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