A unique finding in this
A unique finding in this study is that 12/15-LO influences CREB phosphorylation in the murine brain. While previous reports have found that knockout of 5-lipoxygenase, a related enzyme that also uses arachidonic Thonzonium Bromide for substrate, can regulate CREB phosphoryation in the context of Alzheimer's disease, 12/15-LO influence on CREB has not yet been documented. We hypothesize that since both 12/15-LO and 5-LO compete for arachidonic acid substrate, that overexpression of 12/15-LO results in a similar phenotype to knockout of 5-lipoxygnease. Indeed, we have previously reported that the knockout of 5-lipoxygenase or the 5-lipoxygenase activating protein results in aging-associated anxiety-like behavior. Based on our current findings, we posit that aging-associated anxiety behavior may be influenced by an equilibrium of downstream 12/15-LO and 5-LO hydroperoxyeicosatetraenoic metabolites. While no substantial clinical data exist about the role of hydroperoxyeicosatetraenoic metabolism in psychiatric illness, polymorphisms in the 12/15-LO gene have been linked to schizophrenia risk in a Korean cohort (Kim et al., 2010), and recent evidence suggests lipoxygenase pathway modulators cause neuropsychiatric adverse effects (Schumock et al., 2011a, Schumock et al., 2011b).
Changes in CREB phosphorylation can modulate expression of CREB-sensitive protein such as BDNF or cFOS, but in our study we found that both factors were unaltered despite a reduction in pCREB. However, other work has shown that BDNF and cFOS steady-state levels rely on CREB-independent mechanisms, and it is possible that overexpression of 12/15-LO induces compensatory mechanisms in the brain (Costa et al., 2008, Li et al., 2010, Taurin et al., 2002).
CREB is well known to play a critical role in synaptic plasticity and integrity in the brain, and we found synaptophysin levels to be elevated in H12/15-LO animals without any changes in PSD-95 or MAP2. While disruption of CREB signaling has been linked to loss of synaptic integrity and reduction of various synaptic markers, synaptophysin is increased in several brain regions following stressful stimuli or in association with anxiogenic states (Campos et al., 2013, Ray et al., 2011). Therefore, we hypothesize that the increase in synaptophysin expression observed in H12/15-LO animals is likely a component of the anxiety-phenotype rather than a consequence of 12/15-LO-dependent CREB modulation. In summary, our work highlights a new role for the 12/15-LO pathway in anxiety that could be of use in dissecting the pathophysiology of anxiety disorders in late life. Further investigation of 12/15-LO in this context could lead to a better understanding of anxiety disorders and tailored development of therapeutics that would be of great utility to the aging population.
Acknowledgements This work was supported in part by grants from the Alzheimer's Association and the Alzheimer's Art Quilt Initiative.
Skeletal muscle atrophy is a devastating outcome of a number of chronic diseases such as diabetes, cancer, and cystic fibrosis . In addition, loss of innervation (or denervation) of skeletal muscle fibers by motor neurons as observed during aging and neurodegenerative diseases, such as familial amyotrophic lateral sclerosis (f-ALS), leads to muscle atrophy , , , . We have previously shown that denervation-induced muscle atrophy is accompanied by an increase in the expression of cytosolic phospholipase A (cPLA) , the rate-limiting step in arachidonic acid metabolism. Arachidonic acid released from membrane phospholipids by the action of cPLA acts as a substrate for lipid metabolic pathways catalyzed by lipoxygenases (LOs), cyclooxygenase (COX), and cytochrome P450 . The COX-2 pathway generates prostaglandins such as PGE, paracrine hormones that regulate a number of physiological and pathophysiological processes. It has been reported that genetic and pharmacological inhibition of COX-2 impairs skeletal muscle regeneration, suggesting that activation of the COX-2 pathway may be important in myogenesis , . However, the potential role of the 5- and 12/15-LO lipid metabolic pathways downstream of cPLA in skeletal muscle physiology remains unknown.