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

作者：Brinkmalm Gunnar^*; Portelius Erik; Ohrfelt Annika; Mattsson Niklas; Persson Rita; Gustavsson Mikael K; Vite Charles H; Gobom Johan; Mansson Jan Eric; Nilsson Jonas; Halim Adnan; Larson Goran; Ruetschi Ulla; Zetterberg Henrik; Blennow Kaj; Brinkmalm Ann

来源：Journal of Mass Spectrometry, 2012, 47(5): 591-603.

DOI：10.1002/jms.2987

• immunoprecipitation mass spectrometry
• cerebrospinal fluid
• amyloid beta
• endogenous peptides
• glycosylation

Amyloid precursor protein (APP) is the precursor protein to amyloid beta (A beta), the main constituent of senile plaques in Alzheimer%26apos;s disease (AD). Endogenous A beta peptides reflect the APP processing, and greater knowledge of different APP degradation pathways is important to understand the mechanism underlying AD pathology. When one analyzes longer A beta peptides by low-energy collision-induced dissociation tandemmass spectrometry (MS/MS), mainly long b-fragments are observed, limiting the possibility to determine variations such as amino acid variants or post-translational modifications (PTMs) within the N-terminal half of the peptide. However, by using electron capture dissociation (ECD), we obtained a more comprehensive sequence coverage for several APP/A beta peptide species, thus enabling a deeper characterization of possible variants and PTMs. %26lt;br%26gt;Abnormal APP/A beta processing has also been described in the lysosomal storage disease Niemann-Pick type C and the major large animal used for studying this disease is cat. By ECD MS/MS, a substitution of Asp7 -%26gt; Glu in cat A beta was identified. Further, sialylated core 1 like O-glycans at Tyr10, recently discovered in human A beta (a previously unknown glycosylation type), were identified also in cat cerebrospinal fluid (CSF). It is therefore likely that this unusual type of glycosylation is common for (at least) species belonging to the magnorder Boreoeutheria. We here describe a detailed characterization of endogenous APP/A beta peptide species in CSF by using an online top-down MS-based method.

• 出版日期2012-5