Therapeutic anti-amyloid ß antibodies cause neuronal disturbances.

ABSTRACT

INTRODUCTION: Recent 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 Aß peptide). Similarly, Janssen/Pfizer's Bapineuzumab (amino acids 1-5 of the Aß peptide) and Roche's Gantenerumab (amino acids 2-11/18-27 of the Aß 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-Aß antibodies remain largely unknown, however, recent reports demonstrated that therapeutic anti-prion antibodies activate neuronal allergenic proteomes following cross-linking cellular prion protein. METHODS: Here, 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-Aß1-6, or anti-Aß17-23 antibodies activate a significant number of allergenic-related proteins as assessed by mass spectrometry. RESULTS: Interestingly, 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-Aß1-6, or anti-Aß17-23 antibody treatment. DISCUSSION: These 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 (Aß) immunotherapy on stem cell derived neurons and primary neuronal cells co-cultured with microglia. Anti-Aß 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.