Are mitophagy enhancers therapeutic targets for Alzheimer’s disease?

Pradeepkiran, Jangampalli Adi; Hindle, Ashly; Kshirsagar, Sudhir; Reddy, P. Hemachandra

doi:10.1016/j.biopha.2022.112918

Cited by 39 publications

(27 citation statements)

References 133 publications

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“…UA is an anti-inflammatory compound that enhances mitophagy, the removal of dysfunctional mitochondria in a cell (75). Impaired mitophagy is part of the pathogenesis of AD, as well as general aging processes, making UA and Gordonibacter species promising targets for therapeutics against the disease (76). Equol is an estrogen-like compound that reduces microglial inflammation when stimulated by LPS and downregulates genes in neurons related to apoptosis (77).…”

Section: Discussionmentioning

confidence: 99%

Genetic correlations between gut microbiota genera and Alzheimer’s Disease

Cammann

Cummings

et al. 2022

Preprint

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Background: A growing body of evidence suggests that dysbiosis of the human gut microbiota is associated with neurodegenerative diseases like Alzheimers disease (AD) via neuroinflammatory processes across the microbiota-gut-brain axis (MGBA). The gut microbiota affects brain health through the secretion of toxins and short-chain fatty acids, which modulates gut permeability and numerous immune functions. Observational studies indicate that AD patients have reduced microbiome diversity, which could contribute to the pathogenesis of the disease. Uncovering the genetic basis of microbial abundance and its effect on AD could suggest lifestyle changes that may reduce an individuals risk for the disease. Methods: Using the largest genome-wide association study (GWAS) of gut microbiota genera from the MiBioGen consortium, we conducted the best-fit model from PRSice-2 to determine the genetic correlation between 119 genera and AD in a discovery sample (case/control: 1,278/1,293); we then replicated our findings in an independent sample (case/control: 799/778) and further performed meta-analyses to confirm the correlation. Finally, we conducted a linear regression to assess the correlation between the PRSs for the significant genera and the APOE genotype. Results: In the discovery sample, 20 gut microbiota genera were initially identified as genetically associated with AD case/control status. Three genera (Eubacterium fissicatena as a protective factor, Collinsella and Veillonella as a risk factor) were validated in the replication sample. Meta-analysis confirmed nine genera to have a significant correlation with AD, three of which were significantly associated with the APOE rs429358 risk allele in a direction consistent with their protective/risk designation in AD association. Notably, the proinflammatory genus Collinsella, identified as a risk factor for AD, was positively correlated with the APOE rs429358 risk allele in both samples. Conclusion: Host genetic factors influencing the abundance of nine genera are significantly associated with AD, suggesting that these genera may serve as biomarkers and targets for AD treatment and intervention. Our results highlight that proinflammatory gut microbiota might promote AD development through interaction with APOE. Larger datasets and functional studies are required to understand their causal relationships.

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Section: Discussionmentioning

confidence: 99%

Genetic correlations between gut microbiota genera and Alzheimer’s Disease

Cammann

Cummings

et al. 2022

Preprint

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“…However, solely rescuing mitophagy-associated defects may be beneficial as many different treatments that rescue mitophagy have been shown to improve lifespan, disease-associated behavior, and protein aggregate accumulation in various neurodegenerative disease models ( Wang et al, 2018 ; Wu et al, 2018 ; Fang et al, 2019 ; Li and Chen, 2019 ; Moskal et al, 2020 ; Yang et al, 2020 ; Zhou et al, 2020 ; Chen et al, 2021 ; Tjahjono et al, 2021 ; Wang H. et al, 2021 ). Additional information on treatments targeting mitophagy is reviewed in Clark et al (2021) , Masaldan et al (2022) , and Pradeepkiran et al (2022) .…”

Section: Discussionmentioning

confidence: 99%

Defective PTEN-induced kinase 1/Parkin mediated mitophagy and neurodegenerative diseases

Braun

Puglielli²

2022

Front. Cell. Neurosci.

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The selective degradation of mitochondria through mitophagy is a crucial process for maintaining mitochondrial function and cellular health. Mitophagy is a specialized form of selective autophagy that uses unique machinery to recognize and target damaged mitochondria for mitophagosome- and lysosome-dependent degradation. This process is particularly important in cells with high metabolic activity like neurons, and the accumulation of defective mitochondria is a common feature among neurodegenerative disorders. Here, we describe essential steps involved in the induction and progression of mitophagy, and then highlight the various mechanisms that specifically contribute to defective mitophagy in highly prevalent neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and Amyotrophic Lateral Sclerosis.

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“…Urolithin A (UA), mainly produced by the metabolism of ellagitannins in pomegranate fruits and walnuts in the intestine, has the potential to penetrate BBB (Cásedas et al, 2020). Previous studies have found that UA could inhibit oxidative stress and mitochondrial autophagy in cells, thus playing a neuroprotective role (González-Sarrías et al, 2017;Pradeepkiran et al, 2022). One step further, in the latest study, it was found that UA could increase expression of genes for mitochondrial biogenesis and OXPHOS in SH-SY5Y cells transfected with the amyloidprecursor protein 695 (SY5Y-APP695) (Esselun et al, 2021).…”

Section: Potential Therapeutic Agents From Herbal Medicine For Mitoch...mentioning

confidence: 99%

Regulation of mitochondrial dysfunction induced cell apoptosis is a potential therapeutic strategy for herbal medicine to treat neurodegenerative diseases

Duan

et al. 2022

Front. Pharmacol.

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Neurodegenerative disease is a progressive neurodegeneration caused by genetic and environmental factors. Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) are the three most common neurodegenerative diseases clinically. Unfortunately, the incidence of neurodegenerative diseases is increasing year by year. However, the current available drugs have poor efficacy and large side effects, which brings a great burden to the patients and the society. Increasing evidence suggests that occurrence and development of the neurodegenerative diseases is closely related to the mitochondrial dysfunction, which can affect mitochondrial biogenesis, mitochondrial dynamics, as well as mitochondrial mitophagy. Through the disruption of mitochondrial homeostasis, nerve cells undergo varying degrees of apoptosis. Interestingly, it has been shown in recent years that the natural agents derived from herbal medicines are beneficial for prevention/treatment of neurodegenerative diseases via regulation of mitochondrial dysfunction. Therefore, in this review, we will focus on the potential therapeutic agents from herbal medicines for treating neurodegenerative diseases via suppressing apoptosis through regulation of mitochondrial dysfunction, in order to provide a foundation for the development of more candidate drugs for neurodegenerative diseases from herbal medicine.

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Are mitophagy enhancers therapeutic targets for Alzheimer’s disease?

Cited by 39 publications

References 133 publications

Genetic correlations between gut microbiota genera and Alzheimer’s Disease

Genetic correlations between gut microbiota genera and Alzheimer’s Disease

Defective PTEN-induced kinase 1/Parkin mediated mitophagy and neurodegenerative diseases

Regulation of mitochondrial dysfunction induced cell apoptosis is a potential therapeutic strategy for herbal medicine to treat neurodegenerative diseases

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