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.
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The data used to generate the results that support the findings of this study are available from the corresponding authors upon reasonable request.
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We thank M. Diamond (UT Southwestern Medical Center) for providing the Tau RD-P301S-YFP lentivirus and DS9 clone cell line; K. Zhang and B. Lake (UCSD) and A. Regev, N. Habib, I. Avraham-Davidi, and A. Basu (Broad Institute of MIT and Harvard) for sharing their single-nucleus RNA-seq datasets; L. Honig, J.P. Vonsattel, A. Teich, and E. Cortés (New York Brain Bank, Columbia University Medical Center), the NIH NeuroBrainBank at the University of Maryland Brain and Tissue Bank as well as T. Beach and G. Serrano (Banner Sun Health Research Institute Brain and Body Donation Program) for providing human de-identified brain tissue and for helpful discussions on brain regions and immunostaining techniques; P. Davies (The Feinstein Institute for Medical Research) for providing the MC1 and PHF1 tau antibodies; P. Dolan (Prothena) for providing the 12E8 tau antibody; C. Pröschel (University of Rochester Medical Center) for providing psPAX2 and VSVG; ACDBio for troubleshooting on RNAscope FISH; and W.H. Yu and C.L. Clelland for discussing the results. This work was funded by: NIH/NIA AG056673 (H.F.), Alzheimer’s Association AARF-17-505009 (H.F.), NIH/NINDS NS074874 (K.E.D.), NIH/NIA AG056151 (K.E.D) and by the BrightFocus Foundation, the Rainwater Foundation/Tau Consortium and the Cure Alzheimer’s Fund (K.E.D). The Banner Sun Health Research Institute Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson’s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer’s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer’s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson’s Disease Consortium), and the Michael J. Fox Foundation for Parkinson’s Research.