A new kind of antibody targets a feature shared by proteins thought to cause the most damage in Alzheimer鈥檚 disease, Parkinson鈥檚 disease, and related conditions, creating potential for a unified treatment approach.
This is the finding of a study led by researchers from and published online August 29 in Scientific Reports.
The new study is based on decades of work arguing that the contribution to disease of key proteins鈥攁myloid beta and tau in Alzheimer鈥檚 disease, alpha-synuclein in Parkinson鈥檚 disease, and prion proteins in conditions like mad cow disease鈥攊s driven by certain, toxic forms dominated by a common structure: bundles of 鈥渂eta sheets" in clumped proteins.
In tissues from autopsied patients with these diseases and in live mice, experiments demonstrated how the study antibodies target and remove only these toxic forms, say the authors, and without triggering the immune toxicity that has frustrated treatment development efforts to date.
鈥淚n an atmosphere where countless treatments have failed in clinical trials over the last 15 years, the fact that our approach continues to be effective in rigorous tests should be of interest to our peers and the industry, even if it runs contrary to conventional thinking,鈥 says corresponding author , research associate professor in the at 秘密研究所 Langone Health.
鈥淲hile we still have a number of milestones to reach before this work is ready for clinical testing, our results suggest that these antibodies may halt key pathological mechanisms across several neurological diseases and regardless of disease stage,鈥 says corresponding author Thomas Wisniewski, MD, director of 秘密研究所 Langone鈥檚 , Silberstein Alzheimer鈥檚 Institute, and .
New Approach to Antibody Design
The study focuses on proteins that form important structures in the brain. The instant they form as chains of amino acids, proteins fold into complex shapes needed to do their jobs. Unfortunately, proteins can also 鈥渕isfold鈥 for countless reasons, such as genetic abnormalities, toxins, age-associated cell processes, and inflammation聽that eventually cause the diseases addressed by the current study. Cells and tissues die as misshapen proteins stop working and build up, but the field has struggled to pinpoint which of these shifting forms to target as the key drivers of disease.
Many research efforts, including the current study, seek to design antibodies shaped to attach to and remove the right targets. Past and ongoing attempts have targeted the initial, short chains of amino acids that serve as basic, repeating structural units, or monomers, of each misfolded protein. Still others targeted end-stage fibrils, each made of thousands of monomers, which accumulate in plaques and tangles that tissues cannot eliminate. Neither approach has yielded an effective therapy.
In that light, Dr. Goni, Dr. Wisniewski, and colleagues designed their antibodies to target instead the 鈥渙ligomers鈥 formed as several misfolded monomers associate and acquire the 鈥渂eta-sheet鈥 shape, but before they are large enough to fibrilize. These intermediate forms may be uniquely toxic, say many in the field, because, unlike fibrils, they can dissolve, move in and out of cells, and from one cell to another. This mobility may explain the 鈥減rion-like鈥 progression seen in misfolding diseases where abnormal proteins cause normal ones to misfold in a domino effect that damages nerve cells and their connections in the brain.
Importantly, growing toxic oligomers of amyloid beta, tau, alpha synuclein, and prion protein become increasingly dominated by the twisted strands of amino acids called beta sheets, which have spatial arrangements that let the strands stack up.
To design new kinds of antibodies, the research team zeroed in on a small 13-amino聽acid peptide, derived from the extremely rare genetic disease called British amyloidosis, but not present in the rest of the human population. They converted it into a larger, stable oligomer with more than 90 percent 鈥渂eta-sheet鈥 structure鈥攖he p13Bri immunogen鈥攖hat could be 鈥渟een鈥 by the mammalian immune system, and that could trigger a specific antibody response to solve problems encountered with standard approaches. By immunizing mice with p13Bri at high doses, they forced the production of extremely rare antibodies against beta sheets in toxic oligomers.
The researchers say that their rare antibodies, activated by a protein fragment seen only in a rare disease, have almost zero chance of triggering unwanted immune responses to normal proteins with similar sequences (autotoxicity), the downfall of many previous attempts. Finally, the team screened their lead antibodies against tissues taken from the brains of human patients with Alzheimer鈥檚 disease, Parkinson鈥檚 disease, and prion diseases. Only the six monoclonal antibodies that reacted to toxic oligomers from at least two misfolded proteins from two diseases were selected for further study.
鈥淭his publication details the first system for making antibodies that truly target only toxic oligomers of misfolded proteins dominated by beta sheets across several diseases, and without regard to the amino acid makeup of each misfolded protein鈥檚 monomer,鈥 says Dr. Goni.
Along with Dr. Goni and Dr. Wisniewski, study authors were Mitchell Mart谩-Ariza, Daniel Peyser, and Krystal Herline in the Center for Cognitive Neurology and the Department of Neurology at 秘密研究所 Langone Health. This work was supported by National Institutes of Health grants NS073502 and AG008051, and by Alzheimer鈥檚 Disease Association grant IIRG-13-283707.
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