Document Detail

Paired helical filaments from Alzheimer disease brain induce intracellular accumulation of Tau protein in aggresomes.
MedLine Citation:
PMID:  22496370     Owner:  NLM     Status:  MEDLINE    
Abnormal folding of tau protein leads to the generation of paired helical filaments (PHFs) and neurofibrillary tangles, a key neuropathological feature in Alzheimer disease and tauopathies. A specific anatomical pattern of pathological changes developing in the brain suggests that once tau pathology is initiated it propagates between neighboring neuronal cells, possibly spreading along the axonal network. We studied whether PHFs released from degenerating neurons could be taken up by surrounding cells and promote spreading of tau pathology. Neuronal and non-neuronal cells overexpressing green fluorescent protein-tagged tau (GFP-Tau) were treated with isolated fractions of human Alzheimer disease-derived PHFs for 24 h. We found that cells internalized PHFs through an endocytic mechanism and developed intracellular GFP-Tau aggregates with attributes of aggresomes. This was particularly evident by the perinuclear localization of aggregates and redistribution of the vimentin intermediate filament network and retrograde motor protein dynein. Furthermore, the content of Sarkosyl-insoluble tau, a measure of abnormal tau aggregation, increased 3-fold in PHF-treated cells. An exosome-related mechanism did not appear to be involved in the release of GFP-Tau from untreated cells. The evidence that cells can internalize PHFs, leading to formation of aggresome-like bodies, opens new therapeutic avenues to prevent propagation and spreading of tau pathology.
Ismael Santa-Maria; Merina Varghese; Hanna Ksiezak-Reding; Anastasiya Dzhun; Jun Wang; Giulio M Pasinetti
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-04-10
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-06-11     Completed Date:  2012-09-21     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  20522-33     Citation Subset:  IM    
Center of Excellence for Novel Approaches to Neurodiagnostics and Neurotherapeutics, Brain Institute, Center of Excellence for Research in Complementary and Alternative Medicine in Alzheimer's Disease, Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029, USA.
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MeSH Terms
Alzheimer Disease / metabolism*,  pathology
Axons / metabolism*
Brain / metabolism*,  pathology
Brain Chemistry
Dyneins / chemistry,  metabolism
Protein Folding*
Vimentin / chemistry,  metabolism
tau Proteins / chemistry*,  metabolism*
Grant Support
Reg. No./Substance:
0/MAPT protein, human; 0/Vimentin; 0/tau Proteins; EC

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