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 Ca 2+ 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.
Bibliographical noteFunding Information:
We thank A.B. Robbins, D.L. Corjuc, A.D. Roe, and E. Hudry for their excellent technical support, and all members of the Hyman laboratory for providing comments and advice throughout the project. We thank Matthias Staufenbiel for helpful discussions and experimental suggestions. We acknowledge the Genetically-Encoded Neuronal Indicator and Effector (GENIE) project and the Janelia Research Campus of the Howard Hughes Medical Institute and specifically V. Jayaraman, R.A. Kerr, D.S. Kim, L.L. Looger, and K. Svoboda from the GENIE Project, Janelia Research Campus, Howard Hughes Medical Institute for making AAV.Syn.GCaMP6f publicly available. We thank Dr P. Davies for kindly providing the PHF1 and Alz50 antibodies. We thank the following funding agencies for their support: M.A.B. was supported by an EMBO Long-Term Fellowship (grant no. ALTF 590-2016), the Alzheimer Forschung Initiative, and the UK Dementia Research Institute. I.N. was supported by an advanced ERC grant (project RATLAND; grant no. 340063). B.T.H. received support from the Massachusetts Alzheimer’s Disease Research Center (grant no. P50AG005134), the JPB foundation, the National Institutes of Health (grant no. 1R01AG0586741), and the Tau Consortium.
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