Cerebrospinal fluid biomarkers of β-amyloid metabolism in multiple sclerosis.
BACKGROUND
Amyloid precursor protein (APP) and amyloid β (Aβ) peptides are intensely studied in neuroscience and their cerebrospinal fluid (CSF) measurements may be used to track the metabolic pathways of APP in vivo. Reduced CSF levels of Aβ and soluble APP (sAPP) fragments are reported in inflammatory diseases, including multiple sclerosis (MS); but in MS, the precise pathway of APP metabolism and whether it can be affected by disease-modifying treatments remains unclear.


OBJECTIVE
To characterize the CSF biomarkers of APP degradation in MS, including the effects of disease-modifying therapy.


METHODS
CSF samples from 87 MS patients (54 relapsing-remitting (RR) MS; 33 secondary progressive (SP) MS and 28 controls were analyzed for sAPP and Aβ peptides by immunoassays, plus a subset of samples was analyzed by immunoprecipitation and mass spectrometry (IP-MS). Patients treated with natalizumab or mitoxantrone were examined at baseline, and after 1-2 years of treatment.


RESULTS
CSF sAPP and Aβ peptide levels were reduced in MS patients; but they increased again towards normal, after natalizumab treatment. A multivariate model of IP-MS-measured Aβ species separated the SPMS patients from controls, with RRMS patients having intermediate levels.


CONCLUSIONS
We confirmed and extended our previous observations of altered CSF sAPP and Aβ peptide levels in MS patients. We found that natalizumab therapy may be able to counteract the altered APP metabolism in MS. The CSF Aβ isoform distribution was found to be distinct in SPMS patients, as compared to the controls.
Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. kristin.augutis@neuro.gu.se
Kristin
K
Augutis
Markus
M
Axelsson
Erik
E
Portelius
Gunnar
G
Brinkmalm
Ulf
U
Andreasson
Mikael K
MK
Gustavsson
Clas
C
Malmeström
Jan
J
Lycke
Kaj
K
Blennow
Henrik
H
Zetterberg
Niklas
N
Mattsson
D000328:Adult; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid* / Q000737:chemistry / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000134:cerebrospinal fluid* / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D015415:Biomarkers / Q000134:cerebrospinal fluid / Q000378:metabolism; D016022:Case-Control Studies; D002491:Central Nervous System Agents / Q000627:therapeutic use; D002853:Chromatography, Liquid; D005260:Female; D006801:Humans; D007118:Immunoassay; D047468:Immunoprecipitation; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D008942:Mitoxantrone / Q000627:therapeutic use; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid* / Q000188:drug therapy / Q000378:metabolism; D020528:Multiple Sclerosis, Chronic Progressive / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000378:metabolism; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000378:metabolism; D000069442:Natalizumab; D010446:Peptide Fragments / Q000134:cerebrospinal fluid / Q000378:metabolism; D053719:Tandem Mass Spectrometry
C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D002491:Central Nervous System Agents; D000069442:Natalizumab; D010446:Peptide Fragments; C538897:amyloid beta-protein (40-42); D008942:Mitoxantrone