Fig 1: Speculative model of Aß generation by protease-containing pEV(1) Somatic mutations induced by age, metal ions or other stress stimuli may stimulate liver and/or cells of other organs or the immune system (e.g. PBMC)46 for an inflammatory response that includes the secretion of pEV containing CCF and active proteases. These pEV possibly function to alert or activate the immune defense in the periphery, for example by differentiating precursor cells.65(2) Depending on their ligands on the vesicle surface, in this case Hyaluronan (HA) and/or HA fragments, pEV are incorporated by specific target cells like monocytes, CP cells or neurons in the hippocampus (Figs. 2,3 and S4c). A single vesicles may contain only one type of protease or inflammatory factor. (3) Once incorporated, these incoming vesicles may fuse with early endosomes (18) containing various substrates including APP. (4) Endosomal compartments may fuse with vesicles containing different proteases, including ADAM10/17, cleaving APP in a physiological (non-amyloidogenic) manner, but also non-physiological (amyloidogenic) manner that includes BACE activity. (5) Non-amyloidogenic peptides, like P3, may be secreted or degraded in lysosomes. Conversely, 6) amyloidogenic Aß withstands degradation, may accumulate (not shown) and/or be released by secretion to function as an anti-microbial peptide. (7) Likely, the cleavage of APP leads to a feedback loop to the ER/Golgi inducing the translation of more APP.