Cell-cell transfer and propagation of tau aggregates. Tauopathies are devastating neurodegenerative diseases. All are linked pathologically to misfolding and aggregation of the microtubule-associated protein tau, and include common disorders such as Alzheimer disease and frontotemporal dementia. Both wild-type tau protein and mutant forms associated with dominantly inherited diseases have the propensity to misfold and aggregate. In virtually all cases, disease begins in one brain region before spreading to involve other regions, and there is emerging evidence that this could be based on movement of protein aggregates between cells. This project seeks to understand the cellular mechanisms that govern tau aggregate uptake and release from cells, and how a tau aggregate taken into a cell manages to corrupt the endogenous, normally folded protein. The answers to these questions will provide immediate new opportunities for therapeutic strategies. The goals of this work are as follows: (1) Determine molecular mechanisms of tau uptake. We will use cell-based assays we have developed to study tau aggregate uptake, and to evaluate the molecular mechanisms that underlie this phenomenon. We will use mouse models to test predictions about pathways derived from our experiments in cell models. (2) Determine mechanisms of tau aggregate degradation and release. We believe that cellular pathways linked to protein degradation may play a role in processing tau protein aggregates, and might also be involved in allowing these aggregates to transfer between cells. We will test these ideas using a cellular model of aggregate transfer between cells. (3) Determine mechanisms of tau aggregate propagation. It is unclear how tau protein aggregates that move from one cell to another might lead to misfolding of protein in the recipient cell, and whether this movement can occur across synapses, as is suggested by new clinical studies. We will test whether tau protein aggregates """"""""corrupt"""""""" protein on the cell interior through templated conformation change, whereby normally folded protein directly contacts aggregated forms. We will additionally test whether aggregates can move across synapses using a novel mouse model.

Public Health Relevance

Tauopathies afflict millions of Americans, and hundreds of millions of individuals worldwide. As our population ages, the incidence of these diseases will rise acutely. There is no cure, and we lack sufficient mechanistic understanding of pathogenesis to design well-targeted therapies. This research will help solve these problems, as it is focused on understanding the cellular mechanisms that influence pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS071835-03
Application #
8237034
Study Section
Special Emphasis Panel (ZRG1-BDCN-T (03))
Program Officer
Corriveau, Roderick A
Project Start
2010-05-15
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
3
Fiscal Year
2012
Total Cost
$325,850
Indirect Cost
$111,475
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Furman, Jennifer L; Holmes, Brandon B; Diamond, Marc I (2015) Sensitive Detection of Proteopathic Seeding Activity with FRET Flow Cytometry. J Vis Exp :e53205
Funk, Kristen E; Mirbaha, Hilda; Jiang, Hong et al. (2015) Distinct Therapeutic Mechanisms of Tau Antibodies: Promoting Microglial Clearance Versus Blocking Neuronal Uptake. J Biol Chem 290:21652-62
Wobst, Heike J; Sharma, Apurwa; Diamond, Marc I et al. (2015) The green tea polyphenol (-)-epigallocatechin gallate prevents the aggregation of tau protein into toxic oligomers at substoichiometric ratios. FEBS Lett 589:77-83
Mirbaha, Hilda; Holmes, Brandon B; Sanders, David W et al. (2015) Tau Trimers Are the Minimal Propagation Unit Spontaneously Internalized to Seed Intracellular Aggregation. J Biol Chem 290:14893-903
Sanders, David W; Kaufman, Sarah K; DeVos, Sarah L et al. (2014) Distinct tau prion strains propagate in cells and mice and define different tauopathies. Neuron 82:1271-88
Holmes, Brandon B; Diamond, Marc I (2014) Prion-like properties of Tau protein: the importance of extracellular Tau as a therapeutic target. J Biol Chem 289:19855-61
Holmes, Brandon B; Furman, Jennifer L; Mahan, Thomas E et al. (2014) Proteopathic tau seeding predicts tauopathy in vivo. Proc Natl Acad Sci U S A 111:E4376-85
Diamond, Marc I (2013) A strong consensus has emerged around the role of protein misfolding and aggregation in the pathogenesis of neurodegeneration. Introduction. Neurotherapeutics 10:369-70
Holmes, Brandon B; DeVos, Sarah L; Kfoury, Najla et al. (2013) Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. Proc Natl Acad Sci U S A 110:E3138-47
Yanamandra, Kiran; Kfoury, Najla; Jiang, Hong et al. (2013) Anti-tau antibodies that block tau aggregate seeding in vitro markedly decrease pathology and improve cognition in vivo. Neuron 80:402-14

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