Abstract
Neurons display different levels of vulnerability to Alzheimer's pathology. Roussarie et al. experimentally profile and computationally model several relevant neuron types. Using a mouse-human framework, they identify genes linking Aß, aging, and tau in vulnerable neurons. Finally, they show experimentally that PTB, a regulator of tau splicing, contributes to vulnerability.
Original language | English (US) |
---|---|
Pages (from-to) | 821-835.e12 |
Journal | Neuron |
Volume | 107 |
Issue number | 5 |
DOIs | |
State | Published - Sep 9 2020 |
All Science Journal Classification (ASJC) codes
- Neuroscience(all)
Keywords
- Alzheimer's disease
- PTBP1
- bacTRAP
- machine learning
- network
- selective neuronal vulnerability
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In: Neuron, Vol. 107, No. 5, 09.09.2020, p. 821-835.e12.
Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - Selective Neuronal Vulnerability in Alzheimer's Disease
T2 - A Network-Based Analysis
AU - Roussarie, Jean Pierre
AU - Yao, Vicky
AU - Rodriguez-Rodriguez, Patricia
AU - Oughtred, Rose
AU - Rust, Jennifer
AU - Plautz, Zakary
AU - Kasturia, Shirin
AU - Albornoz, Christian
AU - Wang, Wei
AU - Schmidt, Eric F.
AU - Dannenfelser, Ruth
AU - Tadych, Alicja
AU - Brichta, Lars
AU - Barnea-Cramer, Alona
AU - Heintz, Nathaniel
AU - Hof, Patrick R.
AU - Heiman, Myriam
AU - Dolinski, Kara
AU - Flajolet, Marc
AU - Troyanskaya, Olga G.
AU - Greengard, Paul
N1 - Funding Information: We thank A. Milosevic, R. Chottekalapanda, H. Rebholz, M. Riessland, B. Kolisnyk, R. Sealfon, C. Theesfeld, and R. Zhang for critical reading of the manuscript; E. Griggs for assistance with graphic design; R. Norinsky and Rockefeller University (RU) Transgenic Services for all pronuclear injections; C. Zhao and the RU Genomics Resource Center for all sequencing; and the RU Bioimaging Resource Center. J.-P.R. M.F. and P.G. were supported by the Fisher Center for Alzheimer's Disease Research. V.Y. was supported in part by NIH grant T32 HG003284. O.G.T. is a senior fellow of the Genetic Networks Program of the Canadian Institute for Advanced Research (CIFAR). P.R.-R. was supported in part by the European Union Horizon 2020 Research and Innovation Program under Marie Sklodowska-Curie grant agreement 799638. This study was supported by the JPB Foundation and Cure Alzheimer's Fund (to P.G. and M.H.), United States Army Medical Research and Material Command (USAMRMC) award W81XWH-14-1-0046 (to J.-P.R.), the National Institute on Aging of the NIH (awards RF1AG047779 to P.G. and J.-P.R.; RF1AG054564 to P.G. J.-P.R. and A.B.-C.; and P50 AG005138 to P.R.H.), NIH R01 GM071966 (to O.G.T.), the Office of Research Infrastructure Programs of the NIH (award R01OD010929 to K.D.), the National Institute of Neurological Disorders and Stroke of the NIH (award R01NS091722 to E.F.S.), and the Howard Hughes Medical Institute (to N.H.). The results published here are in part based on data obtained from Agora, a platform initially developed by the NIA-funded AMP-AD Consortium. Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the sponsors. J.-P.R. V.Y. O.G.T. and P.G. conceived and designed the research with input from M.H. and P.R.H. J.-P.R. generated mice with help from E.F.S. N.H. and L.B. J.-P.R. S.K. and C.A. performed bacTRAP experiments. P.R.-R. and Z.P. performed stereotaxic injections. V.Y. and O.G.T. conceived the computational analyses. V.Y. performed all bacTRAP data analyses, generated and analyzed functional networks, reprioritized genes, and re-analyzed publicly available datasets. W.W. performed some additional RNA-seq experiments. V.Y. and J.-P.R. analyzed results from the computational analyses. M.F. R.O. J.R. and K.D. curated amyloid and NFT lists. V.Y. R.D. and A.T. made the data available at http://alz.princeton.edu. J.-P.R. V.Y. O.G.T. and P.G. wrote the manuscript with input from M.F. P.R.H. P.R.-R. and A.B.-C. The authors declare no competing interests. Funding Information: We thank A. Milosevic, R. Chottekalapanda, H. Rebholz, M. Riessland, B. Kolisnyk, R. Sealfon, C. Theesfeld, and R. Zhang for critical reading of the manuscript; E. Griggs for assistance with graphic design; R. Norinsky and Rockefeller University (RU) Transgenic Services for all pronuclear injections; C. Zhao and the RU Genomics Resource Center for all sequencing; and the RU Bioimaging Resource Center. J.-P.R., M.F., and P.G. were supported by the Fisher Center for Alzheimer’s Disease Research . V.Y. was supported in part by NIH grant T32 HG003284 . O.G.T. is a senior fellow of the Genetic Networks Program of the Canadian Institute for Advanced Research (CIFAR). P.R.-R. was supported in part by the European Union Horizon 2020 Research and Innovation Program under Marie Sklodowska-Curie grant agreement 799638 . This study was supported by the JPB Foundation and Cure Alzheimer's Fund (to P.G. and M.H.), United States Army Medical Research and Material Command (USAMRMC) award W81XWH-14-1-0046 (to J.-P.R.), the National Institute on Aging of the NIH (awards RF1AG047779 to P.G. and J.-P.R.; RF1AG054564 to P.G., J.-P.R., and A.B.-C.; and P50 AG005138 to P.R.H.), NIH R01 GM071966 (to O.G.T.), the Office of Research Infrastructure Programs of the NIH (award R01OD010929 to K.D.), the National Institute of Neurological Disorders and Stroke of the NIH (award R01NS091722 to E.F.S.), and the Howard Hughes Medical Institute (to N.H.). The results published here are in part based on data obtained from Agora, a platform initially developed by the NIA-funded AMP-AD Consortium. Opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the sponsors. Publisher Copyright: © 2020 The Authors
PY - 2020/9/9
Y1 - 2020/9/9
N2 - Neurons display different levels of vulnerability to Alzheimer's pathology. Roussarie et al. experimentally profile and computationally model several relevant neuron types. Using a mouse-human framework, they identify genes linking Aß, aging, and tau in vulnerable neurons. Finally, they show experimentally that PTB, a regulator of tau splicing, contributes to vulnerability.
AB - Neurons display different levels of vulnerability to Alzheimer's pathology. Roussarie et al. experimentally profile and computationally model several relevant neuron types. Using a mouse-human framework, they identify genes linking Aß, aging, and tau in vulnerable neurons. Finally, they show experimentally that PTB, a regulator of tau splicing, contributes to vulnerability.
KW - Alzheimer's disease
KW - PTBP1
KW - bacTRAP
KW - machine learning
KW - network
KW - selective neuronal vulnerability
UR - http://www.scopus.com/inward/record.url?scp=85087931939&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85087931939&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2020.06.010
DO - 10.1016/j.neuron.2020.06.010
M3 - Article
C2 - 32603655
AN - SCOPUS:85087931939
SN - 0896-6273
VL - 107
SP - 821-835.e12
JO - Neuron
JF - Neuron
IS - 5
ER -