title: Cell surface expression of the major amyloid-β peptide (Aβ)-degrading enzyme, neprilysin, depends on phosphorylation by mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) and dephosphorylation by protein phosphatase 1a.
abstract: Neprilysin is one of the major amyloid-β peptide (Aβ)-degrading enzymes, the expression of which declines in the brain during aging. The decrease in neprilysin leads to a metabolic Aβ imbalance, which can induce the amyloidosis underlying Alzheimer disease. Pharmacological activation of neprilysin during aging therefore represents a potential strategy to prevent the development of Alzheimer disease. However, the regulatory mechanisms mediating neprilysin activity in the brain remain unclear. To address this issue, we screened for pharmacological regulators of neprilysin activity and found that the neurotrophic factors brain-derived neurotrophic factor, nerve growth factor, and neurotrophins 3 and 4 reduce cell surface neprilysin activity. This decrease was mediated by MEK/ERK signaling, which enhanced phosphorylation at serine 6 in the neprilysin intracellular domain (S6-NEP-ICD). Increased phosphorylation of S6-NEP-ICD in primary neurons reduced the levels of cell surface neprilysin and led to a subsequent increase in extracellular Aβ levels. Furthermore, a specific inhibitor of protein phosphatase-1a, tautomycetin, induced extensive phosphorylation of the S6-NEP-ICD, resulting in reduced cell surface neprilysin activity. In contrast, activation of protein phosphatase-1a increased cell surface neprilysin activity and lowered Aβ levels. Taken together, these results indicate that the phosphorylation status of S6-NEP-ICD influences the localization of neprilysin and affects extracellular Aβ levels. Therefore, maintaining S6-NEP-ICD in a dephosphorylated state, either by inhibition of protein kinases involved in its phosphorylation or by activation of phosphatases catalyzing its dephosphorylation, may represent a new approach to prevent reduction of cell surface neprilysin activity during aging and to maintain physiological levels of Aβ in the brain.
authors: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
authors: Naomasa
authors: N
authors: Kakiya
authors: Takashi
authors: T
authors: Saito
authors: Per
authors: P
authors: Nilsson
authors: Yukio
authors: Y
authors: Matsuba
authors: Satoshi
authors: S
authors: Tsubuki
authors: Nobuyuki
authors: N
authors: Takei
authors: Hiroyuki
authors: H
authors: Nawa
authors: Takaomi C
authors: TC
authors: Saido
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D005663:Furans / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008055:Lipids / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D015260:Neprilysin / Q000096:biosynthesis* / Q000235:genetics; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D020933:Neurotrophin 3 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D005663:Furans; D008055:Lipids; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; C058744:tautomycetin; D020932:Nerve Growth Factor; D020930:MAP Kinase Kinase Kinases; C517187:PPP1CA protein, human; C527795:PPP1CA protein, mouse; D054645:Protein Phosphatase 1; D015260:Neprilysin; C073922:neurotrophin 4