Antibody-based treatments designed to target alpha synuclein and amyloid beta, protein clusters associated with the development of Parkinson disease and Alzheimer disease, were shown to worsen inflammation in the brain.
For such neurological diseases as Parkinson disease (PD) and Alzheimer disease (AD), antibody-based treatments in clinical trials may cause more harm than good, according to study findings published today in Proceedings of the National Academy of Sciences (PNAS).
Although abnormal protein clusters of alpha synuclein (α-synuclein) and amyloid beta in the brain are known to be associated with the development of PD and AD, experimental antibody treatments targeting these proteins have so far proved relatively unsuccessful in clinical trials.
Designed to clear these protein clusters, or aggregates, these therapies target large clusters able to be detected via autopsy, as well as smaller clusters, called oligomers, that are harder to detect and considered the most harmful to the brain. In assessing these oligomers, researchers uncovered that although these small clusters led to the inflammation-related death of neuronal cells in microglia derived from human stem cells, antibody treatments worsened inflammation further rather than improved it.
"Our findings provide a possible explanation for why antibody treatments have not yet succeeded against neurodegenerative diseases," said study co-senior author Stuart Lipton, MD, PhD, Step Family Foundation Endowed Chair in the Department of Molecular Medicine and founding co-director of the Neurodegeneration New Medicines Center at Scripps Research, in a statement.
As the first study to examine antibody-induced brain inflammation in a human context as opposed to via mouse models, the researchers found that once α-synuclein antibodies and amyloid beta antibodies successfully hit their oligomer targets, an inflammatory response was triggered that had yet to be seen in prior studies on mouse microglia.
Specifically, the researchers first examined the effects of the α-synuclein antibody treatment in the human stem cell–derived microglia and traced the resulting inflammation response not to the antibodies themselves, but to the complexes formed between the antibodies and their α-synuclein targets.
Replicating what typically occurs in a clinical case of either PD or AD, which is the co-existence of α-synuclein and amyloid beta, the researchers then added amyloid beta oligomers to the human-derived microglia. As expected, the addition of these oligomers caused more inflammation, but as also shown by the α-synuclein antibodies, amyloid beta antibody treatments worsened inflammation even further.
Noting that this inflammatory response may have been overlooked in the past, Lipton says that it could conceivably reverse any benefit of antibody treatment in a patient without being clinically obvious.
“These findings may have important implications for antibody therapies aimed at depleting misfolded/aggregated proteins from the human brain, as they may paradoxically trigger inflammation in human microglia,” concluded the study authors.
Notably, Lipton said he and his colleagues are currently developing an experimental drug that may be able to counter the inflammation caused by the antibody treatments, which would then restore its benefits without causing harm.
Trudler D, Nazor KL, Eisele YS, et al. Soluble α-synuclein–antibody complexes activate the NLRP3 inflammasome in hiPSC-derived microglia. Proc Natl Acad Sci U S A. Published online March 29, 2021. doi:10.1073/pnas.2025847118