New antibodies target protein structures common to several neurological diseases

August 29, 2017, NYU School of Medicine

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 - and tau in Alzheimer's, alpha-synuclein in Parkinson's, and prion proteins in conditions like - 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 School of Medicine.

"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 the Center for Cognitive Neurology, Silberstein Alzheimer's Institute, and the NYU Alzheimer's Disease Center.

New Approach

The study focuses on proteins that form important structures in the brain. The instant they form as chains of , proteins fold into complex shapes needed to do their jobs. Unfortunately, proteins can also "misfold" for countless reasons (genetic abnormalities, toxins, age-associated cell processes, inflammation, etc.) 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, which are that can attach to and remove a disease-related target molecule. Past and ongoing attempts have used antibodies that target the initial, short chains of amino acids that serve as basic, repeating structural units (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, Goni, Wisniewski and colleagues designed their antibodies to target instead the "oligomers" formed as several misfolded monomers associate and acquire the "beta-sheet" shape, but not yet large enough to fibrilize. These intermediate forms may be uniquely toxic, say many in the field, because, unlike fibrils, they can dissolve and 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 become increasingly dominated by twisted strands of amino acids, the beta sheet 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 large, stable oligomer with more than 90 percent "beta-sheet" structure (the p13Bri immunogen) that could now be "seen" by the mammalian immune system. It also triggered a specific antibody response that solved 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 protein fragments 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, Parkinson's 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 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 's monomer," says Goni.

Explore further: Novel monoclonal antibodies show promise for Alzheimer's disease treatment

Related Stories

Novel monoclonal antibodies show promise for Alzheimer's disease treatment

July 20, 2015
Scientists at NYU Langone Medical Center's Center for Cognitive Neurology have evidence that monoclonal antibodies they developed may provide the blueprint for effective treatments for Alzheimer's disease and other neurodegenerative ...

Computer-designed antibodies target toxins associated with Alzheimer's disease

June 21, 2017
Researchers at the University of Cambridge have designed antibodies that target the protein deposits in the brain associated with Alzheimer's disease, and stop their production.

Alzheimer's researchers find clues to toxic forms of amyloid beta

June 10, 2016
Much of the research on Alzheimer's disease has focused on the amyloid beta protein, which clumps together into sticky fibrils that form deposits in the brains of people with the disease. In recent years, attention has turned ...

Study provides understanding of how nerve cells are damaged by accumulation of abnormal proteins

May 25, 2017
A new study has uncovered a molecular mechanism in the prion protein, a protein responsible for neurodegenerative diseases, which may explain why nerve cells degenerate in these disorders.

Novel antibodies for combating Alzheimer's and Parkinson's disease

December 3, 2012
Antibodies developed by researchers at Rensselaer Polytechnic Institute are unusually effective at preventing the formation of toxic protein particles linked to Alzheimer's disease and Parkinson's disease, as well as Type ...

Recommended for you

Pregnancy history may be tied to Alzheimer's disease

July 18, 2018
A woman's history of pregnancy may affect her risk of Alzheimer's disease decades later, according to a study published in the July 18, 2018, online issue of Neurology, the medical journal of the American Academy of Neurology. ...

Molecular tracer, seen with PET scan, shows concentrations of abnormal proteins

July 17, 2018
In a small study of military personnel who had suffered head trauma and had reported memory and mood problems, UCLA researchers found brain changes similar to those seen in retired football players with suspected chronic ...

Yale-developed test for Alzheimer's disease directly measures synaptic loss

July 16, 2018
Yale researchers have tested a new method for directly measuring synaptic loss in individuals with Alzheimer's disease. The method, which uses PET imaging technology to scan for a specific protein in the brain linked to synapses, ...

New study highlights Alzheimer's herpes link, experts say

July 12, 2018
A new commentary by scientists at the Universities of Manchester and Edinburgh on a study by Taiwanese epidemiologists supports the viability of a potential way to reduce the risk of Alzheimer's disease.

Practice imperfect—repeated cognitive testing can obscure early signs of dementia

July 12, 2018
Alzheimer's disease (AD) is a progressive, neurodegenerative condition that often begins with mild cognitive impairment or MCI, making early and repeated assessments of cognitive change crucial to diagnosis and treatment.

The 'Big Bang' of Alzheimer's: Scientists ID genesis of disease, focus efforts on shape-shifting tau

July 10, 2018
Scientists have discovered a "Big Bang" of Alzheimer's disease – the precise point at which a healthy protein becomes toxic but has not yet formed deadly tangles in the brain.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.