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.

The study was published online August 29 in the journal Scientific Reports.

The new study is based on decades of work arguing that the contribution to disease of key proteins 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.

"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," said corresponding author Thomas Wisniewski, MD, director of the Center for Cognitive Neurology, Silberstein Alzheimer's Institute, and the NYU Alzheimer's Disease Center.

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 (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.

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 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 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 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 large, stable oligomer with more than 90 percent "beta–sheet" structure (the p13Bri immunogen) that could now be "seen" by the mammalian immune system, and could trigger 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.

These rare antibodies have almost zero chance of triggering unwanted immune responses to normal proteins with similar sequences (autotoxicity), the downfall of so 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.