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
- Soybean oil may trigger neurological conditions: Here are healthier alternatives you can opt foron January 18, 2020 at 12:00 am
Soybean oil not only leads to obesity and diabetes but may also affect neurological conditions like autism, Alzheimer’s disease, anxiety and depression, according to a new study. Researchers from ...
- What are common neurosurgical conditions that occur in children?on January 17, 2020 at 2:04 pm
They have neurological deficits of their legs and bowel and experience bladder problems ... Chemotherapy and radiation therapy are then utilized to treat the rest of the disease. Therefore, any ...
- America’s most popular cooking oil linked to many neurological changeson January 17, 2020 at 10:58 am
However, reducing the quantity of that compound doesn’t prevent soybean oil from having a potentially negative effect on neurologic conditions ranging from depression and anxiety to autism and even ...
- CWRU research team receives $1 million to advance therapies for Huntington's diseaseon January 17, 2020 at 10:56 am
With the support of a $1 million grant from the Dr. Ralph and Marian Falk Medical Research Trust, researchers at the Case Western Reserve University School of Medicine are furthering their work on ...
- 2 New Tennessee Counties Now Positive for Deer Diseaseon January 17, 2020 at 1:26 am
The Tennessee Wildlife Resources Agency says two new Tennessee counties have had deer test positive for chronic wasting disease, and a third county has been classified high-risk.
- UB researcher employs eye-tracking technology to detect neurological disorderson January 16, 2020 at 6:28 am
A UB biomedical engineer is gaining recognition outside the United States for his work using high-tech devices to diagnose and ameliorate neurological conditions. Anirban Dutta, assistant professor in ...
- Modeling neurological disease using human stem cell-derived microglia-like cells transplanted into rodent brainson January 13, 2020 at 8:21 am
Microglia play important but incompletely understood roles in the pathogenesis of neurological disease. New chimeric models using transplanted human stem cell-derived microglia-like cells hold great ...
- Biogen to acquire neurological disease candidate from Pfizeron January 13, 2020 at 5:00 am
for the potential treatment of behavioral and neurological symptoms associated with a range of psychiatric and neurological disorders. It plans to develop the asset for the treatment of sundowning ...
- CAMP4 Announces Collaboration to Discover Novel Targets to Address Neurodegenerative and Neurological Diseaseson January 10, 2020 at 4:24 am
As part of the collaboration, the companies will also explore other cell types of the central nervous system beyond microglial cells to potentially expand the number of neurological diseases that ...
- Team uncovers largest US outbreak of neurologic disease to dateon January 8, 2020 at 7:09 am
"Enhanced surveillance is needed in order to determine whether this outbreak was an isolated event, or a warning of impending cyclic outbreaks of EV-A71 neurological disease in the U.S." In ...
via Google News and Bing News