Passive Immunotherapy Targeting Tau Oligomeric Strains Reverses Tauopathy Phenotypes in Aged Human-Tau Mice in a Mouse Model-Specific Manner

Article type: Research Article

Authors: Bittar, Alice^{a; b; 1} | Al-Lahham, Rabab^{a; b; 1} | Bhatt, Nemil^{a; b} | Moore, Kenya^{a; b} | Montalbano, Mauro^{a; b} | Jerez, Cynthia^{a; b} | Fung, Leiana^{a; b} | McAllen, Salome^c | Ellsworth, Anna^{a; b} | Kayed, Rakez^{a; b; *}

Affiliations: [a] Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA | [b] Department of Neurology, University of Texas Medical Branch, Galveston, TX, USA | [c] MD Anderson Cancer Center, University of Texas, Houston, TX, USA

Correspondence: [*] Correspondence to: Dr. Rakez Kayed, Mitchell Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX, USA. Tel.: +1 409 772 0138; E-mail:rakayed@utmb.edu.

Note: [1] These authors contributed equally to this work.

Abstract: Background:Tau oligomers are one of the most toxic species, displaying prion-like strains which have different conformations resulting in different tauopathies. Passive immunotherapy targeting different tau species is a promising therapeutic approach. Age is one of the greatest risk factors; however, most immunotherapy studies are done in young to middle-aged mice tauopathy models, which is not representative of the many clinical trials done with older humans with established tauopathies. Objective:We utilized two different clones of tau oligomer monoclonal antibodies (TOMAs) in aged Htau and JNPL3 mouse models to investigate the potential of passive immunotherapy. Methods:Aged mice received a single intravenous injection of 120 μg/animal of either TOMA1, TOMA3 clones or a non-specific IgG. Their cognitive functions were assessed one-week post-injection using Y-maze and novel object recognition tests. Brain tissues were analyzed using biochemical and immunological assays. Results:TOMA 1 and 3 rescues cognitive phenotypes in aged animals in a mouse model-specific manner, indicative by a reduction in tau oligomers levels. The TOMAs were shown to have strong reactivity with different tau oligomeric species in the different mouse models in vitro and ex vivo. Conclusion:This is the first study testing tau passive immunotherapy in aged animals and supports our previous reports on of the role of oligomeric tau in disease progression further validating the potential of TOMAs to rescue the late-stage disease pathology and phenotype. Moreover, this study suggests that multiple tau oligomeric strains exist in aged animals; therefore, it is of great importance to further characterize these strains.

Keywords: Aged mouse models, brain-derived tau oligomers, tau immunotherapy, tau oligomers, tau oligomers strains, tauopathies, TOMA clones

DOI: 10.3233/JAD-220518

Journal: Journal of Alzheimer's Disease, vol. 90, no. 3, pp. 1103-1122, 2022