Dataset Information

Mitochondria as Potential Targets in Alzheimer Disease Therapy: An Update.

ABSTRACT: Alzheimer disease (AD) is a progressive and deleterious neurodegenerative disorder that affects mostly the elderly population. At the moment, no effective treatments are available in the market, making the whole situation a compelling challenge for societies worldwide. Recently, novel mechanisms have been proposed to explain the etiology of this disease leading to the new concept that AD is a multifactor pathology. Among others, the function of mitochondria has been considered as one of the intracellular processes severely compromised in AD since the early stages and likely represents a common feature of many neurodegenerative diseases. Many mitochondrial parameters decline already during the aging, reaching an extensive functional failure concomitant with the onset of neurodegenerative conditions, although the exact timeline of these events is still unclear. Thereby, it is not surprising that mitochondria have been already considered as therapeutic targets in neurodegenerative diseases including AD. Together with an overview of the role of mitochondrial dysfunction, this review examines the pros and cons of the tested therapeutic approaches targeting mitochondria in the context of AD. Since mitochondrial therapies in AD have shown different degrees of progress, it is imperative to perform a detailed analysis of the significance of mitochondrial deterioration in AD and of a pharmacological treatment at this level. This step would be very important for the field, as an effective drug treatment in AD is still missing and new therapeutic concepts are urgently needed.

SUBMITTER: Cenini G

PROVIDER: S-EPMC6716473 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Mitochondria as Potential Targets in Alzheimer Disease Therapy: An Update.

Cenini Giovanna G Voos Wolfgang W

Frontiers in pharmacology 20190823

Alzheimer disease (AD) is a progressive and deleterious neurodegenerative disorder that affects mostly the elderly population. At the moment, no effective treatments are available in the market, making the whole situation a compelling challenge for societies worldwide. Recently, novel mechanisms have been proposed to explain the etiology of this disease leading to the new concept that AD is a multifactor pathology. Among others, the function of mitochondria has been considered as one of the intr ...[more]

PMID: 31507410

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Project description:Alzheimer's disease (AD) is the most frequent cause of neurodegenerative dementia and affects nearly 50 million people worldwide. Early stage diagnosis of AD is challenging, and there is presently no effective treatment for AD. The specific genetic alterations and pathological mechanisms of the development and progression of dementia remain poorly understood. Therefore, identifying essential genes and molecular pathways that are associated with this disease's pathogenesis will help uncover potential treatments. In an attempt to achieve a more comprehensive understanding of the molecular pathogenesis of AD, we integrated the differentially expressed genes (DEGs) from six microarray datasets of AD patients and controls. We identified ATPase H+ transporting V1 subunit A (ATP6V1A), BCL2 interacting protein 3 (BNIP3), calmodulin-dependent protein kinase IV (CAMK4), TOR signaling pathway regulator-like (TIPRL), and the translocase of outer mitochondrial membrane 70 (TOMM70) as upregulated DEGs common to the five datasets. Our analyses revealed that these genes exhibited brain-specific gene co-expression clustering with OPA1, ITFG1, OXCT1, ATP2A2, MAPK1, CDK14, MAP2K4, YWHAB, PARK2, CMAS, HSPA12A, and RGS17. Taking the mean relative expression levels of this geneset in different brain regions into account, we found that the frontal cortex (BA9) exhibited significantly (p < 0.05) higher expression levels of these DEGs, while the hippocampus exhibited the lowest levels. These DEGs are associated with mitochondrial dysfunction, inflammation processes, and various pathways involved in the pathogenesis of AD. Finally, our blood-brain barrier (BBB) predictions using the support vector machine (SVM) and LiCABEDS algorithm and molecular docking analysis suggested that antrocin is permeable to the BBB and exhibits robust ligand-receptor interactions with high binding affinities to CAMK4, TOMM70, and T1PRL. Our results also revealed good predictions for ADMET properties, drug-likeness, adherence to Lipinskís rules, and no alerts for pan-assay interference compounds (PAINS) Conclusions: These results suggest a new molecular signature for AD parthenogenesis and antrocin as a potential therapeutic agent. Further investigation is warranted.

Dataset Information

Mitochondria as Potential Targets in Alzheimer Disease Therapy: An Update.

Publications

Mitochondria as Potential Targets in Alzheimer Disease Therapy: An Update.

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