Nat. Rev. Neurol. doi:10.1038/nrneurol.2017.162 Figure 1 Pathways of amyloid precursor protein processing and amyloid-β generation Figure 1 | Pathways of amyloid precursor protein processing and amyloid-β generation. Full-length amyloid precursor protein (APP) is synthesized in the endoplasmic reticulum (ER), where it undergoes folding (step 1). APP undergoes post-translational modification, first in the ER and then in the Golgi (step 2). APP then undergoes anterograde transportation through secretory vesicles into presynaptic and postsynaptic compartments (step 3). In the non-amyloidogenic pathway, APP reaches the plasma membrane where it is cleaved by the α-secretase disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), generating soluble APPα (sAPPα) and α-secretase C-terminal fragment (α-CTF; also known as C83) (step 4). Full-length APP and α-CTF are internalized by clathrin-dependent (CD) endocytosis, whereas the lipid-raft-resident β-secretases 1 and 2 (BACE1 and BACE2, respectively) are internalized by clathrin-independent (CI) endocytosis (step 5). APP, BACE1 and BACE2 converge in early endosomes. The low pH of these compartments facilitates activation of these β-secretases, which initiates the amyloidogenic pathway: APP is cleaved into soluble APPβ (sAPPβ) and β-secretase C-terminal fragment (β-CTF; also known as C99). Both nonprocessed, full-length APP and sAPPβ can be reinserted into the plasma membrane through recycling endosomes. The β-CTF fragment can be trafficked via the endocytic pathway to the trans-Golgi network and the ER, as well as to late endosomes, multivesicular bodies (MVBs) and lysosomes (step 6). Trafficking of the γ-secretase components is complex, but the final γ-cleavage of APP probably takes place in mitochondria-associated ER membranes (MAMs), MVBs and lysosomes (step 7). There, β-CTF is recognized by the γ-secretase complex and cleaved to generate the APP intracellular domain (AICD) and amyloid β (Aβ) peptides. In the formation of amyloid plaques, Aβ monomers exist in equilibrium with higher-molecular-mass aggregates (dimers, trimers and oligomers) (step 8). Polanco, J. C. et al. (2017) Amyloid‑β and tau complexity — towards improved biomarkers and targeted therapies Nat. Rev. Neurol. doi:10.1038/nrneurol.2017.162