Cleavage of amyloid precursor protein (APP) by BACE‐1 (β‐site APP cleaving enzyme 1) is the rate‐limiting step in amyloid‐β (Aβ) production and a neuropathological hallmark of Alzheimer's disease (AD). Despite decades of research, mechanisms of amyloidogenic APP processing remain highly controversial. Here, we show that in neurons, APP processing and Aβ production are controlled by the protein complex‐2 (AP‐2), an endocytic adaptor known to be required for APP endocytosis. Now, we find that AP‐2 prevents amyloidogenesis by additionally functioning downstream of BACE1 endocytosis, regulating BACE1 endosomal trafficking and its delivery to lysosomes. AP‐2 is decreased in iPSC‐derived neurons from patients with late‐onset AD, while conditional AP‐2 knockout (KO) mice exhibit increased Aβ production, resulting from accumulation of BACE1 within late endosomes and autophagosomes. Deletion of BACE1 decreases amyloidogenesis and mitigates synapse loss in neurons lacking AP‐2. Taken together, these data suggest a mechanism for BACE1 intracellular trafficking and degradation via an endocytosis‐independent function of AP‐2 and reveal a novel role for endocytic proteins in AD.

Health and disease are directly related to the RTK-RAS-MAPK signalling cascade. After more than three decades of intensive research, understanding its spatiotemporal features is afflicted with major conceptual shortcomings. Here we consider how the compilation of a vast array of accessory proteins may resolve some parts of the puzzles in this field, as they safeguard the strength, efficiency and specificity of signal transduction. Targeting such modulators, rather than the constituent components of the RTK-RAS-MAPK signalling cascade may attenuate rather than inhibit disease-relevant signalling pathways.

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Interleukin‐6 (IL‐6)‐type cytokines not only have key immunomodulatory functions that affect the pathogenesis of diseases such as autoimmune diseases, chronic inflammatory conditions, and cancer, but also fulfill important homeostatic tasks. Even though the pro‐inflammatory arm has hindered the development of therapeutics based on natural‐like IL‐6‐type cytokines to date, current synthetic trends might pave the way to overcome these limitations and eventually lead to immune‐inert designer cytokines to aid type 2 diabetes and brain injuries. Those synthetic biology approaches include mutations, fusion proteins, and inter‐cytokine swapping, and resulted in IL‐6‐type cytokines with altered receptor affinities, extended target cell profiles, and targeting of non‐natural cytokine receptor complexes. Here, we survey synthetic cytokine developments within the IL‐6‐type cytokine family and discuss potential clinical applications.