LAUSR

&NA; Elevated level of homocysteine (Hcy) is considered a risk factor for neurodegenerative diseases, but the mechanisms remain to be established. Because high Hcy is associated with an up‐regulation of the ALOX5 gene product, the 5Lipoxygenase (5LO), herein we investigated whether this activation is responsible for the Hcy effect on neurodegeneration or is a secondary event. To reach this goal, wild type mice and mice genetically deficient for 5LO were assessed after being exposed to a diet known to significantly increase brain levels of Hcy. Confirming compliance with the dietary regimen, we found that by the end of the study brain levels of Hcy were significantly increase in both groups. However, diet‐induced high Hcy resulted in a significant increase in A&bgr;, tau phosphorylation, neuroinflammation, synaptic pathology and memory impairment in control mice, but not in mice lacking ALOX5. Taken together our findings demonstrate that the up‐regulation of the ALOX5 gene pathway is responsible for the development of the biochemical and behavioral sequelae of high Hcy brain levels in the context of a neurodegenerative phenotype. They provide critical support that this gene and its expressed protein are viable therapeutic targets to prevent the onset, or delay neurodegenerative events in subjects exposed to this risk factor.