Institute for Protein Design

The “Three Dreamer” Protein Design Partnership for Alzheimer’s Disease

May 11, 2014

Three Dreamers 2

The Three Dreamers. Photo credit: Steve Martin

The “Three Dreamers” are a group of Seattle-based philanthropists whose family members are suffering from Alzheimer’s disease (AD).  This group of community members approached the UW with interest to invest funds raised towards totally new approaches to treating AD.
Alzheimer’s disease and many other age-related neurological disorders such as Parkinson’s disease and Lewy body dementia share a common pathological mechanism involving the mis-folding or mis-processing of natural proteins, which normally serve important cellular functions. Alzheimer’s disease pathology involves the aggregation of amyloid-beta (A-Beta) protein into various oligomeric states including A-Beta oligomers, fibrils of oligomers, and aggregates of fibrils called plaques; some or all of which can be toxic to nerve cells.

Alzheimer's Pathology Plaques and Tangles Protein Misfolding

The Three Dreamers recognized that despite billions of dollars being spent by large pharmaceutical companies the current therapeutic approaches using anti-A-beta monoclonal antibodies (mAbs) to neutralize A-Beta do not seem to be working in clinical trials (see Bapineuzumab, and Solanezumab). New approaches to develop therapeutic and diagnostics for AD are needed.

Inspired by the Three Dreamer’s request, the Institute for Protein Design under the direction of Dr. David Baker (head of the IPD) has partnered with several stakeholders to apply our protein design capabilities to the problem of Alzheimer’s disease.  We have teamed up with fellow University of Washington experts in neuropathology from the laboratory of Dr. Thomas (Tom) Montine (Alvord Endowed Chair in Neuropathology and Chair of the Department of Pathology) to start to design new synthetic proteins that will bind with high affinity to the A-Beta protein in its various forms.  These new anti-amyloid proteins are being designed for (i) use as new agents to visualize different forms of A-beta in tissues, and (ii) also to be tested for their ability to neutralize A-beta pathologies in animal model systems of the disease.

Designs for Amyloid

The Three Dreamers asked the Institute for Protein Design to work with the Foldit community of protein folding puzzle solver citizen scientists to computationally design novel A-beta binder proteins that are smaller than antibodies, so that they might be better at getting across the blood brain barrier, and could one day become new diagnostic or therapeutic agents for Alzheimer’s disease.  Baker lab postdoctoral fellow, Vikram Mulligan describes how Foldit can help Alzheimer’s disease research in this post to the Foldit players, who have responded by working on a series of increasingly complicated puzzles where players are asked to design from scratch new proteins that are predicted to sequester A-Beta.  Let the games begin.  Already the Foldit players have begun to design new proteins to sequester A-Beta.

In summary, the Institute for Protein Design is executing a strategy to deploy its protein design capabilities in collaborative partnerships with philanthropists like the Three Dreamers, Alzheimer’s disease experts like Dr. Montine, and the citizen science Foldit gaming community to address real world challenges.

 

Foldit Player Designs Anti-Amyloid

 

Related References Include:

Amyloid β peptide cleavage by kallikrein 7 attenuates fibril growth and rescues neurons from Aβ-mediated toxicity in vitro.