Converging Pathways of Chromogranin and Amyloid Metabolism in the Brain

Article type: Research Article

Authors: Mattsson, Niklas^{a; *;} | Johansson, Per^{b; c;} | Hansson, Oskar^d | Wallin, Anders^a | Johansson, Jan-Ove^c | Andreasson, Ulf^a | Andersen, Oluf^e | Haghighi, Sara^e | Olsson, Maria^a | Stridsberg, Mats^f | Svensson, Johan^{c; g} | Blennow, Kaj^a | Zetterberg, Henrik^a

Affiliations: [a] Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, Gothenburg and Mölndal, Sweden | [b] Department of Neuropsychiatry, Skaraborg Hospital, Falköping and Skövde, Sweden | [c] Department of Endocrinology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden | [d] Clinical Memory Research Unit, Clinical Sciences Malmö, Lund University, Lund, Sweden | [e] Institute of Neuroscience and Physiology, Department of Neurology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden | [f] Department of Medical Sciences, Clinical Chemistry, University Hospital, Uppsala, Sweden | [g] Department of Endocrinology, Skaraborg Hospital, Falköping and Skövde, Sweden

Correspondence: [*] Correspondence to: Dr. Niklas Mattsson, Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital/Mölndal, S-431 80 Mölndal, Sweden. Tel.: +46 31 3432377; Fax: +46 31 3432426; E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Much is unknown regarding the regulation of Alzheimer-related amyloid-β protein precursor (AβPP)-processing in the human central nervous system. It has been hypothesized that amyloidogenic AβPP-processing preferentially occurs in the regulated secretory pathway of neurons. To test this hypothesis we looked for correlations of AβPP-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 Aβ1-42, Aβx-42, Aβx-40, Aβx-38, α-cleaved soluble AβPP (sAβPPα), β-cleaved soluble AβPP (sAβPPβ), and peptides derived from CgB and SgII (Secretogranin-II, CgC). We investigated CSF levels of the protease BACE1, which processes AβPP into Aβ, 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 sAβPP and Aβ 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 AβPP in the human central nervous system is processed in the regulated secretory pathway of neurons.

Keywords: Amyloid, BACE1, chromogranin, metabolism, regulated secretory pathway

DOI: 10.3233/JAD-2010-091651

Journal: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1039-1049, 2010