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
- Singapore’s first brain bank will study neurological disorderson November 28, 2019 at 1:56 am
Nanyang Technological University, Singapore’s (NTU Singapore) Lee Kong Chian School of Medicine (LKCMedicine), in partnership with National Healthcare Group (NHG) and National Neuroscience Institute ...
- New brain bank to boost research into neurological disorderson November 27, 2019 at 1:40 pm
Scientists say the bank is important as there are significant differences in the way Caucasian and Asian brains are affected by neurological disorders such as Alzheimer's disease and Parkinson's ...
- National brain bank to study neurological disorders launched in Singaporeon November 27, 2019 at 5:35 am
SINGAPORE — Singapore’s first national brain bank resource to study neurological disorders was launched on Wednesday (27 November). Brain Bank Singapore is co-funded by Nanyang Technological ...
- NTU, NNI and NHG launch Singapore’s first brain bank to study neurological disorderson November 27, 2019 at 2:36 am
Named Brain Bank Singapore, the joint research centre is co-funded by the three partners. Tissue donations from both healthy donors and from those with neurodegenerative conditions and neurological ...
- Study advances understanding of mechanisms involved in functional neurological disorderon November 26, 2019 at 9:12 pm
Individuals with functional neurological disorder (FND) have symptoms not explained by traditional neurological conditions, including limb weakness, tremor, gait abnormalities, seizures and sensory ...
- Supplements to reduce the risk of neurological diseaseson November 25, 2019 at 1:47 am
As people age, many parts of the body begin to diminish in health. One such organ is the brain, but the good news is that there are supplements that can be taken as early as now to reduce the risk of ...
- One Brain Supplement Can Help Reduce Your Risk Of Neurological Diseaseson November 23, 2019 at 3:50 am
However, with fast food getting a fair share of one’s daily intake, getting all the right nutrients in a day becomes a daunting task. This then puts you at risk of developing neurological diseases.
- Is chronic wasting disease in deer dangerous for humans?on November 23, 2019 at 3:06 am
My husband and I are going hunting and I read about this in the news. Should I be worried? Thanks for your question. Chronic wasting disease is a contagious, neurological disease found in elk, deer, ...
- Accelerating Medicines Partnership launches data knowledge portal for Parkinson’s diseaseon November 22, 2019 at 7:26 am
“AMP PD is a true example of the whole being greater than the sum of its parts,” said Walter Koroshetz, M.D., director, National Institute of Neurological Disorders and Stroke (NINDS). “The ...
- Best supplements for the brain: This supplement could reduce risk of neurological diseaseson November 22, 2019 at 2:10 am
Creatine is the number one supplement for improving performance in the gym, however, it has also been shown to help with the brain and protecting against neurological disease. Creatine is an amino ...
via Google News and Bing News