Overexpression of APP stimulates basal and constitutive exocytosis in PC12 cells.
The mechanisms that underlie the altered neurotransmitter system in Alzheimer's disease (AD) are not well understood. Amyloid precursor protein (APP) is a precursor protein for beta-amyloid, an important trigger protein in the pathogenesis of AD. Duplication of the APP gene as well as APP genes that contain certain mutations has been reported to be associated with familial AD (FAD), and a role of APP in neurotransmission has been suggested recently. This study examines the role of APP in exocytosis in PC12 cells using transfected human growth hormone (hGH) as a reporter for secretion. It was found that overexpression of APP or expression of the Swedish FAD mutation (APPsw) in PC12 cells significantly increased the basal secretion and constitutive secretion of hGH. Expression of an APP phosphorylation-deficient mutant decreased both basal and constitutive secretion relative to the APP wild-type, suggesting a role for APP-Thr668 phosphorylation in secretion in PC12 cells. Overexpression of X11alpha, a protein that stabilizes cellular APP, also increased the basal secretion of hGH but, contrary to APP, decreased the constitutive secretion of hGH, suggesting that basal and constitutive secretion is likely to proceed via distinct pathways and that the increase in the basal secretion of hGH may result from APP-X11alpha interaction. These results demonstrate an unknown role for APP in secretion, and suggest that elevated levels of APP or APP mutation in FAD brains contribute to the altered neurotransmitter pathology of AD through stimulation of basal and constitutive secretion.
Lee
Hye-Won
HW
Graduate Program in Neuroscience, Institute for Brain Science and Technology, Inje University, 633-146 Gaegeum 2-dong, Busanjin-gu, Busan 614-735, South Korea.
Park
Jeong Won
JW
Sandagsuren
Enkh-Undraa
EU
Kim
Ki-Bae
KB
Yoo
Jin-Ju
JJ
Chung
Sul-Hee
SH
D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology*; D013006:Growth Hormone / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016716:PC12 Cells / Q000187:drug effects; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D013997:Time Factors; D014162:Transfection
D016564:Amyloid beta-Protein Precursor; C109650:Apba2 protein, rat; D015820:Cadherins; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; D011189:Potassium Chloride; D013006:Growth Hormone