Immunotherapy Targeting Tau Oligomeric Strains in Aged Transgenic Animals of Tauopathy

Background: Alzheimer`s disease (AD) is characterized by the accumulation of amyloid plaques as well as Neurofibrillary tangles (NFT) of hyperphosphorylated tau. Passive immunotherapy targeting different tau species is a promising approach for developing therapeutic approaches for AD and other neurodegenerative tauopathies. However, recent studies demonstrate that tau aggregates, fibrils and oligomers, are diverse and may represent prion-like strains, displaying different conformations with distinct toxicity profiles. Thus, one antibody may not be sufficient for targeting all toxic tau oligomeric species.
The goal of this study is to investigate the potential of passive immunotherapy with different clones of Tau oligomer monoclonal antibodies (TOMAs), in two complementary mouse models; hTau, which overexpresses WT human Tau, and JNPL3 overexpressing the P301L mutant. Previous studies, including ours, used middle aged mice (3-8 months), therefore it is critical to evaluate TauO passive immunotherapy in aged mice, since age is the main risk factor for neurodegenerative diseases and the disease pathology changes with age.
Methods: Aged mice received a single injection of 120 µg/animal of different TOMA clones as well as non-specific IgG intravenously, and their cognitive functions were assessed one week post-injection using Y-maze and novel object recognition (NOR) tests, and their motor activity assessed using Rotarod test. Brain tissues were homogenized, and analyzed by standard biochemical assays, or cryosectioned and immunostained by immunohistochemical assays.
Results: We found that certain TOMA clones reverse some of the tauopathy-related cognitive and motor phenotypes in aged animals. This rescuing of phenotypes was parallel to a reduction in TauO levels. The effective clones were shown to have strong reactivity with different tau oligomeric species in vitro.
Conclusions: This is the first study testing tau passive immunotherapy in aged animals, although it supports our previous reports of oligomeric tau role in disease progression and validate the potential for TOMAs in reversing disease course. Moreover, this study suggests that multiple tau oligomeric strains exist in aged animals, therefore it is of great importance to characterize these strains in aged mouse models as well as human tissues and evaluate antibodies using different tau strains.