%0 Journal Article
%T A novel A¦Â isoform pattern in CSF reflects ¦Ã-secretase inhibition in Alzheimer disease
%A Erik Portelius
%A Robert A Dean
%A Mikael K Gustavsson
%A Ulf Andreasson
%A Henrik Zetterberg
%A Eric Siemers
%A Kaj Blennow
%J Alzheimer's Research & Therapy
%D 2010
%I BioMed Central
%R 10.1186/alzrt30
%X In a phase II clinical trial, 35 individuals with mild to moderate AD were randomized to placebo (n = 10) or LY450139 (100 mg (n = 15) or 140 mg (n = 10)) and underwent lumbar puncture at baseline and after 14 weeks of treatment. The CSF A¦Â isoform pattern was analyzed with immunoprecipitation combined with MALDI-TOF mass spectrometry.The CSF levels of A¦Â1-14, A¦Â1-15, and A¦Â1-16 showed a dose-dependent increase by 57% and 74%, 21% and 35%, and 30% and 67%, respectively in the 100-mg and 140-mg treatment groups. A¦Â1-40 and A¦Â1-42 were unaffected by treatment.CSF A¦Â1-14, A¦Â1-15, and A¦Â1-16 increase during ¦Ã-secretase inhibitor treatment in AD, even at doses that do not affect A¦Â1-42 or A¦Â1-40, probably because of increased substrate availability of the C99 APP stub (APP ¦Â-CTF) induced by ¦Ã-secretase inhibition. These A¦Â isoforms may be novel sensitive biomarkers to monitor the biochemical effect in clinical trials.Clinical Trials.gov NCT00244322Accumulation of amyloid ¦Â (A¦Â) peptides in senile plaques in the cerebral cortex is an early event in the pathogenesis of Alzheimer disease (AD) [1]. The longest isoform of A¦Â, consisting of 42 amino acids (A¦Â1-42), is produced from amyloid precursor protein (APP) by sequential cleavage by ¦Â- and ¦Ã-secretase in the amyloidogenic APP-processing pathway (Figure 1A) [2]. ¦Â-Secretase activity originates from an integral membrane aspartyl protease encoded by the ¦Â-site APP-cleaving enzyme 1 gene (BACE1) [3-6] whereas ¦Ã-secretase is an intramembrane-cleaving complex composed of at least four essential subunits with the presenilin (PS1 or PS2) proteins at its enzymatic core [7-9]. ¦Ã-Secretase, which is one of the top targets for developing AD therapeutics with disease-modifying effects, cleaves the transmembrane region of APP to produce A¦Â of variable length [10-12], with A¦Â1-40 being the most abundant isoform, whereas A¦Â1-42 is most prone to aggregation [13,14].The main focus of using disease-modifying drugs is to inhibit brain A¦Â pr
%U http://alzres.com/content/2/2/7