β-Secretase1 biological markers for Alzheimer's disease: state-of-art of validation and qualification

Abstract

β-Secretase1 (BACE1) protein concentrations and rates of enzyme activity, analyzed in human bodily fluids, are promising candidate biological markers for guidance in clinical trials investigating BACE1 inhibitors to halt or delay the dysregulation of the amyloid-β pathway in Alzheimer's disease (AD). A robust body of evidence demonstrates an association between cerebrospinal fluid/blood BACE1 biomarkers and core pathophysiological mechanisms of AD, such as brain protein misfolding and aggregration, neurodegeneration, and synaptic dysfunction.In pharmacological trials, BACE1 candidate biomarkers may be applied to a wide set of contexts of use (CoU), including proof of mechanism, dose-finding, response and toxicity dose estimation. For clinical CoU, BACE1 biomarkers show good performance for prognosis and disease prediction.The roadmap toward validation and qualification of BACE1 biomarkers requires standardized pre-analytical and analytical protocols to reduce inter-site variance that may have contributed to inconsistent results.BACE1 biomarker-drug co-development programs, including biomarker-guided outcomes and endpoints, may support the identification of sub-populations with a higher probability to benefit from BACE1 inhibitors with a reduced risk of adverse effects, in line with the evolving precision medicine paradigm.

Keywords: Alzheimer’s disease; Amyloid-β pathway; Axonal damage; BACE1; Clinical trials; Context of use; Fluid biomarkers; Neurodegeneration.

Fig. 1

Schematic representation of amyloidogenic and non-amyloidogenic pathways. Footnote: Three main proteases—α-, β-, and γ-secretases—are involved in APP processing through the amyloidogenic pathway (sequential cleavage by β- and γ-secretases), promoting amyloid-β (Aβ) production, and the non-amyloidogenic pathway in which Aβ is cleaved in the middle, either directly by α-secretase (generating soluble APPα) or by the sequential cleavage by β-secretase and α-secretase (generating shorter Aβ species such as Aβ1–15 and Aβ1–16). The two pathways lead to the production of different by-products with different intrinsic functional properties, putative physiological roles, and pathophysiological potential. In particular, BACE1 serves as the β-secretase enzyme by cleaving the transmembrane APP to release the β-stubs. BACE1 cleavage of APP represents the rate-limiting step for Aβ production. Cleavage of APP by BACE1 liberates the soluble N-terminus of APP, while the C-terminal fragment (CTF-β or C99) remains bound to the membrane. To produce Aβ, the fragment CTF-β is cleaved by γ-secretase, an aspartyl-type protease membrane protein complex, which finally releases Aβ into the extracellular space and the APP intracellular domain into the cytoplasm. The γ-secretase consists of different components. The catalytic components of the membrane-embedded tetrameric γ-secretase complex are represented by presenilins 1 and 2, intramembrane-cleaving proteases (I-CLIPs), responsible for generating the Aβ carboxyl terminus from APP. In a parallel competing non-amyloidogenic pathway, APP is cleaved either by α-secretase or η-secretase to release two additional variants of the APP ectodomain, namely sAPP-α and sAPP-η. In vitro studies have shown that ADAM-10, a disintegrin and metalloprotease belonging to the family proteases, is the major α-secretase responsible for the ectodomain shedding of APP in the mouse brain and likely to be active in humans. APP is a type I transmembrane protein, highly expressed in neurons and abundant at the synapse. Although a full understanding of its function remains elusive, studies have suggested a role in the remodeling of dendritic spines, neurotransmission, synaptic plasticity, and maintenance of excitation-inhibition (E/I) balance. Soluble sAPPα and sAPPβ are hypothesized to modulate basal synaptic transmission and short-term synaptic facilitation likely through GABAB receptor subunit 1a-mediated synaptic effect. Note: Adapted from [4]. Reproduced with permission