Converging pathways of chromogranin and amyloid metabolism in the brain.
Much is unknown regarding the regulation of Alzheimer-related amyloid-beta protein precursor (AbetaPP)-processing in the human central nervous system. It has been hypothesized that amyloidogenic AbetaPP-processing preferentially occurs in the regulated secretory pathway of neurons. To test this hypothesis we looked for correlations of AbetaPP-derived molecules in cerebrospinal fluid (CSF) with chromogranin (Cg) derived peptides, representing the regulated secretion. Patients with Alzheimer's disease (AD, N=32), multiple sclerosis (MS, N=50), and healthy controls (N= 70) were enrolled. CSF was analyzed for the amyloid peptides Abeta1-42, Abetax-42, Abetax-40, Abetax-38, alpha-cleaved soluble AbetaPP (sAbetaPPalpha), beta-cleaved soluble AbetaPP (sAbetaPPbeta), and peptides derived from CgB and SgII (Secretogranin-II, CgC). We investigated CSF levels of the protease BACE1, which processes AbetaPP into Abeta, in relation to Cg-levels. Finally, we measured Cg levels in cell media from untreated and BACE1-inhibited SH-SY5Y human neuroblastoma cells. CSF Cg levels correlated to sAbetaPP and Abeta peptides in AD, MS, and controls, and to CSF BACE1. Cell medium from BACE1-inhibited cells had decreased CgB levels. These results suggest that a large part of AbetaPP in the human central nervous system is processed in the regulated secretory pathway of neurons.
Mattsson
Niklas
N
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg and Mölndal, Sweden. niklas.mattsson@neuro.gu.se
Johansson
Per
P
Hansson
Oskar
O
Wallin
Anders
A
Johansson
Jan-Ove
JO
Andreasson
Ulf
U
Andersen
Oluf
O
Haghighi
Sara
S
Olsson
Maria
M
Stridsberg
Mats
M
Svensson
Johan
J
Blennow
Kaj
K
Zetterberg
Henrik
H
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid / Q000378:metabolism; D000682:Amyloid / Q000134:cerebrospinal fluid / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000134:cerebrospinal fluid; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000134:cerebrospinal fluid / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000134:cerebrospinal fluid; D015415:Biomarkers; D053898:Biosynthetic Pathways; D001923:Brain Chemistry / Q000502:physiology*; D045744:Cell Line, Tumor; D002864:Chromogranins / Q000134:cerebrospinal fluid / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid / Q000378:metabolism; D055815:Young Adult
D000682:Amyloid; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D002864:Chromogranins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human