Dissecting the Role of 5-Lipoxygenase in the Homocysteine-Induced Alzheimer's Disease Pathology

Alzheimer's disease (AD) affects over 40 million patients around the world and poses a huge economic burden on society since no effective therapy is available yet. While the cause(s) for the most common sporadic form of the disease are still obscure, lifestyle and different environmental factors have emerged as modulators of AD susceptibility. Hyperhomocysteinemia (HHCY), a condition of high circulating levels of homocysteine, is an independent but modifiable risk factor for AD. Studies in AD mouse models have linked HHCY with memory impairment, amyloidosis, tau pathology, synaptic dysfunction, and neuroinflammation. However, the exact mechanism by which HHCY affects AD pathogenesis is unclear. The 5-lipoxygenase (5LO) is a protein upregulated in postmortem AD brains and plays a functional role in AD pathogenesis. Recently, in vitro and in vivo studies showed that HHCY effects on amyloid-beta and tau pathology, synapse and memory impairments are dependent on the activation of the 5LO enzymatic pathway, since its genetic absence or pharmacological inhibition prevents them. HHCY induces 5LO gene upregulation by lowering the methylation of its promoter, which results in increased translation and transcription of its mRNA. Based on these findings, we propose that epigenetic modification of 5LO represents the missing biological link between HHCY and AD pathogenesis, and for this reason it represents a viable therapeutic target to prevent AD development in individuals bearing this risk factor.