Neurofibrillary tangle-bearing neurons are functionally integrated in cortical circuits in vivo

Kishore V. Kuchibhotla, Susanne Wegmann, Katherine J. Kopeikina, Jonathan Hawkes, Nikita Rudinskiy, Mark L. Andermann, Tara L. Spires-Jones, Brian J. Bacskai, Bradley T. Hyman

Research output: Contribution to journalArticlepeer-review

Abstract

Alzheimer's disease (AD) is pathologically characterized by the deposition of extracellular amyloid-β plaques and intracellular aggregation of tau protein in neurofibrillary tangles (NFTs) (1, 2). Progression of NFT pathology is closely correlated with both increased neurodegeneration and cognitive decline in AD (3) and other tauopathies, such as frontotemporal dementia (4, 5). The assumption that mislocalization of tau into the somatodendritic compartment (6) and accumulation of fibrillar aggregates in NFTs mediates neurodegeneration underlies most current therapeutic strategies aimed at preventing NFT formation or disrupting existing NFTs (7, 8). Although several disease-associated mutations cause both aggregation of tau and neurodegeneration, whether NFTs per se contribute to neuronal and network dysfunction in vivo is unknown (9). Here we used awake in vivo two-photon calcium imaging to monitor neuronal function in adult rTg4510 mice that overexpress a human mutant form of tau (P301L) and develop cortical NFTs by the age of 7-8 mo (10). Unexpectedly, NFT-bearing neurons in the visual cortex appeared to be completely functionally intact, to be capable of integrating dendritic inputs and effectively encoding orientation and direction selectivity, and to have a stable baseline resting calcium level. These results suggest a reevaluation of the common assumption that insoluble tau aggregates are sufficient to disrupt neuronal function.

Original languageEnglish (US)
Pages (from-to)510-514
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number1
DOIs
StatePublished - 2014
Externally publishedYes

Keywords

  • Neuronal networks
  • Paired helical filaments
  • Tau pathology

ASJC Scopus subject areas

  • General

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