Abstract
Serotoninergic activation which decreases brain Aβ peptides is considered beneficial in mouse models for Alzheimer’s disease (AD), but the mechanisms involved remain unclear. Because growing evidence suggested that the stimulation of proteases digesting Aβ, especially the endopeptidase neprilysin (NEP) may be effective for AD therapy/prevention, we explored the involvement of serotonin precursors and derivatives in NEP regulation. We found that 5-hydroxyindolacetic acid (5-HIAA), the final metabolite of serotonin, considered until now as a dead-end and inactive product of serotonin catabolism, significantly reduces brain Aβ in the transgenic APPSWE mouse model for AD-related Aβ pathology and in the phosphoramidon-induced cerebral NEP inhibition mouse model. 5-HIAA treatment improves memory performance in APPSWE mice. Furthermore, 5-HIAA and its precursors increase NEP level in vivo and in neuroblastoma cells. Inhibition of ERK 1/2 cascade by 5-HIAA or SCH772984 enhanced NEP levels, suggesting MAP-kinase pathway involvement in 5-HIAA-induced regulation of NEP expression. Our results provide the first demonstration that 5-HIAA is an active serotonin metabolite that increases brain Aβ degradation/clearance and improves symptoms in the APPSWE mouse model for AD.
Highlights
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder resulting from proteinopathies characterized by the accumulation/ aggregation of β amyloid peptides (Aβ) and hyperphosphorylation followed by aggregation of microtubule-associated protein Tau [48, 52]
Because several indications favor a role of SSRI and serotonin receptors in AD pathophysiology and progression in human and animal models [24], we examined the possible interference of serotonin intermediates on brain Aβ clearance and evidenced a specific role for 5-hydroxyindolacetic acid (5-HIAA) which is generally thought to be a dead-end and inactive product of serotonin catabolism
This therapeutic strategy includes the potentiation of serotonin synthesis by tryptophan or 5-HTP administration, the inhibition of serotonin transport by SSRI’s or degradation by IMAO
Summary
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder resulting from proteinopathies characterized by the accumulation/ aggregation of β amyloid peptides (Aβ) and hyperphosphorylation followed by aggregation of microtubule-associated protein Tau [48, 52]. It is postulated that various accumulated mutations determine or favor deleterious proteinopathies, the most frequent being an anomaly in the synthesis or elimination of amyloid peptides [41]. This in turn initiates a cascade of post-translational disturbances, including mainly the hyperphosphorylation and accumulation of Tau. This in turn initiates a cascade of post-translational disturbances, including mainly the hyperphosphorylation and accumulation of Tau These events produce an early symptomatology made of significant memory and cognitive impairment, generally accompanied by measurable brain atrophy due to neurodegeneration [49]
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