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Nat Neurosci. 2019 Jan;22(1):47-56. doi: 10.1038/s41593-018-0298-7. Epub 2018 Dec 17.

A tau homeostasis signature is linked with the cellular and regional vulnerability of excitatory neurons to tau pathology.

Author information

1
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, NY, USA. Hongjun.Fu@osumc.edu.
2
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA. Hongjun.Fu@osumc.edu.
3
Department of Neuroscience, Chronic Brain Injury, Discovery Themes, The Ohio State University, Columbus, OH, USA. Hongjun.Fu@osumc.edu.
4
Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, UK.
5
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, NY, USA.
6
Department of Anesthesiology, University of Rochester, Rochester, NY, USA.
7
Federal University of Uberlândia, Uberlândia, Brazil.
8
Departments of Psychiatry and Neurology, Columbia University, New York, NY, USA.
9
Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge, UK. mv245@cam.ac.uk.
10
Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, NY, USA. ked2115@columbia.edu.
11
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA. ked2115@columbia.edu.
12
Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY, USA. ked2115@columbia.edu.

Abstract

Excitatory neurons are preferentially impaired in early Alzheimer's disease but the pathways contributing to their relative vulnerability remain largely unknown. Here we report that pathological tau accumulation takes place predominantly in excitatory neurons compared to inhibitory neurons, not only in the entorhinal cortex, a brain region affected in early Alzheimer's disease, but also in areas affected later by the disease. By analyzing RNA transcripts from single-nucleus RNA datasets, we identified a specific tau homeostasis signature of genes differentially expressed in excitatory compared to inhibitory neurons. One of the genes, BCL2-associated athanogene 3 (BAG3), a facilitator of autophagy, was identified as a hub, or master regulator, gene. We verified that reducing BAG3 levels in primary neurons exacerbated pathological tau accumulation, whereas BAG3 overexpression attenuated it. These results define a tau homeostasis signature that underlies the cellular and regional vulnerability of excitatory neurons to tau pathology.

PMID:
30559469
PMCID:
PMC6330709
[Available on 2019-06-17]
DOI:
10.1038/s41593-018-0298-7

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