aRuthheimer’s disease (AD) is a progressive neurodegenerative disease, and researchers now believe that its symptoms are due to the deposition of tau amyloid fibrils. Although scientists have developed many therapeutic agents that are effective in vitro, most of these drugs have shown limited success in clinical trials, some due to inefficient delivery to the brain. It failed for some reason.
Ke HouA postdoctoral fellow in David Eisenberg’s lab at the University of California, Los Angeles, he is devising an innovative approach to improve the transport of Alzheimer’s disease drugs across the blood-brain barrier (BBB). In a recently published book scientific progress According to the paper, Hou and her team modified an existing therapeutic peptide that binds to tau fibrils and inhibits their growth in vitro and attached them to magnetic nanoparticles (MNPs).1 Unexpectedly, these changes also enabled the complex to function as a degrader of tau fibrils.
Ke Hou and colleagues developed a seven-residue peptide conjugated to magnetic nanoparticles. This complex inhibits tau aggregation and fragments tau fibrils present in the brain.
Ke Hou
Why have previous anti-tau therapies shown limited efficacy in vivo?
For decades, researchers have produced a number of AD drugs that target amyloid beta, but they have failed in clinical trials. Scientists have only recently shifted their focus to developing anti-tau therapies. Of the tau aggregation inhibitors and antibodies generated to date, many do not cross the BBB efficiently, limiting their bioavailability. Additionally, some therapeutic antibodies can cause serious side effects.
Before I joined the group, the Eisenberg team used the structure of tau to design a six-residue D-enantiomeric peptide (6-DP). However, the research group hypothesized that this tau aggregation inhibitor would not be able to penetrate the BBB. My background is in materials science, so I was able to attach peptides to nanomaterials such as MNPs and test the efficiency of the conjugates to prevent tau aggregation in mouse brains.
Why did you choose to use MNP as a drug carrier?
MNPs can efficiently cross the BBB and may improve peptide delivery to the brain. Furthermore, the US Food and Drug Administration has already approved MNP-based therapies for the treatment of chronic kidney disease, suggesting that they are well tolerated in carriers. This nanomaterial also possesses superparamagnetic properties, which means that the peptide-MNP complexes may serve as diagnostic AD probes for magnetic resonance imaging.
What happened when you attached the peptide to MNP?
To easily attach the peptide to the nanoparticles, one cysteine ​​had to be added to the end of 6-DP to form a seven-residue peptide (7-DP). We tested the properties of the peptide-MNP complex in vitro and found that it could not only prevent tau aggregation but also degrade existing tau fibrils. To determine which components are responsible for this surprising function, we investigated the ability of nanoparticles and peptides alone to degrade heparin-induced tau fibrils and extracted pathological tau fibrils, whereas MNPs It was found that 6-DP and 6-DP cannot be decomposed. From human brain tissue. We also evaluated the effects of peptide MNPs on an AD mouse model and observed that the conjugates cross the BBB, leading to reduced tau pathology in the brain and improved memory function. This suggests that peptide MNPs may reverse the progression of AD.
We wanted to understand why the single cysteine ​​difference between 6-DP and 7-DP confers such disaggregation properties to the peptides, so we began to evaluate the potential mechanisms and analyzed the results. It has been compiled into a preprint. BioRxiv.2 We confirmed that 7-DP can self-aggregate to form right-handed fibrils. When the peptide binds to left-handed tau fibrils and aggregates, 7-DP initially follows a left-handed twist. However, to relieve the torsional strain, the peptide must untwist itself, thereby disrupting the tau fibrils and allowing their fragmentation.
What’s the next step?
We are currently using mass spectrometry and electron microscopy to characterize the fragments generated after 7-DP degrades tau fibrils. We know that these fragments cannot seed the growth of new tau fibrils, so we want to learn more about their structure. We are also using information from this study to design degrading agents for other amyloid fibrils, such as alpha-synuclein, and potentially develop drugs for other neurological diseases.
This interview has been condensed and edited for clarity.
