Ammonia as a Potential Neurotoxic Factor in Alzheimer's Disease

Adlimoghaddam, Aida; Sabbir, Mohammad Golam; Albensi, Benedict C.

doi:10.3389/fnmol.2016.00057

Cited by 70 publications

(62 citation statements)

References 123 publications

(140 reference statements)

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“…In addition, NH 4 is produced in the degradation pathway of purines through several reactions driven by AMP deaminase (AMP to IMP), adenosine deaminase (adenosine to inosine) and guanine deaminase (guanine to xanthine) ( 44 ). Ammonium is particularly toxic for neuronal cells by damaging mitochondrial function and cellular metabolism ( 45 ). Brain exposure to NH 4 reduces also cellular creatine content, affecting its neuroprotective function ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

DNMT1 mutations leading to neurodegeneration paradoxically reflect on mitochondrial metabolism

Maresca

Dotto

Capristo

et al. 2020

Human Molecular Genetics

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ADCA-DN and HSN-IE are rare neurodegenerative syndromes caused by dominant mutations in the replication foci targeting sequence (RFTS) of the DNA methyltransferase 1 (DNMT1) gene. Both phenotypes resemble mitochondrial disorders, and mitochondrial dysfunction was first observed in ADCA-DN. To explore mitochondrial involvement, we studied the effects of DNMT1 mutations in fibroblasts from four ADCA-DN and two HSN-IE patients. We documented impaired activity of purified DNMT1 mutant proteins, which in fibroblasts results in increased DNMT1 amount. We demonstrated that DNMT1 is not localized within mitochondria, but it is associated with the mitochondrial outer membrane. Concordantly, mitochondrial DNA failed to show meaningful CpG methylation. Strikingly, we found activated mitobiogenesis and OXPHOS with significant increase of H2O2, sharply contrasting with a reduced ATP content. Metabolomics profiling of mutant cells highlighted purine, arginine/urea cycle and glutamate metabolisms as the most consistently altered pathways, similar to primary mitochondrial diseases. The most severe mutations showed activation of energy shortage AMPK-dependent sensing, leading to mTORC1 inhibition. We propose that DNMT1 RFTS mutations deregulate metabolism lowering ATP levels, as a result of increased purine catabolism and urea cycle pathways. This is associated with a paradoxical mitochondrial hyper-function and increased oxidative stress, possibly resulting in neurodegeneration in non-dividing cells.

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Section: Discussionmentioning

confidence: 99%

DNMT1 mutations leading to neurodegeneration paradoxically reflect on mitochondrial metabolism

Maresca

Dotto

Capristo

et al. 2020

Human Molecular Genetics

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“…Interestingly, the importance of ammonia is underscored by its excessive formation in brains of AD subjects, and elevation of blood ammonia concentrations (Seiler, 2002 ). Ammonia exerts neurotoxicity via modulation of neuroinflammation, mitochondrial dysfunction, altered glutamate/GABA neurotransmission, these perturbations are manifested clinically in the form of cognitive decline (Adlimoghaddam et al, 2016 ). Phenylbutyrate, an ammonia quencher, was able to rescue learning deficits due to clearance of intraneuronal Aß and restoration of dendritic spine densities of hippocampal CA1 pyramidal neurons to control levels in Tg2576 mice (Ricobaraza et al, 2012 ).…”

Section: Effect Of Systemic Iron Overload On Brain Ironmentioning

confidence: 99%

The Aging of Iron Man

Ashraf

Clark

2018

Front. Aging Neurosci.

125

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Brain iron is tightly regulated by a multitude of proteins to ensure homeostasis. Iron dyshomeostasis has become a molecular signature associated with aging which is accompanied by progressive decline in cognitive processes. A common theme in neurodegenerative diseases where age is the major risk factor, iron dyshomeostasis coincides with neuroinflammation, abnormal protein aggregation, neurodegeneration, and neurobehavioral deficits. There is a great need to determine the mechanisms governing perturbations in iron metabolism, in particular to distinguish between physiological and pathological aging to generate fruitful therapeutic targets for neurodegenerative diseases. The aim of the present review is to focus on the age-related alterations in brain iron metabolism from a cellular and molecular biology perspective, alongside genetics, and neuroimaging aspects in man and rodent models, with respect to normal aging and neurodegeneration. In particular, the relationship between iron dyshomeostasis and neuroinflammation will be evaluated, as well as the effects of systemic iron overload on the brain. Based on the evidence discussed here, we suggest a synergistic use of iron-chelators and anti-inflammatories as putative anti-brain aging therapies to counteract pathological aging in neurodegenerative diseases.

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“…Regarding causative factors in AD, various neurotoxins have been proposed but the effect of ammonia as a potent neurotoxin in relation to the pathology of AD has received less attention [ 84 ]. A high concentration of ammonia causes deleterious effects on the cell.…”

Section: Consumption Of a Large Quantity Of Lactobacilli In The Mementioning

confidence: 99%

Blood Ammonia as a Possible Etiological Agent for Alzheimer’s Disease

et al. 2018

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Alzheimer’s disease (AD), characterized by cognitive decline and devastating neurodegeneration, is the most common age-related dementia. Since AD is a typical example of a complex disease that is affected by various genetic and environmental factors, various factors could be involved in preventing and/or treating AD. Extracellular accumulation of beta-amyloid peptide (Aβ) and intracellular accumulation of tau undeniably play essential roles in the etiology of AD. However, interestingly enough, medications targeting Aβ or tau all failed and the only clinically efficient medications for AD are drugs targeting the cholinergic pathway. Also, a very intriguing discovery in AD is that the Mediterranean diet (MeDi), containing an unusually large quantity of Lactobacilli, is very effective in preventing AD. Based on recently emerging findings, it is our opinion that the reduction of blood ammonia levels by Lactobacilli in MeDi is the therapeutic agent of MeDi for AD. The recent evidence of Lactobacilli lowering blood ammonia level not only provides a link between AD and MeDi but also provides a foundation of pharmabiotics for hyperammonemia as well as various neurological diseases.

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Ammonia as a Potential Neurotoxic Factor in Alzheimer's Disease

Cited by 70 publications

References 123 publications

DNMT1 mutations leading to neurodegeneration paradoxically reflect on mitochondrial metabolism

DNMT1 mutations leading to neurodegeneration paradoxically reflect on mitochondrial metabolism

The Aging of Iron Man

Blood Ammonia as a Possible Etiological Agent for Alzheimer’s Disease

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