Implications of the kynurenine pathway and quinolinic acid in Alzheimer's disease.
The kynurenine pathway (KP) is a major route of L-tryptophan catabolism leading to production of a number of biologically active molecules. Among them, the neurotoxin quinolinic acid (QUIN), is considered to be involved in the pathogenesis of a number of inflammatory neurological diseases. Alzheimer's disease is the major dementing disorder of the elderly that affects over 20 million peoples world-wide. Most of the approaches to explain the pathogenesis of Alzheimer's disease focus on the accumulation of amyloid beta peptide (A beta), in the form of insoluble deposits leading to formation of senile plaques, and on the formation of neurofibrillary tangles composed of hyperphosphorylated Tau protein. Accumulation of A beta is believed to be an early and critical step in the neuropathogenesis of Alzheimer's disease. There is now evidence for the KP being associated with Alzheimer's disease. Disturbances of the KP have already been described in Alzheimer's disease. Recently, we demonstrated that A beta 1-42, a cleavage product of amyloid precursor protein, induces production of QUIN, in neurotoxic concentrations, by macrophages and, more importantly, microglia. Senile plaques in Alzheimer's disease are associated with evidence of chronic local inflammation (especially activated microglia) A major aspect of QUIN toxicity is lipid peroxidation and markers of lipid peroxidation are found in Alzheimer's disease. Together, these data imply that QUIN may be one of the critical factors in the pathogenesis of neuronal damage in Alzheimer's disease. This review describes the multiple correlations between the KP and the neuropathogenesis of Alzheimer's disease and highlights more particularly the aspects of QUIN neurotoxicity, emphasizing its roles in lipid peroxidation and the amplification of the local inflammation.
Guillemin
Gilles J
GJ
Centre for Immunology and Department of Neurology, St Vincent's Hospital and University of New South Wales, Sydney, Australia. g.guillemin@cfi.unsw.edu.au
Brew
Bruce J
BJ
D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D006801:Humans; D007737:Kynurenine / Q000378:metabolism*; D017378:Quinolinic Acid / Q000633:toxicity*; D014364:Tryptophan / Q000378:metabolism
D016229:Amyloid beta-Peptides; D007737:Kynurenine; D014364:Tryptophan; D017378:Quinolinic Acid