A new kind of antibody targets a feature shared by proteins thought to cause the most damage in Alzheimer’s disease, Parkinson’s disease, and related conditions, creating potential for a unified treatment approach.
This is the finding of a study led by researchers from NYU School of Medicine 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—amyloid beta and tau in Alzheimer’s disease, alpha-synuclein in Parkinson’s disease, and prion proteins in conditions like mad cow disease—is driven by certain, toxic forms dominated by a common structure: bundles of “beta 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.
“In 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,” says corresponding author Fernando Goni, PhD, research associate professor in the Department of Neurology at NYU Langone Health.
“While 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,” says corresponding author Thomas Wisniewski, MD, director of NYU Langone’s Center for Cognitive Neurology, Silberstein Alzheimer’s Institute, and Alzheimer’s Disease Center.
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 “misfold” for countless reasons, such as genetic abnormalities, toxins, age-associated cell processes, and inflammation 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 “oligomers” formed as several misfolded monomers associate and acquire the “beta-sheet” 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 “prion-like” 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 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 “beta-sheet” structure—the p13Bri immunogen—that could be “seen” 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’s disease, Parkinson’s 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.
“This 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’s monomer,” says Dr. Goni.
The Latest on: Neurological diseases
- ‘A terrible gift’: Parents of Violet, 2, begin fundraiser weeks after daughter is diagnosed with fatal conditionon June 11, 2021 at 5:17 pm
David and Veena Law hoped to raise $25,000 by Friday, June 11—Violet’s birthday. They’ve more than tripled that amount, with donations coming from colleagues, coworkers, long-ago fraternity brothers ...
- COVID-19 Linked to Alzheimer’s Disease-Like Cognitive Impairmenton June 11, 2021 at 12:02 pm
Combining artificial intelligence technology with data sets related to both Alzheimer's and COVID-19, researchers were able to identify a mechanism by which coronavirus can lead to Alzheimer's-like ...
- Parkinson’s disease: The three symptoms found in the muscles warning of your riskon June 11, 2021 at 10:23 am
Parkinson's disease signs and symptoms can be different for everyone. Early signs may be mild and go unnoticed. Suffering with any of these three muscle symptoms could be indicators of your risk to ...
- 4-year-old girl fights against rare neurological conditionon June 11, 2021 at 6:32 am
It's a rare neurological condition that has no cure. But one little girl manages to keep smiling despite all that. Like most 4-year-olds, Audrey likes to play, sing, and smile. But she's also been ...
- Global Intracranial Stents Market Will Benefit from High Prevalence of Neurological Disorders, says Fortune Business Insightson June 10, 2021 at 11:14 pm
The global intracranial stents market is likely to grow in the coming years due to product advancements introduced in the last couple of years. According to a report by Fortune Business Insights, ...
- Study identifies mechanisms by which COVID-19 can lead to Alzheimer's disease-like dementiaon June 10, 2021 at 10:23 pm
A new Cleveland Clinic-led study has identified mechanisms by which COVID-19 can lead to Alzheimer's disease-like dementia.
- Chronic Gut Inflammation Associated With Onset of Parkinson Diseaseon June 10, 2021 at 2:00 pm
The results of the study are consistent with several large-scale epidemiological studies that show an association between Parkinson and inflammatory bowel diseases, such as ulcerative colitis and ...
- Study identifies how COVID-19 linked to Alzheimer's disease-like cognitive impairmenton June 10, 2021 at 1:25 pm
A new Cleveland Clinic-led study has identified mechanisms by which COVID-19 can lead to Alzheimer's disease-like dementia. The findings, published in Alzheimer's Research & Therapy, indicate an ...
- Alcyone Therapeutics Launches to Advance Next-Generation Gene Therapies for CNS Disorderson June 9, 2021 at 4:00 am
PRNewswire/ -- ("Alcyone"), a biotechnology company pioneering next-generation precision central nervous system (CNS) therapies to improve the lives of patients and families impacted ...
- Brain study may lead to new treatments for neuro-immune conditionson June 7, 2021 at 11:00 pm
The immune system is the brain's best frenemy. It protects the brain from infection and helps injured tissues heal, but it also causes autoimmune diseases and creates inflammation that drives ...
via Google News and Bing News