Extracellular monomeric tau protein is sufficient to initiate the spread of tau protein pathology.
Understanding the formation and propagation of aggregates of the Alzheimer disease-associated Tau protein in vivo is vital for the development of therapeutics for this devastating disorder. Using our recently developed live-cell aggregation sensor in neuron-like cells, we demonstrate that different variants of exogenous monomeric Tau, namely full-length Tau (hTau40) and the Tau-derived construct K18 comprising the repeat domain, initially accumulate in endosomal compartments, where they form fibrillar seeds that subsequently induce the aggregation of endogenous Tau. Using superresolution imaging, we confirm that fibrils consisting of endogenous and exogenous Tau are released from cells and demonstrate their potential to spread Tau pathology. Our data indicate a greater pathological risk and potential toxicity than hitherto suspected for extracellular soluble Tau.
From the Department of Chemical Engineering and Biotechnology, University of Cambridge, Pembroke Street, Cambridge CB2 3RA, United Kingdom.
Claire H
CH
Michel
Satish
S
Kumar
Dorothea
D
Pinotsi
Alan
A
Tunnacliffe
Peter
P
St George-Hyslop
Eckhard
E
Mandelkow
Eva-Maria
EM
Mandelkow
Clemens F
CF
Kaminski
Gabriele S
GS
Kaminski Schierle
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D005089:Exocytosis; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D018613:Microscopy, Confocal; D008854:Microscopy, Electron; D008954:Models, Biological; D016874:Neurofibrillary Tangles / Q000378:metabolism* / Q000648:ultrastructure; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D024801:Tauopathies / Q000378:metabolism; D022161:Transport Vesicles / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
D016875:tau Proteins
Alzheimer Disease; Amyloid; Endocytosis; Fluorescence Lifetime Imaging Microscopy; Propagation; Protein Aggregation; Superresolution Microscopy; Tau