Interneuronal transfer of human tau between Lamprey central neurons in situ.
The mechanisms by which tau-containing lesions are propagated between adjacent and synaptically interconnected parts of the brain are a potentially important but poorly understood component of human tauopathies such as Alzheimer's disease, Pick's disease, and corticobasal degeneration. Since the utility of currently available transgenic models for studying intercellular aspects of tauopathy is limited by their broad patterns of tau expression in the central nervous system, we used an in situ tauopathy model that replicates tau-induced cytodegeneration in identified neurons on a tau-negative background to determine whether tau secretion or interneuronal transfer might play a role in lesion propagation. We found that the N-terminal half of tau is required for tau secretion and is efficiently exported to the extracellular space and adjacent neurons at relatively low levels of overexpression. By contrast, full-length tau is secreted by a separate mechanism that is correlated with phosphorylation of tau at tyrosine 18 and dendritic degeneration, is exacerbated by tauopathy mutations, and blocked by mutations that inhibit tau:tau interactions. Anterograde transneuronal tau movement occurred with the expression of tau containing the P301L tauopathy mutant, but not with wild type tau isoforms. Our results are consistent with recent studies suggesting a role for molecular "templating" in the propagation of neurofibrillary lesions and provide a novel conceptual and experimental basis for studying the mechanisms of interneuronal propagation and toxicity in human neurodegenerative disease.
Kim
Wonhee
W
Department of Biological Sciences, Center for Cellular Neuroscience and Neurodegeneration Research, University of Massachusetts Lowell, Lowell, MA, USA.
Lee
Sangmook
S
Jung
Cheolwha
C
Ahmed
Ambar
A
Lee
Gloria
G
Hall
Garth F
GF
D000818:Animals; D045744:Cell Line, Tumor; D002490:Central Nervous System / Q000166:cytology*; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D007798:Lampreys / Q000033:anatomy & histology; D051379:Mice; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D021381:Protein Transport / Q000235:genetics; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D014161:Transduction, Genetic / Q000379:methods*; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
C054369:MAPT protein, human; D016900:Neurofilament Proteins; D016875:tau Proteins; D049452:Green Fluorescent Proteins; D014443:Tyrosine