Stanford University
Principal Investigator: Annelise E. Barron
Research Team: Kristian Sørensen, Jennifer Lin, Josefine Eilsø Nielsen, and John Fortkort
The aging brain is vulnerable to invasion by infectious microbes, and there is compelling evidence that some of these pathogens drive neurodegenerative aging of the Alzheimer’s type (AD). One of the ways these microbes promote the disease is by provoking brain neurons to release beta-amyloid, which appears to act as an antimicrobial peptide (AMP). That might be fine if the brain’s resident immune cells (microglia) followed up by clearing out the amyloid-microbe complex. But over time, the burden of pathogens and beta-amyloid aggregates overcomes the microglia, and beta-amyloid accumulates and begins driving neurodegenerative changes. Meanwhile, as the demands on the microglia progressively outstrip their abilities, they become increasingly aggressive and unruly, ultimately setting the brain ablaze with inflammation and destroying the very neurons that they exist to protect.
Research Highlights:
SRF is sponsoring work by Dr. Annelise Barron to develop dual-action drugs that could simultaneously tackle the two key forms of damage in this scenario: the microbes that infiltrate the brain and the beta-amyloid that is in part released to disable them. Much of Dr. Barron’s biomedical engineering research is on peptoids — modified versions of short protein-like structures that allow them to persist longer in the body and modify their functions. For this project, she is working on peptoids that will mimic the natural AMP LL-37, which is produced in humans and helps clear pathogens through a variety of mechanisms.
The first benefit of the optimized peptoid would be to destroy key pathogens implicated in AD, thereby preventing them from damaging the brain and making the release of beta-amyloid to contain the infection unnecessary, which would in turn lower the brain’s exposure to the aggregates.
The optimized peptoid would also safely mimic a a second property of LL-37 identified by Dr. Barron and Dr. Jevgenij Raskatov: the ability to safely complement and ‘tame’ beta-amyloid. LL-37 seems in some ways to be a pairmate to beta-amyloid: the two molecules’ molecular weights are almost identical to one another’s, and their specific amino acid sequences and opposing charges create strong and selective binding interactions. When the two are in each other’s presence, LL-37 and beta-amyloid strongly bind to each other and hold each other safely in check, thereby blocking one another’s toxicity. It may not be a coincidence that LL-37 levels in the brain decline with age, roughly coinciding with the rise in beta-amyloid levels that occurs up until the verge of clinical dementia.
