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Extracellular low‐n oligomers of tau cause selective synaptotoxicity without affecting cell viability
Author(s) -
Kaniyappan Senthilvelrajan,
Chandupatla Ram Reddy,
Mandelkow EvaMaria,
Mandelkow Eckhard
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.04.002
Subject(s) - viability assay , toxicity , extracellular , lactate dehydrogenase , reactive oxygen species , biochemistry , cell , chemistry , intracellular , microbiology and biotechnology , biophysics , biology , enzyme , organic chemistry
Tau‐mediated toxicity in Alzheimer's disease is thought to operate through low‐n oligomers, rather than filamentous aggregates. However, the nature of oligomers and pathways of toxicity are poorly understood. Therefore, we investigated structural and functional aspects of highly purified oligomers of a pro‐aggregant tau species. Methods Purified oligomers of the tau repeat domain were characterized by biophysical and structural methods. Functional aspects were investigated by cellular assays ((3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assay of cell viability, lactate dehydrogenase release assay [for cell toxicity], reactive oxygen species production, and calcium assay), combined with analysis of neuronal dendritic spines exposed to oligomers. Results Purified low‐n oligomers are roughly globular, with sizes around 1.6 to 5.4 nm, exhibit an altered conformation, but do not have substantial β‐structure. Treatment of primary neurons with oligomers impairs spine morphology and density, accompanied by increased reactive oxygen species and intracellular calcium, but without affecting cell viability (by (3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assay of cell viability and lactate dehydrogenase release assay [for cell toxicity]). Discussion Tau oligomers are toxic to synapses but not lethal to cells.