Tau oligomers impair memory and induce synaptic and mitochondrial dysfunction in wild-type mice

C.A. Lasagna-Reeves, D.L. Castillo-Carranza, U. Sengupta, A.L. Clos, G.R. Jackson, R. Kayed

Research output: Contribution to journalArticlepeer-review

294 Citations (Scopus)

Abstract

Background: The correlation between neurofibrillary tangles of tau and disease progression in the brains of Alzheimer's disease (AD) patients remains an area of contention. Innovative data are emerging from biochemical, cell-based and transgenic mouse studies that suggest that tau oligomers, a pre-filament form of tau, may be the most toxic and pathologically significant tau aggregate. Results: Here we report that oligomers of recombinant full-length human tau protein are neurotoxic in vivo after subcortical stereotaxic injection into mice. Tau oligomers impaired memory consolidation, whereas tau fibrils and monomers did not. Additionally, tau oligomers induced synaptic dysfunction by reducing the levels of synaptic vesicle-associated proteins synaptophysin and septin-11. Tau oligomers produced mitochondrial dysfunction by decreasing the levels of NADH-ubiquinone oxidoreductase (electron transport chain complex I), and activated caspase-9, which is related to the apoptotic mitochondrial pathway. Conclusions: This study identifies tau oligomers as an acutely toxic tau species in vivo, and suggests that tau oligomers induce neurodegeneration by affecting mitochondrial and synaptic function, both of which are early hallmarks in AD and other tauopathies. These results open new avenues for neuroprotective intervention strategies of tauopathies by targeting tau oligomers.

Original languageEnglish
Article number39
Pages (from-to)39
JournalMolecular Neurodegeneration
Volume6
Issue number1
DOIs
Publication statusPublished - 2011
Externally publishedYes

Bibliographical note

Funding Information:
Supported by the Cullen Trust, the Alzheimer’s Drug Discovery foundation (ADDF), and the Mitchell Center for Neurodegenerative Diseases. We thank Dr. Bridget E. Hawkins for her suggestions and critical reading of the manuscript. We are grateful to Prof. Martin Margittai for providing recombinant tau and plasmid, and Dr. Marcos Guerrero-Munoz for his help in the purification and characterization of tau oligomers.

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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