Role of genes GSTM1, GSTT1, and MnSOD in the development of late-onset Alzheimer disease and their relationship with APOE*4

Mendonça, E. de; Alcalá, Eva Salazar; Fernández‐Mestre, Mercedes

doi:10.1016/j.nrleng.2014.10.007

Cited by 10 publications

(8 citation statements)

References 38 publications

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“…However, they also bind tau in AD neurofibrillary tangles (Qureshi et al, 2013;Jia et al, 2014), and mutant huntingtin (86Q) in an HD model (Jia et al, 2014), and they have been implicated in aggresome formation (Jia et al, 2014). Mu-class GST variants are risk factors for PD (Wahner et al, 2007) as well as AD (de Mendonca et al, 2014). Heat-shock protein defects have been implicated in PD and AD (Ou et al, 2014), and HspB1 mutations are associated with familial motor neuron diseases (Muranova et al, 2015).…”

Section: Roles Of Aggregate Proteins Enriched or Depleted In Admentioning

confidence: 99%

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

et al. 2016

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SummaryNeurodegenerative diseases are distinguished by characteristic protein aggregates initiated by disease‐specific ‘seed’ proteins; however, roles of other co‐aggregated proteins remain largely unexplored. Compact hippocampal aggregates were purified from Alzheimer's and control‐subject pools using magnetic‐bead immunoaffinity pulldowns. Their components were fractionated by electrophoretic mobility and analyzed by high‐resolution proteomics. Although total detergent‐insoluble aggregates from Alzheimer's and controls had similar protein content, within the fractions isolated by tau or Aβ1–42 pulldown, the protein constituents of Alzheimer‐derived aggregates were more abundant, diverse, and post‐translationally modified than those from controls. Tau‐ and Aβ‐containing aggregates were distinguished by multiple components, and yet shared >90% of their protein constituents, implying similar accretion mechanisms. Alzheimer‐specific protein enrichment in tau‐containing aggregates was corroborated for individuals by three analyses. Five proteins inferred to co‐aggregate with tau were confirmed by precise in situ methods, including proximity ligation amplification that requires co‐localization within 40 nm. Nematode orthologs of 21 proteins, which showed Alzheimer‐specific enrichment in tau‐containing aggregates, were assessed for aggregation‐promoting roles in C. elegans by RNA‐interference ‘knockdown’. Fifteen knockdowns (71%) rescued paralysis of worms expressing muscle Aβ, and 12 (57%) rescued chemotaxis disrupted by neuronal Aβ expression. Proteins identified in compact human aggregates, bound by antibody to total tau, were thus shown to play causal roles in aggregation based on nematode models triggered by Aβ1–42. These observations imply shared mechanisms driving both types of aggregation, and/or aggregate‐mediated cross‐talk between tau and Aβ. Knowledge of protein components that promote protein accrual in diverse aggregate types implicates common mechanisms and identifies novel targets for drug intervention.

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Section: Roles Of Aggregate Proteins Enriched or Depleted In Admentioning

confidence: 99%

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

et al. 2016

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“…Two studies described their results for HLA-A2 allele in terms of differences in ages of onset of LOAD, but no OR was given [15,16]. Although data for risk SNP or genotype in the APOE ε4/ε4 subgroup were published, the alternate SNP/genotype data were not given in two articles, and therefore, it could not be determined if the alternate allele conferred any protection [17,18]. One study was a family case report that only described the clinical effect of the risk SNP without any ORs [19] and another had inconclusive results in the APOE ε4/ε4 subgroup due to the absence of the PLAU T/T genotype in their APOE ε4 homozygotes [20].…”

Section: Summary Of Resultsmentioning

confidence: 99%

Genetic resilience to Alzheimer's disease in APOE ε4 homozygotes: A systematic review

Huq

Fransquet

Laws

et al. 2019

Alzheimer's & Dementia

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Introduction: Individuals with homozygosity for the apolipoprotein E (APOE) ε4 allele are in the highest risk category for late-onset Alzheimer's disease (LOAD). However, some individuals in this category do not develop LOAD beyond the age of 75 years, despite being at elevated genetic risk. These "resilient" individuals may carry protective genetic factors. Methods: This study aimed to systematically review any previous studies that involved resilient APOE ε4 homozygotes and to identify possible modifying or protective genetic factors. Results: Fifteen studies met our inclusion criteria and reported genetic factors contributing to reduced risk. We found that only two single nucleotide polymorphisms, CASP7 rs10553596 and SER-PINA3 rs4934-A/A, had strong evidence. Discussion: We found a paucity of studies adequately designed to discover protective genetic factors against LOAD. Many studies combined APOE ε4 homozygotes and heterozygotes together because of small sample sizes and used control populations too young to be clearly defined as controls for LOAD.

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“…The removal of toxins and toxicants via glutathione transferases is important for maintaining brain health and cognition. When there are variants or deletions in these pathways, heavy metals, and other toxicants such as pesticides and herbicides can build up in the brain, compromising brain heath ( de Mendonça et al, 2016 ; Wang et al, 2016 ; Andreoli and Sprovieri, 2017 ). The patient was found to have Glutathione S-Transferase mu 1 (GSTM1) null (i.e., both copies of this gene are absent), Glutathione S-Transferase theta 1 (GSTT1) null, as well as two copies of the Glutathione S-Transferase pi 1 (GSTP1) Ile105Val variant, which is highly clinically significant.…”

Section: Case Studies To Support This Hypothesismentioning

confidence: 99%

“…Both the GSTM1 null and GSTP1 homozygous Ile105Val have been associated with a significantly higher risk of AD ( Wang et al, 2016 ). The cognitive effects of GSTM1 null are amplified when combined with ApoE ε4 conveying 3.07x the risk of dementia as well as 2.1x the risk of atherosclerosis ( de Mendonça et al, 2016 ; Grubisa et al, 2018 ). GSTP1 Ile105Val has been shown to be associated with a 1.87x the risk of AD/MCI and greater susceptibility to the negative effects from lead exposure ( Wang et al, 2016 ).…”

Section: Case Studies To Support This Hypothesismentioning

confidence: 99%

“…Like Mr. A, in the case above, Mr. B was also found to have significant issues in his glutathione transferase-related pathways with deletions of both GSTT1 and GSTM1 as well as homozygous variants in GSTP1. N -acetylcysteine (NAC) was started (1,200 mg a day), as well as glutathione using a combination of daily oral and weekly IV glutathione treatments to promote detoxification ( Moradi et al, 2009 ; Hauser et al, 2009 ; Pizzorno, 2014 ; de Mendonça et al, 2016 ).…”

Section: Case Studies To Support This Hypothesismentioning

confidence: 99%

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Genomics as a Clinical Decision Support Tool for Identifying and Addressing Modifiable Causes of Cognitive Decline and Improving Outcomes: Proof of Concept Support for This Personalized Medicine Strategy

Hausman-Cohen

Bilich

Kapoor³

et al. 2022

Front. Aging Neurosci.

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The landscape of therapeutics for mild cognitive impairment and dementia is quite limited. While many single-agent trials of pharmaceuticals have been conducted, these trials have repeatedly been unable to show improvement in cognition. It is hypothesized that because Alzheimer’s, like many other chronic illnesses, is not a monogenic illness, but is instead caused by the downstream effects of an individual’s genetic variants interacting with each other, the environment, and lifestyle, that improving outcomes will require a personalized, precision medicine approach. This approach requires identifying and then addressing contributing genomic and other factors specific to each individual in a simultaneous fashion. Until recently, the utility of genomics as part of clinical decision-making for Alzheimer’s and cognitive decline has been limited by the lack of availability of a genomic platform designed specifically to evaluate factors contributing to cognitive decline and how to respond to these factors The clinical decision support (CDS) platform used in the cases presented focuses on common variants that relate to topics including, but not limited to brain inflammation, amyloid processing, nutrient carriers, brain ischemia, oxidative stress, and detoxification pathways. Potential interventions based on the scientific literature were included in the CDS, but the final decision on what interventions to apply were chosen by each patient’s physician. Interventions included supplements with “generally regarded as safe (GRAS)” rating, along with targeted diet and lifestyle modifications. We hypothesize that a personalized genomically targeted approach can improve outcomes for individuals with mild cognitive impairment who are at high risk of Alzheimer’s. The cases presented in this report represent a subset of cases from three physicians’ offices and are meant to provide initial proof of concept data demonstrating the efficacy of this method and provide support for this hypothesis. These patients were at elevated risk for Alzheimer’s due to their apolipoprotein E ε4 status. While further prospective and controlled trials need to be done, initial case reports are encouraging and lend support to this hypothesis of the benefit of a genomically targeted personalized medicine approach to improve outcomes in individuals with cognitive decline who are at high risk for Alzheimer’s.

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Role of genes GSTM1, GSTT1, and MnSOD in the development of late-onset Alzheimer disease and their relationship with APOE*4

Cited by 10 publications

References 38 publications

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls

Genetic resilience to Alzheimer's disease in APOE ε4 homozygotes: A systematic review

Genomics as a Clinical Decision Support Tool for Identifying and Addressing Modifiable Causes of Cognitive Decline and Improving Outcomes: Proof of Concept Support for This Personalized Medicine Strategy

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