Unique pathological tau conformers from Alzheimer's brains transmit tau pathology in nontransgenic mice.
Filamentous tau aggregates are hallmark lesions in numerous neurodegenerative diseases, including Alzheimer's disease (AD). Cell culture and animal studies showed that tau fibrils can undergo cell-to-cell transmission and seed aggregation of soluble tau, but this phenomenon was only robustly demonstrated in models overexpressing tau. In this study, we found that intracerebral inoculation of tau fibrils purified from AD brains (AD-tau), but not synthetic tau fibrils, resulted in the formation of abundant tau inclusions in anatomically connected brain regions in nontransgenic mice. Recombinant human tau seeded by AD-tau revealed unique conformational features that are distinct from synthetic tau fibrils, which could underlie the differential potency in seeding physiological levels of tau to aggregate. Therefore, our study establishes a mouse model of sporadic tauopathies and points to important differences between tau fibrils that are generated artificially and authentic ones that develop in AD brains.
Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.
Jing L
0000-0002-8503-3746
JL
Guo
Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.
Sneha
0000-0002-1665-9681
S
Narasimhan
Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.
Lakshmi
L
Changolkar
Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.
Zhuohao
0000-0003-1505-8750
Z
He
Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.
Anna
A
Stieber
Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.
Bin
0000-0003-1119-4886
B
Zhang
Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.
Ronald J
0000-0001-5706-0803
RJ
Gathagan
Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.
Michiyo
M
Iba
Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.
Jennifer D
JD
McBride
Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104.
John Q
0000-0002-9239-8794
JQ
Trojanowski
Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104 vmylee@upenn.edu.
Virginia M Y
0000-0003-3536-6902
VM
Lee
D000375:Aging / Q000473:pathology; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D006493:Heparin / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000473:pathology / Q000648:ultrastructure; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D066329:Protein Aggregates; D011487:Protein Conformation; D020033:Protein Isoforms / Q000378:metabolism; D024801:Tauopathies / Q000378:metabolism* / Q000473:pathology*; D014020:Tissue Extracts; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
D066329:Protein Aggregates; D020033:Protein Isoforms; D014020:Tissue Extracts; D016875:tau Proteins; D006493:Heparin