Therapeutic anti‐amyloid β antibodies cause neuronal disturbances

AbstractIntroductionRecent published clinical trial safety data showed that 41% of Alzheimer patients experienced amyloid‐related imaging abnormalities (ARIA), marks of microhemorrhages and edema in the brain, following administration of Biogen's Aduhelm/aducanumab (amino acids 3‐7 of the Aβ peptide). Similarly, Janssen/Pfizer's Bapineuzumab (amino acids 1‐5 of the Aβ peptide) and Roche's Gantenerumab (amino acids 2‐11/18‐27 of the Aβ peptide) also displayed ARIA in clinical trials, including microhemorrhage and focal areas of inflammation or vasogenic edema, respectively. The molecular mechanisms underlying ARIA caused by therapeutic anti‐Aβ antibodies remain largely unknown, however, recent reports demonstrated that therapeutic anti‐prion antibodies activate neuronal allergenic proteomes following cross‐linking cellular prion protein.MethodsHere, we report that treatment of human induced pluripotent stem cells‐ derived neurons (HSCN) from a non‐demented donor, co‐cultured with human primary microglia with anti‐Aβ1‐6, or anti‐Aβ17‐23 antibodies activate a significant number of allergenic‐related proteins as assessed by mass spectrometry.ResultsInterestingly, a large proportion of the identified proteins included cytokines such as interleukin (IL)‐4, IL‐12, and IL‐13 suggesting a type‐1 hypersensitivity response. Following flow cytometry analysis, several proinflammatory cytokines were significantly elevated following anti‐Aβ1‐6, or anti‐Aβ17‐23 antibody treatment.DiscussionThese results justify further and more robust investigation of the molecular mechanisms of ARIA during immunotherapy study trials of AD.HIGHLIGHTS Allergenic‐related proteins are often linked with Alzheimer's disease (AD). We investigated the effects of amyloid beta (Aβ) immunotherapy on stem cell derived neurons and primary neuronal cells co‐cultured with microglia. Anti‐Aβ antibody treatment of neurons or neurons co‐cultured with microglia led to activation of a substantial number of allergenic‐related genes. These allergenic‐related genes are associated with endothelial dysfunction possibly responsible for ARIA.