Evaluating Tau Oligomers Passive Immunotherapy using Aged Transgenic Animals of Tauopathy

An estimated 5.5 million Americans have Alzheimer’s disease (AD), the most common type of dementia. With the incidence of AD and related dementias growing, due to the increase in life span, it is critical to develop approaches for early diagnosis and therapeutics to halt the progress of the disease. AD has been characterized by the accumulation of amyloid plaques as well as fibrillar tangles of hyperphosphorylated tau proteins. We and others have shown that Tau oligomers (TauO) are the toxic species responsible for the pathology of the disease. Passive immunotherapy targeting different tau species, which reduces the risks of immunological side effects and provides the flexibility needed to adjust the treatment for patients, is the most promising approach and have shown to be efficacious in many animals regardless of the target.
The goal of this project is to investigate the potential of passive immunotherapy with different clones of Tau oligomer monoclonal antibodies (TOMAs), in two different but complementary mouse models; hTau, which overexpresses WT human Tau, and JNPL3 overexpressing the P301L mutant. These animals were aged to 20-24 months for hTau, and 14-16 months for JNPL3 mice. Previous studies, including ours, used middle aged mice (3-8 months), therefore it is critical to evaluate TauO passive immunotherapy in aged mice since the disease pathology changes with age. We injected mice with 120 µg of different TOMA clones as well as non-specific IgG intravenously, and we assessed the cognitive functions of mice one-week post-injection using Y-maze and novel object recognition (NOR) tests, as well as the motor activity using Rotarod test. Brain tissues were analyzed by standard biochemical and immunohistochemical assays.
We found that certain TOMA clones reverse the tauopathy-related memory deficit of JNPL3 mice, in addition to improving motor function of hTau mice. This rescuing of the cognitive and motor phenotypes was parallel to a reduction in TauO levels, using western blot and slot blot analysis.
This is the first study testing tau passive immunotherapy in elderly animals and support our previous reports of oligomeric tau role in disease progression and validate the potential for TOMAs in reversing disease course. Currently, we are humanizing these TOMA clones for potential clinical trials for AD and related tauopathies