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

Busche, MA; Wegmann, S; Dujardin, S; Commins, C; Schiantarelli, J; Klickstein, N; Kamath, T; ... Hyman, BT; + view all (2019) Tau impairs neural circuits, dominating amyloid-beta effects, in Alzheimer models in vivo. Nature Neuroscience , 22 (1) pp. 57-64. 10.1038/s41593-018-0289-8. Green open access

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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.

Type: Article
Title: Tau impairs neural circuits, dominating amyloid-beta effects, in Alzheimer models in vivo
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/s41593-018-0289-8
Publisher version: https://doi.org/10.1038/s41593-018-0289-8
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Neurosciences, Neurosciences & Neurology, TRANSGENIC MICE, NEUROFIBRILLARY TANGLES, MOUSE MODEL, ENTORHINAL CORTEX, A-BETA, DISEASE, PLAQUES, MEMORY, DYSFUNCTION, REDUCTION
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10067673
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