BACE1 Inhibition Induces a Specific Cerebrospinal Fluid β-Amyloid Pattern That Identifies Drug Effects in the Central Nervous System

Abstract

BACE1 is a key enzyme for amyloid-β (Aβ) production, and an attractive therapeutic target in Alzheimer's disease (AD). Here we report that BACE1 inhibitors have distinct effects on neuronal Aβ metabolism, inducing a unique pattern of secreted Aβ peptides, analyzed in cell media from amyloid precursor protein (APP) transfected cells and in cerebrospinal fluid (CSF) from dogs by immunoprecipitation-mass spectrometry, using several different BACE1 inhibitors. Besides the expected reductions in Aβ1-40 and Aβ1-42, treatment also changed the relative levels of several other Aβ isoforms. In particular Aβ1-34 decreased, while Aβ5-40 increased, and these changes were more sensitive to BACE1 inhibition than the changes in Aβ1-40 and Aβ1-42. The effects on Aβ5-40 indicate the presence of a BACE1 independent pathway of APP degradation. The described CSF Aβ pattern may be used as a pharmacodynamic fingerprint to detect biochemical effects of BACE1-therapies in clinical trials, which might accelerate development of novel therapies.

Brain Amyloid-Beta Fragment Signatures in Pathological Ageing and Alzheimer's Disease by Hybrid Immunoprecipitation Mass Spectrometry

“…MALDI-TOF/TOFMS measurements were performed using a Bruker Daltonics UltraFleXtreme instrument (Bruker Daltonics, Bremen, Germany) operating in reflector mode, as described previously [21]. …”

The Metalloprotease Meprin β Is an Alternative β-Secretase of APP

“…This was supported, when using potent BACE-1 inhibitors in vitro and in vivo (Asai et al, 2006; Nishitomi et al, 2006; Hussain et al, 2007; Stanton et al, 2007; Sankaranarayanan et al, 2008). Interestingly, some studies showed that by inhibition of Aβ1-x generating β-secretase activity, alternative N-terminally truncated Aβ peptides increase (Haass et al, 1995; Schrader-Fischer and Paganetti, 1996; Takeda et al, 2004; Schieb et al, 2010; Mattsson et al, 2012). Analysis of Aβ species in BACE-1 knock-out mice likewise revealed that the generation of Aβ1-x peptides was completely abolished while N-terminally truncated Aβ variants could still be generated (Nishitomi et al, 2006).…”

CSF in Alzheimer's Disease

“…One of the truly longitudinal studies of cognitively normal individuals with repeated CSF samples suggests that Ab42 and tau changes occur in parallel and predict upcoming cognitive symptoms better than absolute baseline levels [101]. CSF measurements may track trajectories of specific Ab and APP metabolites [104][105][106][107], and downstream effects on secondary phenomena, such as reduced axonal degeneration in response to a disease-modifying drug as measured by CSF tau levels [108,109].…”