RESUMO
BACKGROUND: Amyloid precursor protein (APP) and amyloid ß (Aß) 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 Aß 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 Aß 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 Aß peptide levels were reduced in MS patients; but they increased again towards normal, after natalizumab treatment. A multivariate model of IP-MS-measured Aß 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 Aß peptide levels in MS patients. We found that natalizumab therapy may be able to counteract the altered APP metabolism in MS. The CSF Aß isoform distribution was found to be distinct in SPMS patients, as compared to the controls.
Assuntos
Peptídeos beta-Amiloides/líquido cefalorraquidiano , Precursor de Proteína beta-Amiloide/líquido cefalorraquidiano , Esclerose Múltipla/líquido cefalorraquidiano , Adulto , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/metabolismo , Estudos de Casos e Controles , Fármacos do Sistema Nervoso Central/uso terapêutico , Cromatografia Líquida , Feminino , Humanos , Imunoensaio , Imunoprecipitação , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Mitoxantrona/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/metabolismo , Esclerose Múltipla Crônica Progressiva/líquido cefalorraquidiano , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Esclerose Múltipla Crônica Progressiva/metabolismo , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/metabolismo , Natalizumab , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fragmentos de Peptídeos/metabolismo , Espectrometria de Massas em TandemRESUMO
Intensive research over the last decades has provided increasing evidence for neuroinflammation as an integral part in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Inflammatory responses in the central nervous system (CNS) are initiated by activated microglia, representing the first line of the innate immune defence of the brain. Therefore, biochemical markers of microglial activation may help us understand the underlying mechanisms of neuroinflammation in AD as well as the double-sided qualities of microglia, namely, neuroprotection and neurotoxicity. In this paper we summarize candidate biomarkers of microglial activation in AD along with a survey of recent neuroimaging techniques.