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Serotonin metabolite 5-HIAA up-regulates the expression of neprilysin

 

Amyloid plaques are extracellular aggregates of amyloid beta peptides presenting in patients with Alzheimer’s disease. Different approaches have been proposed to inhibit plaque formation or to increase its clearance. 

Neprilysin (NEP) is a metalloendopeptidase, which is able to digest amyloids. It was shown to decrease the incidence of amyloid plaques in mouse models of Alzheimer’s disease.  

A recent study explored the role of serotonin precursors and metabolites on NEP regulation and plaque clearance. Interestingly, they found that the final product of serotonin catabolism, 5-hydroxyindole-3-acetic acid (5-HIAA), reduced brain amyloid beta proteinopathy in transgenic rodent model for Alzheimer’s disease. 

As a next step, they looked at the phosphorylation levels of principal components of the MAP pathway. They detected down-regulation of ERK phosphorylation in 5-HIAA-treated cells, which pointed to a possible involvement of the ERK cascade in NEP expression. To investigate this, they added the ERK ½ inhibitor from Carbosynth, SCH 772984, either alone or in combination with 5-HIAA to SHSY-5Y cells. In SCH 772984-treated cells, the NEP levels were significantly higher than in controls. The up-regulation of NEP levels was amplified by concomitant addition of the ERK inhibitor and 5-HIAA.

This interesting study demonstrated that 5-HIAA induces neprilysin expression via down-regulation of the ERK signalling pathway. 

 

For more details, read the original paper published in Acta Neuropathologica Communications: Klein et al., 2018. 

 

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