UCLA researchers in the Department of Biological Chemistry, Chemistry and Biochemistry developed a new tau-inhibiting seven residue peptide and conjugated it to magnetic nanoparticles for the treatment of Alzheimer’s disease. These compounds disaggregate pathogenic tau amyloid fibrils at atomic resolution, restore normal neuronal function, and rescue cognitive deficits in AD mouse models.
BACKGROUND: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that destroys memory and other cognitive function. According to the CDC, as many as 5.8 million Americans were living with Alzheimer's disease in 2020. The number of people living with the disease doubles every 5 years beyond age 65. AD is pathologically characterized by the aggregation of extracellular amyloid-beta plaques and intracellular tau neurofibrillary tangles formed by tau protein aggregates. Recent studies indicate that tau fibrils correlate more closely with cognitive decline than amyloid-β plaques. Tau, a microtubule-associated protein, normally stabilizes neuronal microtubules, but post-translational and conformational changes cause tau to detach, misfold, and self-assemble into β-sheet rich amyloid fibrils. These aggregates propagate from cell to cell and drive neurodegeneration. Therapeutic strategies that inhibit tau fibril formation or promote their disassembly are therefore considered among the most direct disease-modifying approaches for AD.
INNOVATION: UCLA researchers developed a seven-residue D-amino acid peptide, termed DS, and a corresponding iron-oxide magnetic nanoparticle conjugate (DS-MNP) that potently inhibit tau aggregation and actively fragment pre-formed fragments. The complexation of this peptide with an iron-based magnetic nanoparticle helps to deliver the peptide into the brain. Using cryo-electron microscopy and molecular dynamics analyses, the team revealed that the D-peptide binds to a specific β-strand interface within the tau protofilament core, destabilizing the amyloid architecture through steric repulsion and hydrogen-bond disruption. This precise binding mode allows the peptide to unzip and disassemble tau fibrils into non-toxic oligomeric fragments without generating new seeds. Further, researchers showed that DS-MNP penetrates the blood brain barrier, localizes to tau deposits, and restores synaptic and behavioral function in an AD mouse models. In addition to recombinant tau fibrils and AD mouse models, DS and DS-MNP can disaggregate tau fibrils extracted from the autopsied brain of an AD patient. In summary, these studies establish DS and DS-MNP as first in class therapeutics capable of crossing the blood brain barrier, disassembling tau fibrils via a structurally defined mechanism, and reversing AD pathology in vivo.
POTENTIAL APPLICATIONS:
- Disease-modifying treatment for Alzheimer’s disease
- A blood-brain-barrier penetrable drug delivery system for other neurodegenerative tauopathies
- Medical imaging of tau aggregation states with MNPs.
ADVANTAGES:
- Approach of DS-MNPs to treat Alzheimer’s disease (AD) is entirely novel and different from the unsuccessful strategy of using antibodies that is adopted by Pharma.
- DS-MNPs combines efficient tau-disaggregation activity, MRI visualization property, and cognitive function rescue effects, which allows versatile application in both treatment and diagnosis of AD.
- Can inhibit further tau fibril formation and disaggregate existing tau fibrils for the halt and reversal of AD
- Novel mechanism of action via atomic-level disassembly of tau fibrils via D-peptide binding to amyloid core interfaces
DEVELOPMENT-TO-DATE: The invention from this concept was successfully demonstrated October 4, 2021, and has shown efficacy in memory and motor function in an AD mice model.
Related Papers (from the inventors only)
- Hou, K., Ge, P., Sawaya, M.R. et al. How short peptides disassemble tau fibrils in Alzheimer’s disease. Nature 644, 1020–1027 (2025). https://doi.org/10.1038/s41586-025-09244-z
- Hou K, Pan H, Shahpasand-Kroner H, Hu C, Abskharon R, Seidler P, Mekkittikul M, Balbirnie M, Lantz C, Sawaya MR, Dolinsky JL, Jones M, Zuo X, Loo JA, Frautschy S, Cole G, Eisenberg DS. D-peptide-magnetic nanoparticles fragment tau fibrils and rescue behavioral deficits in a mouse model of Alzheimer's disease. Sci Adv. 2024 May 3;10(18):eadl2991. doi: 10.1126/sciadv.adl2991. Epub 2024 May 1. PMID: 38691615; PMCID: PMC11062580.
Categories:
Therapeutics & Vaccines > Neurodegenerative Diseases
Drug Delivery > Nanoparticles
Drug Delivery > Peptide Base
Keywords: Alzheimer’s disease, Tau, Tau aggregation, amyloid fibril, tauopathy, magnetic nanoparticle, DS peptide, memory deficit, blood brain barrier, D-peptide, fibril disassembly