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.