A novel Aβ isoform pattern in CSF reflects γ-secretase inhibition in Alzheimer disease

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 Aβ isoform pattern was analyzed with immunoprecipitation combined with MALDI-TOF mass spectrometry.The CSF levels of Aβ1-14, Aβ1-15, and Aβ1-16 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. Aβ1-40 and Aβ1-42 were unaffected by treatment.CSF Aβ1-14, Aβ1-15, and Aβ1-16 increase during γ-secretase inhibitor treatment in AD, even at doses that do not affect Aβ1-42 or Aβ1-40, probably because of increased substrate availability of the C99 APP stub (APP β-CTF) induced by γ-secretase inhibition. These Aβ isoforms may be novel sensitive biomarkers to monitor the biochemical effect in clinical trials.Clinical Trials.gov NCT00244322Accumulation of amyloid β (Aβ) peptides in senile plaques in the cerebral cortex is an early event in the pathogenesis of Alzheimer disease (AD) [1]. The longest isoform of Aβ, consisting of 42 amino acids (Aβ1-42), is produced from amyloid precursor protein (APP) by sequential cleavage by β- and γ-secretase in the amyloidogenic APP-processing pathway (Figure 1A) [2]. β-Secretase activity originates from an integral membrane aspartyl protease encoded by the β-site APP-cleaving enzyme 1 gene (BACE1) [3-6] whereas γ-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]. γ-Secretase, which is one of the top targets for developing AD therapeutics with disease-modifying effects, cleaves the transmembrane region of APP to produce Aβ of variable length [10-12], with Aβ1-40 being the most abundant isoform, whereas Aβ1-42 is most prone to aggregation [13,14].The main focus of using disease-modifying drugs is to inhibit brain Aβ pr