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Abstract

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.

Keywords

Amyloid beta amyloid precursor protein APP metabolism biomarkers cerebrospinal fluid multiple sclerosis natalizumab mitoxantrone relapsing–remitting MS secondary progressive MS

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References

Blennow

Hampel

Weiner

. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 2010; 6:131–144.

Gisslen

Krut

Andreasson

. Amyloid and tau cerebrospinal fluid biomarkers in HIV infection. BMC Neurol 2009; 9: 63.

Sjogren

Gisslen

Vanmechelen

. Low cerebrospinal fluid beta-amyloid 42 in patients with acute bacterial meningitis and normalization after treatment. Neurosci Lett 2001; 314: 33–36.

Trysberg

Hoglund

Svenungsson

. Decreased levels of soluble amyloid beta-protein precursor and beta-amyloid protein in cerebrospinal fluid of patients with systemic lupus erythematosus. Arthritis Res Ther 2004; 6: R129–136.

Mattsson

Axelsson

Haghighi

. Reduced cerebrospinal fluid BACE1 activity in multiple sclerosis. Mult Scler 2009;15:448–454.

Mattsson

Bremell

Anckarsater

. Neuroinflammation in Lyme neuroborreliosis affects amyloid metabolism. BMC Neurol 2010; 10: 51.

Rinaldi

Calabrese

Grossi

. Cortical lesions and cognitive impairment in multiple sclerosis. Neurol Sci 2010;31: S235–237.

Mori

Rossi

Sancesario

. Cognitive and cortical plasticity deficits correlate with altered amyloid-beta CSF levels in multiple sclerosis. Neuropsychopharmacol 2011; 36: 559–568.

Gehrmann

Banati

Cuzner

. Amyloid precursor protein (APP) expression in multiple sclerosis lesions. Glia 1995;15: 141–151.

10.

Portelius

Price

Brinkmalm

. A novel pathway for amyloid precursor protein processing. Neurobiol Aging 2011;32: 1090–1098.

11.

Andreasson

Portelius

Andersson

. Aspects of beta-amyloid as a biomarker for Alzheimer’s disease. Biomark Med 2007; 1: 59–78.

12.

Axelsson

Malmestrom

Nilsson

. Glial fibrillary acidic protein: A potential biomarker for progression in multiple sclerosis. J Neurol 2010; 258: 882–888.

13.

Gunnarsson

Malmestrom

Axelsson

. Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumab. Ann Neurol 2011; 69: 83–89.

14.

Kurtzke

. Rating neurologic impairment in multiple sclerosis: An Expanded Disability Status Scale (EDSS). Neurol 1983; 33: 1444–1452.

15.

Roxburgh

Seaman

Masterman

. Multiple sclerosis severity score: Using disability and disease duration to rate disease severity. Neurol 2005; 64: 1144–1151.

16.

Polman

Wolinsky

Reingold

. Multiple sclerosis diagnostic criteria: Three years later. Mult Scler 2005; 11: 5–12.

17.

MS Association. Ts. Criteria for MS-treatment, http://www.mssallskapet.se/ (accessed 16 April 2012).

18.

Malmestrom

Haghighi

Rosengren

. Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS. Neurol 2003; 61: 1720–1725.

19.

Teunissen

Petzold

Bennett

. A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking. Neurol 2009; 73: 1914–1922.

20.

Olsson

Vanderstichele

Andreasen

. Simultaneous measurement of beta-amyloid(1–42), total tau, and phosphorylated tau (Thr181) in cerebrospinal fluid by the xMAP technology. Clin Chem 2005;51: 336–345.

21.

Portelius

Westman-Brinkmalm

Zetterberg

. Determination of beta-amyloid peptide signatures in cerebrospinal fluid using immunoprecipitation-mass spectrometry. J Proteome Res 2006; 5: 1010–1016.

22.

Portelius

Tran

Andreasson

. Characterization of amyloid beta peptides in cerebrospinal fluid by an automated immunoprecipitation procedure followed by mass spectrometry. J Proteome Res 2007; 6: 4433–4439.

23.

Brinkmalm

Portelius

Ohrfelt

. An online nano-LC-ESI-FTICR-MS method for comprehensive characterization of endogenous fragments from amyloid beta and amyloid precursor protein in human and cat cerebrospinal fluid. J Mass Spectrom 2012; 47: 591–603.

24.

Bylesjo

Eriksson

Sjodin

. Orthogonal projections to latent structures as a strategy for microarray data normalization. BMC Bioinformatics 2007; 8: 207.

25.

Rossi

Mancino

Bergami

. Potential role of IL-13 in neuroprotection and cortical excitability regulation in multiple sclerosis. Mult Scler 2011; 17: 1301–1312.

26.

Mai

. Cerebrospinal fluid levels of soluble amyloid precursor protein and beta-amyloid 42 in patients with multiple sclerosis, neuromyelitis optica and clinically isolated syndrome. J Int Med Res 2011; 39: 2402–2413.

27.

Dal Bianco

Bradl

Frischer

. Multiple sclerosis and Alzheimer’s disease. Ann Neurol 2008; 63: 174–183.

28.

Cirrito

Kang

Lee

. Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron 2008; 58: 42–51.

29.

Mattsson

Johansson

Hansson

. Converging pathways of chromogranin and amyloid metabolism in the brain. J Alzheimers Dis 2010; 20: 1039–1049.

30.

Wake

Lee

Fields

RD.

Control of local protein synthesis and initial events in myelination by action potentials. Science 2011; 16; 333(6049): 1647–51.

31.

Rosen

Andreasson

Mattsson

. Cerebrospinal fluid profiles of amyloid-related biomarkers in Alzheimer’s disease. Neuromolec Med 2012; 14 (1): 65–73.

32.

Mattsson

Zetterberg

Bianconi

. Gamma-secretase-dependent amyloid-beta is increased in Niemann-Pick type C: A cross-sectional study. Neurol 2011; 76: 366–372.

33.

Hicks

. Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci 2006; 9: 1520–1525.

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Cerebrospinal fluid biomarkers of β-amyloid metabolism in multiple sclerosis

Abstract

Background:

Objective:

Methods:

Results:

Conclusions:

Keywords

Get full access to this article

References

Supplementary Material