Hypoxia and the Kynurenine Pathway: Implications and Therapeutic Prospects in Alzheimer’s Disease

Abstract

Neurodegenerative diseases (NDs) like Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, and Huntington’s disease predominantly pose a significant socioeconomic burden. Characterized by progressive neural dysfunction coupled with motor or intellectual impairment, the pathogenesis of ND may result from contributions of certain environmental and molecular factors. One such condition is hypoxia, characterized by reduced organ/tissue exposure to oxygen. Reduced oxygen supply often occurs during the pathogenesis of ND and the aging process. Despite the well-established relationship between these two conditions (i.e., hypoxia and ND), the underlying molecular events or mechanisms connecting hypoxia to ND remain ill-defined. However, the relatedness may stem from the protective or deleterious effects of the transcription factor, hypoxia-inducible factor 1-alpha (HIF-1α). The upregulation of HIF-1α occurs in the pathogenesis of most NDs. The dual function of HIF-1α in acting as a “killer factor” or a “protective factor” depends on the prevailing local cellular condition. The kynurenine pathway is a metabolic pathway involved in the oxidative breakdown of tryptophan. It is essential in neurotransmission and immune function and, like hypoxia, associated with ND. Thus, a good understanding of factors, including hypoxia (i.e., the biochemical implication of HIF-1α) and kynurenine pathway activation in NDs, focusing on Alzheimer’s disease could prove beneficial to new therapeutic approaches for this disease, thus the aim of this review.

α-Synuclein Induces Neuroinflammation Injury through the IL6ST-AS/STAT3/HIF-1α Axis

“…In vitro models of AD and PD verified that stimulation by certain neuroprotective drugs, such as multifunctional brain-penetrating iron chelator M30 or deferoxamine (DFO), could increase the expression level of HIF-1α to promote the activation of antioxidant pathways and exert neuroprotective effects. In a cellular model of AD, it was observed that an increase in HIF-1α was associated with the degradation of the Aβ protein in hippocampal neurons; however, the detailed mechanism underlying this phenomenon is unclear [ 28 ].…”

Comprehensive analysis of dysregulated circular RNAs and construction of a ceRNA network involved in the pathology of Alzheimer’s disease in a 5 × FAD mouse model

“…Many target genes of miR-6240 have been proposed to be related to AD etiopathogenesis, including serine and arginine-rich splicing factor 1 ( SRSF1 ), hypoxia-inducible factor-1α ( HIF1α ), mesenchyme homeobox 2 ( MEOX2 ), cAMP-responsive element-binding protein 1 ( CREB1 ), pericentriolar material-1 ( PCM1 ), coiled-coil containing protein kinases ( ROCK2 ), synaptosomal-associated protein 23 ( SNAP23 ), and myocyte enhancer factor 2A ( MEF2A ). These genes are involved in plaque deposition, tau protein biosynthesis, neuronal dysfunction, neuroinflammation, autophagy, and other pathological processes related to AD ( Chakravarthy et al, 2013 ; Soto et al, 2016 ; Muhammad et al, 2019 ; Adeyemi et al, 2021 ; Li et al, 2021 ; Weber and Herskowitz, 2021 ). SRSF1 is a member of the serine/arginine-rich proteins family, which is involved in the process of exon selection and mRNA output and localization.…”

Metabolomic Footprint of Disrupted Energetics and Amino Acid Metabolism in Neurodegenerative Diseases: Perspectives for Early Diagnosis and Monitoring of Therapy

“…Kinurein in microglia cells is transformed to 3-HK, which induces oxidative damage, allowing the entry of QUIN, which is excitotoxic and neurotoxic [ 83 , 84 ]. Inflammation and high levels of inflammatory cytokinins cause QUIN to be produced in excess, and instead of being converted to NAD+ to protect neurons, it becomes saturated, leading to neuronal apoptosis [ 85 ].…”