Tauopathies are a class of heterogeneous neurodegenerative diseases, including Alzheimer?s disease (AD), characterized by intracellular accumulation of misfolded tau protein into paired helical filaments (PHFs). Emerging evidence suggests that distinct conformations of misfolded tau, referred to as strains, act as proteinaceous seeds that corrupt the structure of normally soluble tau propagating the aberrant conformation. Our lab and others have demonstrated that introduction of minuscule amounts of recombinant tau preformed fibrils (PFFs) into cultured primary neurons from mice results in abundant recruitment of cellular tau into cytoplasmic aggregates. Intriguingly, tau enriched brain extracts from different tauopathies including AD, corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP) recapitulate clinical and morphological phenotypes of the individual diseases and spread to neuroanatomically connected brain regions following intracerebral injection into transgenic (Tg) mice. Furthermore, evidence of pathological tau spread provides strong rationale for the development of passive immune therapy approaches as therapeutic intervention in tauopathies. I have generated a panel of novel anti-tau monoclonal antibodies (mAbs), including conformation-selective mAbs that recognize tau NFTs in AD, primary age-related tauopathy (PART) and normal aging, but not other tauopathies CBD, PSP or Pick?s disease. These findings compel us to investigate whether tau strains have distinct conformational features that are propagated via templated recruitment of unstructured tau resulting in spread of tau pathology via cell-to-cell transmission. We propose the following aims, 1) characterize distinct tau strains using novel conformation-selective tau mAbs 2) use tauopathy brain-derived insoluble tau to seed recombinant tau protein and evaluate the properties of seeded- PFFs 3) evaluate the efficacy of novel anti-tau mAbs to block the transmission of pathological tau strains in vivo. The successful completion of these studies will provide new insights into the etiology of tauopathies by providing novel characterization of human brain-derived tau strains, establish a method to faithfully propagate tau strains to recombinant material enabling future biophysical and structural studies, and provide essential preliminary evaluation of tau mAbs as potential therapeutics for the treatment of tauopathies.
Misfolded tau protein forms intracellular tangles that are a pathological hallmark of tauopathies, a diverse class of neurodegenerative diseases, including Alzheimer?s disease (AD). Although tau is misfolded in each of these diseases, they present with distinct clinical and pathological features. The proposed study uses novel conformation-selective tau antibodies that recognize tau pathology in a subset of tauopathies to characterize distinct tau strains. Faithful propagation of tau strains by a seeded fibrillization reaction with recombinant tau protein is essential to expand the limited quantity of available brain-derived pathological tau for future biophysical and structural studies. Evaluation of novel tau antibodies as immunotherapies will be conducted in a pathological tau transmission model system to advance efforts to develop disease modifying therapies for AD and related tauopathies.
| Gibbons, Garrett S; Banks, Rachel A; Kim, Bumjin et al. (2018) Detection of Alzheimer Disease (AD)-Specific Tau Pathology in AD and NonAD Tauopathies by Immunohistochemistry With Novel Conformation-Selective Tau Antibodies. J Neuropathol Exp Neurol 77:216-228 |
| Gibbons, Garrett S; Lee, Virginia M Y; Trojanowski, John Q (2018) Mechanisms of Cell-to-Cell Transmission of Pathological Tau: A Review. JAMA Neurol : |
| Gibbons, Garrett S; Banks, Rachel A; Kim, Bumjin et al. (2017) GFP-Mutant Human Tau Transgenic Mice Develop Tauopathy Following CNS Injections of Alzheimer's Brain-Derived Pathological Tau or Synthetic Mutant Human Tau Fibrils. J Neurosci 37:11485-11494 |
