Identification of novel N-terminal fragments of amyloid precursor protein in cerebrospinal fluid

Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy, University of Gothenburg, S-431 80 Mölndal, Sweden.
Experimental Neurology (Impact Factor: 4.62). 07/2009; 223(2):351-8. DOI: 10.1016/j.expneurol.2009.06.011
Source: PubMed

ABSTRACT Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system. Two pathological hallmarks in the brain of AD patients are neurofibrillary tangles and senile plaques. The plaques consist mainly of beta-amyloid (Abeta) peptides that are produced from the amyloid precursor protein (APP), by sequential cleavage by beta- and gamma-secretase. Most previous studies have been focused on the C-terminal fragments of APP, where the Abeta sequence is localized. The purpose of this study was to search for N-terminal fragments of APP in cerebrospinal fluid (CSF) using mass spectrometry (MS). By using immunoprecipitation (IP) combined with matrix-assisted laser desorption/ionization time-of-flight MS as well as nanoflow liquid chromatography coupled to high resolution tandem MS we were able to detect and identify six novel N-terminal APP fragments [APP((18-119)), APP((18-121)), APP((18-122)), APP((18-123)), APP((18-124)) and APP((18-126))], having molecular masses of approximately 12 kDa. The presence of these APP derivatives in CSF was also verified by Western blot analysis. Two pilot studies using either IP-MS or Western blot analysis indicated slightly elevated levels of N-terminal APP fragments in CSF from AD patients compared with controls, which are in need of replications in independent and larger patient materials.

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    • "For example, APP is cleaved by a-or b-secretase to produce ectodomain fragments (sAPPa or sAPPb) that are secreted into the extracellular milieu (Nunan and Small, 2000). Several studies have shown that sAPPa and APP can be cleaved, both in vitro and in vivo, to yield smaller N-terminal fragments (Small et al., 1994; Caswell et al., 1999: Esh et al., 2005; Nikolaev et al., 2009; Portelius et al., 2010; Jefferson et al., 2011; Vella and Cappai, 2012). The level of APP N-terminal fragments has been reported to increase during development as cells differentiate into neurons (Vella and Cappai, 2012). "
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