Can Arginase Inhibitors Be the Answer to Therapeutic Challenges in Alzheimer's Disease?

Ovsepian, Saak V.; O’Leary, Valerie B.

doi:10.1007/s13311-018-0668-6

Cited by 8 publications

(6 citation statements)

References 31 publications

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“…It catalyzes the conversion of arginine to ornithine with urea as a byproduct and has been previously linked to AD pathology due to its involvement in microglial activation and autophagy (66–68). Moreover, the reduction of urea levels through the inhibition of arginase (ARG2) has been suggested as a promising target in the context of AD (69).…”

Section: Resultsmentioning

confidence: 99%

“…Urea buildup to neurotoxic levels has been observed in postmortem brains of Huntington's disease and has furthermore been linked to dementia 58 . Inhibition of arginase (ARG2) has been suggested to reduce the production of urea 59 . Arginase was positively associated with AD in our data; it catalyzes the conversion of arginine to ornithine, with urea as a byproduct.…”

Section: Integration Of Complementary Omics Provides Comprehensive View Of Biochemical Cascade Downstream Of Neurotransmittersmentioning

confidence: 99%

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The landscape of metabolic brain alterations in Alzheimer’s disease

Batra

Arnold

Wörheide

et al. 2021

Preprint

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We present a comprehensive reference map of metabolic brain changes in Alzheimer’s disease (AD). In a multi-center study within the Accelerating Medicines Partnership in AD, we metabolically profiled 500 samples from the dorsolateral prefrontal cortex (DLPFC) and 83 samples from the temporal cortex (TCX). In the DLPFC, 298 metabolites were correlated with AD-related traits, including late-life cognitive performance and neuropathological β-amyloid and tau tangle burden. Out of these 298 metabolites, 35 replicated in TCX and a previous study. A conditional analysis suggests that metabolic associations with tangle burden were largely independent of β-amyloid load in the brain. Our results provide evidence of brain alterations in bioenergetic pathways, cholesterol metabolism, neuroinflammation, osmoregulation, and other pathways. In a detailed investigation of the glutamate/GABA neurotransmitter pathway, we demonstrate how integration of complementary omics data can provide a comprehensive view of dysregulated biochemical processes. All associations are available as an interactive network at https://omicscience.org/apps/brainmwas/.

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Section: Resultsmentioning

confidence: 99%

Section: Integration Of Complementary Omics Provides Comprehensive View Of Biochemical Cascade Downstream Of Neurotransmittersmentioning

confidence: 99%

The landscape of metabolic brain alterations in Alzheimer’s disease

Batra

Arnold

Wörheide

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…Furthermore, inhibition of immunosuppressive functions of arginases is being explored in the treatment of cancer. Modulation of L-arg metabolism is also being explored as a therapeutic strategy in Alzheimer's disease (268).…”

Section: Arginase Inhibitorsmentioning

confidence: 99%

Myeloid Cell-Derived Arginase in Cancer Immune Response

et al. 2020

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Amino acid metabolism is a critical regulator of the immune response, and its modulating becomes a promising approach in various forms of immunotherapy. Insufficient concentrations of essential amino acids restrict T-cells activation and proliferation. However, only arginases, that degrade L-arginine, as well as enzymes that hydrolyze L-tryptophan are substantially increased in cancer. Two arginase isoforms, ARG1 and ARG2, have been found to be present in tumors and their increased activity usually correlates with more advanced disease and worse clinical prognosis. Nearly all types of myeloid cells were reported to produce arginases and the increased numbers of various populations of myeloid-derived suppressor cells and macrophages correlate with inferior clinical outcomes of cancer patients. Here, we describe the role of arginases produced by myeloid cells in regulating various populations of immune cells, discuss molecular mechanisms of immunoregulatory processes involving L-arginine metabolism and outline therapeutic approaches to mitigate the negative effects of arginases on antitumor immune response. Development of potent arginase inhibitors, with improved pharmacokinetic properties, may lead to the elaboration of novel therapeutic strategies based on targeting immunoregulatory pathways controlled by L-arginine degradation.

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“…Taken together, NLR elevation in severe viral illnesses and AD likely reflects arginase upregulation. Arginase inhibitors may comprise a new therapeutic strategy for both viral illness and neurodegeneration ( Ovsepian and O’Leary, 2018 ). (Please see section “ Arginine: The Fusion Confusion ”).…”

Section: Cell-cell Fusion the Molecular Actorsmentioning

confidence: 99%

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

Osorio

Sfera

Anton

et al. 2022

Front. Cell. Infect. Microbiol.

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A growing body of epidemiological and research data has associated neurotropic viruses with accelerated brain aging and increased risk of neurodegenerative disorders. Many viruses replicate optimally in senescent cells, as they offer a hospitable microenvironment with persistently elevated cytosolic calcium, abundant intracellular iron, and low interferon type I. As cell-cell fusion is a major driver of cellular senescence, many viruses have developed the ability to promote this phenotype by forming syncytia. Cell-cell fusion is associated with immunosuppression mediated by phosphatidylserine externalization that enable viruses to evade host defenses. In hosts, virus-induced immune dysfunction and premature cellular senescence may predispose to neurodegenerative disorders. This concept is supported by novel studies that found postinfectious cognitive dysfunction in several viral illnesses, including human immunodeficiency virus-1, herpes simplex virus-1, and SARS-CoV-2. Virus-induced pathological syncytia may provide a unified framework for conceptualizing neuronal cell cycle reentry, aneuploidy, somatic mosaicism, viral spreading of pathological Tau and elimination of viable synapses and neurons by neurotoxic astrocytes and microglia. In this narrative review, we take a closer look at cell-cell fusion and vesicular merger in the pathogenesis of neurodegenerative disorders. We present a “decentralized” information processing model that conceptualizes neurodegeneration as a systemic illness, triggered by cytoskeletal pathology. We also discuss strategies for reversing cell-cell fusion, including, TMEM16F inhibitors, calcium channel blockers, senolytics, and tubulin stabilizing agents. Finally, going beyond neurodegeneration, we examine the potential benefit of harnessing fusion as a therapeutic strategy in regenerative medicine.

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Can Arginase Inhibitors Be the Answer to Therapeutic Challenges in Alzheimer's Disease?

Cited by 8 publications

References 31 publications

The landscape of metabolic brain alterations in Alzheimer’s disease

The landscape of metabolic brain alterations in Alzheimer’s disease

Myeloid Cell-Derived Arginase in Cancer Immune Response

Virus-Induced Membrane Fusion in Neurodegenerative Disorders

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