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Nat Neurosci. 2019 Jan;22(1):57-64. doi: 10.1038/s41593-018-0289-8. Epub 2018 Dec 17.

Tau impairs neural circuits, dominating amyloid-β effects, in Alzheimer models in vivo.

Author information

1
MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. m.busche@ucl.ac.uk.
2
UK Dementia Research Institute, University College London, London, UK. m.busche@ucl.ac.uk.
3
MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
4
German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany.
5
McLaughlin Research Institute for Biomedical Sciences, Great Falls, MT, USA.
6
Department of Neurobiology, Silberman Institute of Life Sciences and Edmond and Lily Safra Center for Brain Sciences, Hebrew University of Jerusalem, Jerusalem, Israel.
7
MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA. bhyman@mgh.harvard.edu.

Abstract

The coexistence of amyloid-β (Aβ) plaques and tau neurofibrillary tangles in the neocortex is linked to neural system failure and cognitive decline in Alzheimer's disease. However, the underlying neuronal mechanisms are unknown. By employing in vivo two-photon Ca2+ imaging of layer 2/3 cortical neurons in mice expressing human Aβ and tau, we reveal a dramatic tau-dependent suppression of activity and silencing of many neurons, which dominates over Aβ-dependent neuronal hyperactivity. We show that neurofibrillary tangles are neither sufficient nor required for the silencing, which instead is dependent on soluble tau. Surprisingly, although rapidly effective in tau mice, suppression of tau gene expression was much less effective in rescuing neuronal impairments in mice containing both Aβ and tau. Together, our results reveal how Aβ and tau synergize to impair the functional integrity of neural circuits in vivo and suggest a possible cellular explanation contributing to disappointing results from anti-Aβ therapeutic trials.

PMID:
30559471
DOI:
10.1038/s41593-018-0289-8

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