Expression of p25, an aberrant cyclin-dependent kinase 5 activator, stimulates basal secretion in PC12 cells.
Although alterations in the functions of neurotransmitter systems have been implicated in the pathology of Alzheimer's disease (AD), the mechanisms that give rise to these alterations are not well understood. The amount of p25, an aberrant cleavage product of p35 that activates cyclin-dependent kinase 5 (Cdk5), is elevated in AD brains. The role of Cdk5 in neurotransmitter release has been well established. In this study, we examined whether p25 was linked to altered neurotransmitter release in AD. Transient or stable expression of p25 significantly increased basal secretion of human growth hormone (hGH) or neurotransmitter in PC12 cells. Expression of a p25 phosphorylation-deficient mutant, T138A, inhibited basal hGH secretion relative to the p25 wild type, suggesting the involvement of Thr138 phosphorylation in secretion. The expression and activity of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), a key protease in the generation of beta-amyloid, are increased in AD brains. Our previous studies indicated that overexpression of BACE1 enhanced basal secretion of hGH in PC12 cells. Transient coexpression of p25 and BACE1 further stimulated spontaneous basal secretion. These results indicate a novel role for p25 in the secretory pathway and suggest that elevated levels of p25 and BACE1 in AD brains may contribute to altered neurotransmitter pathology of AD through enhancing spontaneous basal secretion.
Son
Mi-Young
MY
Graduate Program in Neuroscience, Institute for Brain Science and Technology, Inje University, Busan, 614-735, Korea.
Chung
Sul-Hee
SH
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D013006:Growth Hormone / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009489:Neurosecretion; D018377:Neurotransmitter Agents / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D013912:Threonine / Q000235:genetics; D014162:Transfection; D019076:Transgenes / Q000235:genetics
C492235:Cdk5r1 protein, rat; D018377:Neurotransmitter Agents; D013912:Threonine; D013006:Growth Hormone; D010770:Phosphotransferases; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509281:Bace1 protein, rat