treatment of tau in pathology in Alzheimer disease
Introduction
Neurofibrillary tangles & amyloid plaques are the histopathological hallmarks of Alzheimer's disease. The neurofibrillary tangles are formed from paired helical filaments of hyperphosphorylated microtubule-associated protein tau. Aggregation of tau & neurodegeneration are closely associated with cognitive decline in Alzheimer's disease. The paired helical filaments of tau consist of pairs of approximately 10 nm filaments wound into left-handed helices with a periodicity of 160 nm visible on electron microscopy.
See: histopathology of Alzheimer's disease
Ke Hou, a postdoctoral fellow in David Eisenberg's laboratory at UCLA synthesized a therapeutic 7-residue D-enantiomeric peptide (7-D-peptide) with N-terminal D-Cys conjugated to magnetic nanoparticles.* The 7-D-peptide binds to tau fibrils & inhibits their growth in vitro. ** The magnetic nanoparticle complex acts as a disaggregator of tau fibrils as well as an inhibitor of their growth.
* magnetic nanoparticles can efficiently cross the blood-brain barrier ** the 7-D-peptide can self-aggregate forming a right-handed fibril
Upon binding to tau fibrils, the 7-D-peptide initially conforms to the left-handed twist of tau fibrils. However, the 7-D-peptide reverses its twist to relieve the torsional strain and by doing so disrupts the tau fibril, enabling its fragmentation[1]. The fragments produced after the 7-D-peptide disassembles tau fibrils do not seed the growth of new tau fibrils[1]
See:
- investigational treatment of Alzheimer's disease
- Comparative biology section
- conjugated nanoparticles subsection
- Comparative biology section
Preventing & reversing the histopathology of Alzheimer's disease would be the most significant development in prevention and treatment of Alzheimer's disease to date. Ke Hou et al have published their proof of concept using a mouse model of Alzheimer's disease[2] & and tau fibrils extracted from Alzheimer brain[3]. I look forward to clinical trials.
More general terms
References
- ↑ 1.0 1.1 1.2 Lancaster C Uncovering the Unexpected: Developing a Novel Anti-Tau Therapy. The Scientist. Dec 31, 2024 https://www.the-scientist.com/uncovering-the-unexpected-developing-a-novel-anti-tau-therapy-72439
- ↑ 2.0 2.1 Hou K, Pan H, Shahpasand-Kroner H et al 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. PMID: https://pubmed.ncbi.nlm.nih.gov/38691615 PMCID: PMC11062580 Free PMC article. https://www.science.org/doi/10.1126/sciadv.adl2991
- ↑ 3.0 3.1 Hou K, Ge P, Sawaya MR et al How short peptides can disassemble ultra-stable tau fibrils extracted from Alzheimer's disease brain by a strain-relief mechanism. bioRxiv [Preprint]. 2024 Mar 29:2024.03.25.586668. PMID: https://pubmed.ncbi.nlm.nih.gov/38585812 PMCID: PMC10996594. Free PMC article. Preprint