Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, and researchers now attribute its symptoms to the deposition of tau amyloid fibrils. Although scientists developed many therapeutics that are effective in vitro, most of these drugs have shown limited success in clinical trials, with some of these failures due to inefficient delivery to the brain.
Ke Hou, a postdoctoral fellow in David Eisenberg’s laboratory at the University of California, Los Angeles, is devising innovative approaches to improve the transportation of AD treatments across the blood-brain barrier (BBB). In a recently published Science Advances paper, Hou and her team modified their existing therapeutic peptide, which binds to tau fibrils and inhibits their growth in vitro, to conjugate it to magnetic nanoparticles (MNPs).1 Unexpectedly, these changes also allowed the complex to act as a disaggregator of tau fibrils.
Why have the previous anti-tau therapies shown limited efficacy in vivo?
For decades, researchers have produced numerous AD drugs targeting amyloid beta only for them to fail in clinical trials. Scientists have only shifted focus more recently to developing anti-tau therapies. Of the tau aggregation inhibitors and antibodies that they have generated so far, many of them do not efficiently cross the BBB, which limits their bioavailability. Additionally, some of the therapeutic antibodies can cause serious side effects.
Before I joined the group, the Eisenberg team used tau’s structure to design a six-residue, D-enantiomeric peptide (6-DP). However, the group hypothesized that this tau aggregation inhibitor would not be able to penetrate the BBB. Because my background is in material science, I could conjugate the peptide to nanomaterials, such as MNPs, and test the efficiency of the complex to prevent tau aggregation in mouse brains.
Why did you choose to use MNPs as a drug carrier?
MNPs can efficiently cross the BBB, which could help improve the peptide’s delivery to the brain. Additionally, the US Food and Drug Administration had already approved an MNP-based therapy for the treatment of chronic kidney disease, suggesting that the carriers are well tolerated. This nanomaterial also has superparamagnetic properties, which means that the peptide-MNP complex could serve as a diagnostic AD probe for magnetic resonance imaging.
What happened when you conjugated the peptide to the MNPs?
To easily attach the peptide to the nanoparticles, I needed to add one extra cysteine to the end of the 6-DP, forming a seven-residue peptide (7-DP). When I tested the properties of the peptide-MNP complex in vitro, it not only could prevent tau aggregation but could also disassemble existing tau fibrils. To determine which component was responsible for this surprising function, we examined the abilities of the nanoparticle and peptides alone and found that the 7-DP but not the MNPs or 6-DP could disaggregate heparin-induced tau fibrils and pathological tau fibrils that we extracted from human brain tissue. We also assessed the effects of the peptide-MNPs on an AD mouse model and observed that the complex transversed the BBB and led to reduced tau pathology in their brains and improved memory function. This suggests that the peptide-MNPs could reverse AD’s progression.
We wanted to figure out why the one cysteine difference between the 6-DP and the 7-DP enabled the peptide to have this disaggregation property, so we started evaluating its potential mechanism and have summarized our results in a pre-print posted on bioRxiv.2 We determined that the 7-DP can self-aggregate forming a right-handed fibril. When the peptide binds to and aggregates onto the left-handed tau fibrils, the 7-DP initially conforms to its left-handed twist. However, the peptide must reverse its twist to relieve the torsional strain and by doing so disrupts the tau fibril, enabling its fragmentation.
What are your next steps?
We are currently characterizing the fragments produced after the 7-DP disassembles tau fibrils using mass spectrometry and electron microscopy. We know that these fragments cannot seed the growth of new tau fibrils, so we would like to learn more about their structure. We also are using the information we learned from this study to design disaggregators against other amyloid fibrils, such as alpha-synuclein, and hopefully develop drugs for other neuronal diseases.
This interview has been condensed and edited for clarity.
- Hou K, et al. D-peptide-magnetic nanoparticles fragment tau fibrils and rescue behavioral deficits in a mouse model of Alzheimer’s disease. Sci Adv. 2024;10(18):eadl2991.
- Hou K, et al. How short peptides can disassemble ultra-stable tau fibrils extracted from Alzheimer’s disease brain by a strain-relief mechanism. bioRxiv. 2024.03.25.586668.
