Alzheimer's Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines

Dénes Zádori, Gábor Veres, Levente Szalárdy, Péter Klivényi, László Vécsei

Research output: Contribution to journalReview article

14 Citations (Scopus)

Abstract

The pathomechanism of Alzheimer's disease (AD) certainly involves mitochondrial disturbances, glutamate excitotoxicity, and neuroinflammation. The three main aspects of mitochondrial dysfunction in AD, i.e., the defects in dynamics, altered bioenergetics, and the deficient transport, act synergistically. In addition, glutamatergic neurotransmission is affected in several ways. The balance between synaptic and extrasynaptic glutamatergic transmission is shifted toward the extrasynaptic site contributing to glutamate excitotoxicity, a phenomenon augmented by increased glutamate release and decreased glutamate uptake. Neuroinflammation in AD is predominantly linked to central players of the innate immune system, with central nervous system (CNS)-resident microglia, astroglia, and perivascular macrophages having been implicated at the cellular level. Several abnormalities have been described regarding the activation of certain steps of the kynurenine (KYN) pathway of tryptophan metabolism in AD. First of all, the activation of indolamine 2,3-dioxygenase, the first and rate-limiting step of the pathway, is well-demonstrated. 3-Hydroxy-L-KYN and its metabolite, 3-hydroxy-anthranilic acid have pro-oxidant, antioxidant, and potent immunomodulatory features, giving relevance to their alterations in AD. Another metabolite, quinolinic acid, has been demonstrated to be neurotoxic, promoting glutamate excitotoxicity, reactive oxygen species production, lipid peroxidation, and microglial neuroinflammation, and its abundant presence in AD pathologies has been demonstrated. Finally, the neuroprotective metabolite, kynurenic acid, has been associated with antagonistic effects at glutamate receptors, free radical scavenging, and immunomodulation, giving rise to potential therapeutic implications. This review presents the multiple connections of KYN pathway-related alterations to three main domains of AD pathomechanism, such as mitochondrial dysfunction, excitotoxicity, and neuroinflammation, implicating possible therapeutic options.

Original languageEnglish
Pages (from-to)523-547
Number of pages25
JournalJournal of Alzheimer's Disease
Volume62
Issue number2
DOIs
Publication statusPublished - Jan 1 2018

Fingerprint

Kynurenine
Alzheimer Disease
Glutamic Acid
Reactive Oxygen Species
Indoleamine-Pyrrole 2,3,-Dioxygenase
Kynurenic Acid
Quinolinic Acid
Immunomodulation
Glutamate Receptors
Microglia
Synaptic Transmission
Tryptophan
Astrocytes
Energy Metabolism
Lipid Peroxidation
Free Radicals
Immune System
Central Nervous System
Antioxidants
Macrophages

Keywords

  • 3-hydroxy-L-kynurenine
  • Alzheimer's disease
  • glutamate excitotoxicity
  • kynurenic acid
  • kynurenine pathway
  • mitochondrial dysfunction
  • neuroinflammation
  • quinolinic acid
  • tryptophan metabolism

ASJC Scopus subject areas

  • Clinical Psychology
  • Geriatrics and Gerontology
  • Psychiatry and Mental health

Cite this

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title = "Alzheimer's Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines",
abstract = "The pathomechanism of Alzheimer's disease (AD) certainly involves mitochondrial disturbances, glutamate excitotoxicity, and neuroinflammation. The three main aspects of mitochondrial dysfunction in AD, i.e., the defects in dynamics, altered bioenergetics, and the deficient transport, act synergistically. In addition, glutamatergic neurotransmission is affected in several ways. The balance between synaptic and extrasynaptic glutamatergic transmission is shifted toward the extrasynaptic site contributing to glutamate excitotoxicity, a phenomenon augmented by increased glutamate release and decreased glutamate uptake. Neuroinflammation in AD is predominantly linked to central players of the innate immune system, with central nervous system (CNS)-resident microglia, astroglia, and perivascular macrophages having been implicated at the cellular level. Several abnormalities have been described regarding the activation of certain steps of the kynurenine (KYN) pathway of tryptophan metabolism in AD. First of all, the activation of indolamine 2,3-dioxygenase, the first and rate-limiting step of the pathway, is well-demonstrated. 3-Hydroxy-L-KYN and its metabolite, 3-hydroxy-anthranilic acid have pro-oxidant, antioxidant, and potent immunomodulatory features, giving relevance to their alterations in AD. Another metabolite, quinolinic acid, has been demonstrated to be neurotoxic, promoting glutamate excitotoxicity, reactive oxygen species production, lipid peroxidation, and microglial neuroinflammation, and its abundant presence in AD pathologies has been demonstrated. Finally, the neuroprotective metabolite, kynurenic acid, has been associated with antagonistic effects at glutamate receptors, free radical scavenging, and immunomodulation, giving rise to potential therapeutic implications. This review presents the multiple connections of KYN pathway-related alterations to three main domains of AD pathomechanism, such as mitochondrial dysfunction, excitotoxicity, and neuroinflammation, implicating possible therapeutic options.",
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year = "2018",
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T2 - Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines

AU - Zádori, Dénes

AU - Veres, Gábor

AU - Szalárdy, Levente

AU - Klivényi, Péter

AU - Vécsei, László

PY - 2018/1/1

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N2 - The pathomechanism of Alzheimer's disease (AD) certainly involves mitochondrial disturbances, glutamate excitotoxicity, and neuroinflammation. The three main aspects of mitochondrial dysfunction in AD, i.e., the defects in dynamics, altered bioenergetics, and the deficient transport, act synergistically. In addition, glutamatergic neurotransmission is affected in several ways. The balance between synaptic and extrasynaptic glutamatergic transmission is shifted toward the extrasynaptic site contributing to glutamate excitotoxicity, a phenomenon augmented by increased glutamate release and decreased glutamate uptake. Neuroinflammation in AD is predominantly linked to central players of the innate immune system, with central nervous system (CNS)-resident microglia, astroglia, and perivascular macrophages having been implicated at the cellular level. Several abnormalities have been described regarding the activation of certain steps of the kynurenine (KYN) pathway of tryptophan metabolism in AD. First of all, the activation of indolamine 2,3-dioxygenase, the first and rate-limiting step of the pathway, is well-demonstrated. 3-Hydroxy-L-KYN and its metabolite, 3-hydroxy-anthranilic acid have pro-oxidant, antioxidant, and potent immunomodulatory features, giving relevance to their alterations in AD. Another metabolite, quinolinic acid, has been demonstrated to be neurotoxic, promoting glutamate excitotoxicity, reactive oxygen species production, lipid peroxidation, and microglial neuroinflammation, and its abundant presence in AD pathologies has been demonstrated. Finally, the neuroprotective metabolite, kynurenic acid, has been associated with antagonistic effects at glutamate receptors, free radical scavenging, and immunomodulation, giving rise to potential therapeutic implications. This review presents the multiple connections of KYN pathway-related alterations to three main domains of AD pathomechanism, such as mitochondrial dysfunction, excitotoxicity, and neuroinflammation, implicating possible therapeutic options.

AB - The pathomechanism of Alzheimer's disease (AD) certainly involves mitochondrial disturbances, glutamate excitotoxicity, and neuroinflammation. The three main aspects of mitochondrial dysfunction in AD, i.e., the defects in dynamics, altered bioenergetics, and the deficient transport, act synergistically. In addition, glutamatergic neurotransmission is affected in several ways. The balance between synaptic and extrasynaptic glutamatergic transmission is shifted toward the extrasynaptic site contributing to glutamate excitotoxicity, a phenomenon augmented by increased glutamate release and decreased glutamate uptake. Neuroinflammation in AD is predominantly linked to central players of the innate immune system, with central nervous system (CNS)-resident microglia, astroglia, and perivascular macrophages having been implicated at the cellular level. Several abnormalities have been described regarding the activation of certain steps of the kynurenine (KYN) pathway of tryptophan metabolism in AD. First of all, the activation of indolamine 2,3-dioxygenase, the first and rate-limiting step of the pathway, is well-demonstrated. 3-Hydroxy-L-KYN and its metabolite, 3-hydroxy-anthranilic acid have pro-oxidant, antioxidant, and potent immunomodulatory features, giving relevance to their alterations in AD. Another metabolite, quinolinic acid, has been demonstrated to be neurotoxic, promoting glutamate excitotoxicity, reactive oxygen species production, lipid peroxidation, and microglial neuroinflammation, and its abundant presence in AD pathologies has been demonstrated. Finally, the neuroprotective metabolite, kynurenic acid, has been associated with antagonistic effects at glutamate receptors, free radical scavenging, and immunomodulation, giving rise to potential therapeutic implications. This review presents the multiple connections of KYN pathway-related alterations to three main domains of AD pathomechanism, such as mitochondrial dysfunction, excitotoxicity, and neuroinflammation, implicating possible therapeutic options.

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KW - glutamate excitotoxicity

KW - kynurenic acid

KW - kynurenine pathway

KW - mitochondrial dysfunction

KW - neuroinflammation

KW - quinolinic acid

KW - tryptophan metabolism

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U2 - 10.3233/JAD-170929

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JO - Journal of Alzheimer's Disease

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