SUMMARY
UCLA researchers in the Department of Chemistry & Biochemistry have developed a method for efficiently producing tau oligomers and a single-chain antibody against oligomeric tau protein with potential for theranostic utility in the treatment of Alzheimer’s and other tauopathies.
BACKGROUND:
Alzheimer’s disease (AD) is the most prevalent form of dementia and is characterized by histological hallmarks including plaques of amyloid-beta (Aβ) and neurofibrillary tangles of tau. In addition, aggregated tau, but not Aβ, is observed in dozens of related dementias, called tauopathies. Soluble oligomers of aggregated tau accompany the accumulation of insoluble fibrils, and both oligomers and fibrils seed the spread of tau pathology. These amyloidogenic proteins may play an important role in disease progression, and by virtue of their low molecular weight and relative solubility, oligomers may be particularly pernicious seeds. However, studying the oligomer form of tau has been hindered by the difficulty of producing pure preparations of recombinant tau oligomers, and an inability to rapidly differentiate the oligomeric states of tau with antibodies or stains. Identification of tau oligomers is crucial to advancing our understanding of the importance of these oligomers to tauopathy disease progression as it relates to seeding. Furthermore, because oligomers of tau are thought to represent the earliest seeding-competent species, the antibody developed here may have potential as an early-stage diagnostic or therapeutic tool for tauopathies. With no available treatments or reliable early-stage diagnostics for Alzheimer’s in the clinic, there is a great need for a new platform upon which effective therapeutics and diagnostics can be built.
INNOVATION
To address the need for a research tool that advances our understanding of tau oligomers, which also has applications in diagnostics and therapeutics, UCLA researchers have developed a single-chain antibody, M204-scFv, which specifically binds to tau oligomers while showing no affinity for aggregated tau fibrils. Furthermore, the UCLA research group has developed a method for producing pure preparations of recombinant tau oligomers in vitro. Thereby facilitating advanced research into the importance of these oligomers in tauopathy progression, and allowing further development of interventions and diagnostics targeting them. The developed single-chain antibody inhibits seeding from recombinantly derived tau oligomers in vitro. The smaller size of M204-scFv, when compared with conventional monoclonal antibodies used as therapeutics allows for more efficient and economical production and could allow for more desirable pharmacokinetics when administered in vivo.
POTENTIAL APPLICATIONS:
- Treatment of Alzheimer’s and other tauopathies.
- Early-stage diagnostic of Alzheimer’s disease and other tauopathies.
- Tauopathy research tool.
ADVANTAGES
- Smaller size than conventional antibody-based therapeutics.
- Binds specifically to tau oligomers (not cross-reactive with fibrils).
DEVELOPMENT-TO-DATE:
The researchers have demonstrated the effectiveness of the designed scFv at inhibiting seeding in vitro, as well as demonstrated specificity using blots.
Related Papers (from the inventors only)
Abskharon R, Seidler PM, Sawaya MR, Cascio D, Yang TP, Philipp S, Williams CK, Newell KL, Ghetti B, DeTure MA, Dickson DW, Vinters HV, Felgner PL, Nakajima R, Glabe CG, Eisenberg DS. Crystal structure of a conformational antibody that binds tau oligomers and inhibits pathological seeding by extracts from donors with Alzheimer's disease. J Biol Chem. 2020 Jul 31;295(31):10662-10676. doi: 10.1074/jbc.RA120.013638. Epub 2020 Jun 3. PMID: 32493775; PMCID: PMC7397112.