Alzheimer’s disease and frontotemporal dementia are devastating conditions that develop due to the buildup of misfolded proteins in the brain.
The latest generation of Alzheimer’s disease drugs targets the accumulation of the protein amyloid beta with artificial antibodies, but the results are disappointing, with some adverse effects, not to mention that the use of artificial antibodies can be prohibitively expensive are.
Researchers at Washington University in St. Louis are taking a new approach and want to design vaccines that train a person’s own immune system to remove these build-ups of amyloid beta and tau proteins.
With a $2.9 million grant from the National Institute on Aging, part of the National Institutes of Health (NIH), researchers Jai Rudra, PhD, associate professor of biomedical engineering at the McKelvey School of Engineering, and Meredith Jackrel, PhD , an associate professor of chemistry in Arts & Sciences, will design vaccines that generate anti-amyloid beta and anti-tau antibodies using Rudra’s peptide nanofiber vaccine platform.
Key to the success of this project are vaccine designs that do not cause inflammation, as a constant challenge for the field is to counter the chronic inflammation that comes with age.
Rudra said previous trials used strong vaccine adjuvants to ensure amyloid beta targeting, but this caused adverse effects in some patients. Adjuvants can cause the immune system to view misfolded proteins as ‘foreign material’, but the inflammation that results can cause more damage than it’s worth. Instead, Rudra uses a nanofiber platform that he developed in previous vaccine research.
Nanofibers have unique properties that make them attractive for making antibodies against tau and amyloid beta proteins, and they do not cause inflammation like other adjuvants.”
Jai Rudra, PhD, Associate Professor, Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis
Jackrel noted that recent trials of treatments for dementia have failed in part because of the brain inflammation that results. That is why they are taking a different route with nanofibers.
“The non-inflammatory nature of this is a good strategy to counteract that,” she said.
The nanofibers work better because amyloid beta and tau are presented on the surface of the nanofiber in such a way that the immune system will not generate as much inflammation in its wake.
Big photo
Jackrel and Rudra will work with researchers at WashU Medicine to test their vaccines. Tim Miller, MD, PhD, the David Clayson Professor of Neurology, and Kathleen Schoch, PhD, an assistant professor of neurology, will help by testing the vaccines on transgenic mice that develop conditions that mimic various forms of dementia in the brain.
They will test it as both a preventive treatment and as a post-symptom treatment, although Rudra expects the prophylactic use to be more effective. The problem with breaking down tau and amyloid clumps after people are symptomatic for dementia is that it may already be too late.
“It will be quite a challenge to break them down,” says Rudra, noting that it will likely be much easier to try to prevent the increase in dementia symptoms by nipping all that neuroinflammation in the bud, possibly already in middle age.
This also aligns with other initiatives at WashU to develop blood tests for the early detection of a variety of neurodegenerative diseases. Further projects outside of biomedical engineering aim to apply a variety of medical and lifestyle treatments that go beyond just the big guns of the immune system.
Dementia and neurodegeneration are not a single disease or arise from a single source, so a multifaceted approach will be needed, Jackrel said.