Beta‐site amyloid precursor protein cleaving enzyme 1 (BACE1) as a biological candidate marker of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is characterized by the progressive formation of insoluble amyloid plaques and vascular deposits consisting of the amyloid β‐peptide (Aβ) in the brain. Pathological mechanisms are already active early in the presymptomatic stage of AD. BACE1, β‐secretase, is one of the two key enzymes in amyloid precursor protein (APP) processing; the other being γ‐secretase. The Aβ peptide results from cleavage of APP initially by BACE1 to produce the C99 fragment and releases soluble APPβ (sAPPβ); C99 is then further cleaved by γ‐secretase leading to the Aβ peptide. Increased BACE1 activity and elevated levels of insoluble Aβ peptide have been shown in brain tissue of patients with sporadic AD. Since the CSF is in direct contact with the extracellular space of the central nervous system, biochemical changes in the brain can potentially be reflected in CSF. Therefore, CSF‐based detection of BACE1 levels and activity might be valuable in aiding early detection and prediction, particularly in preclinical or even presymptomatic subjects who are at risk of AD. Recently, we were among the first groups to quantitatively analyse the enzymatic activities and protein levels of BACE1 in the CSF. Preliminary research using recently developed BACE1 ELISAs, BACE1 enzymatic activity, sAPPβ and total Aβ1−x ELISAs were used by examining these hypothesis driven functional candidate markers in subjects with clinically diagnosed AD and amnestic MCI. Two sandwich ELISAs were used and BACE1 enzymatic activities were seen by synthetic fluorescence substrate and total Aβ levels by sandwich‐ELISA. Moreover, elevated CSF levels of BACE1 protein were associated with an increased risk ratio in MCI. Interestingly, amnestic MCI subjects showed increased levels of BACE1 activity compared to HC and AD patients. For total Aβ and tau, increased CSF levels were associated with a higher risk of MCI compared to HC as well. BACE1 activity was significantly correlated with BACE1 protein concentration and total Aβ levels, with Aβ being itself correlated with the BACE1 protein level. Currently, independent studies are ongoing to validate BACE1 and functionally associated proteins as candidate biomarkers for early detection, prediction, progression as well as for biological activity in AD.