecular mechanism (“first-in-class”), and (3) “next-in-class”, i.e., a drug using an already exploited molecular mechanism. We identify 21 first-in-class, 28 next-in-class, and only one first-in-indication drugs. By treatment area, the largest group is once again cancer drugs, many of which target specific genetic alterations. Every second drug approved in 2021 targets an orphan disease, half of them being cancers. Small molecules continue to dominate new drug approvals, followed by antibodies and non-antibody biopharmaceuticals. In 2021, the FDA continued to approve drugs without strong evidence of clinical effects, best exemplified by the aducanumab controversy.

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“…Recently, a monoclonal antibody has been developed just against beta-amyloid (aducanumab), capable of reducing beta-amyloid plaques and, reasonably, clinical AD decline. In June 2021, aducanumab was approved for the treatment of Alzheimer’s disease by the US Food and Drug Administration (FDA) [ 100 ].…”

Section: Alzheimer Disease and Insulinmentioning

confidence: 99%

Insulin and Its Key Role for Mitochondrial Function/Dysfunction and Quality Control: A Shared Link between Dysmetabolism and Neurodegeneration

Galizzi

Carlo

2022

Biology

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This review will comprise an overview of insulin and its history, structure, synthesis, secretion, signaling, and peripheral and brain roles. Further, the impact that metabolic diseases and the insulin resistance (IR) condition can exert on brain function will be surveyed. Later, attention will be given to the complex relation of mitochondrial dysfunction, brain insulin resistance, and neurodegenerative disease, especially Alzheimer’s disease (AD). We will also focus our consideration on the role played by insulin or the IR condition in mitochondrial homeostasis by analyzing the different processes involved in the quality control of mitochondria (MQC), such as mitochondrial dynamics, mitochondrial biogenesis, and selective autophagy (mitophagy), as well as pathophysiological implications of these aspects. Finally, the possibility of employing the mitochondrion as a target to fight dysmetabolism and AD-related effects will also be reviewed.Abstract: Insulin was discovered and isolated from the beta cells of pancreatic islets of dogs and is associated with the regulation of peripheral glucose homeostasis. Insulin produced in the brain is related to synaptic plasticity and memory. Defective insulin signaling plays a role in brain dysfunction, such as neurodegenerative disease. Growing evidence suggests a link between metabolic disorders, such as diabetes and obesity, and neurodegenerative diseases, especially Alzheimer’s disease (AD). This association is due to a common state of insulin resistance (IR) and mitochondrial dysfunction. This review takes a journey into the past to summarize what was known about the physiological and pathological role of insulin in peripheral tissues and the brain. Then, it will land in the present to analyze the insulin role on mitochondrial health and the effects on insulin resistance and neurodegenerative diseases that are IR-dependent. Specifically, we will focus our attention on the quality control of mitochondria (MQC), such as mitochondrial dynamics, mitochondrial biogenesis, and selective autophagy (mitophagy), in healthy and altered cases. Finally, this review will be projected toward the future by examining the most promising treatments that target the mitochondria to cure neurodegenerative diseases associated with metabolic disorders.

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Comparative Analysis of Aducanumab, Zagotenemab and Pioglitazone as Targeted Treatment Strategies for Alzheimer’s Disease

Cited by 45 publications

References 79 publications

Key Genes and Biochemical Networks in Various Brain Regions Affected in Alzheimer’s Disease

Key Genes and Biochemical Networks in Various Brain Regions Affected in Alzheimer’s Disease

A year in pharmacology: new drugs approved by the US Food and Drug Administration in 2021

Insulin and Its Key Role for Mitochondrial Function/Dysfunction and Quality Control: A Shared Link between Dysmetabolism and Neurodegeneration

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