Pathological tau strains and transmission in Alzheimer's disease and other tauopathies

University Of Pennsylvania, Philadelphia PA

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Abstract

Project Summary 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.