@article{9d119a95cc2f4fa2999abcfef03220c5,
title = "Pulse-Chase Proteomics of the App Knockin Mouse Models of Alzheimer's Disease Reveals that Synaptic Dysfunction Originates in Presynaptic Terminals",
abstract = "Hark et al. use dynamic metabolic 15N labeling and mass-spectrometry-based proteomics to investigate changes to protein turnover in App knockin mice. In this preclinical Alzheimer's disease mouse model, they find that proteostasis in the presynaptic terminal is specifically altered. Synaptic vesicle (SV)-associated proteins functioning in exo- and endocytosis have impaired degradation and elevated levels in the cortex and hippocampus. Finally, the readily releasable SV pool and presynaptic potentiation is enhanced at the earliest stages of amyloid beta accumulation.",
keywords = "APP knockin mice, Alzheimer's disease, amyloid beta, mass spectrometry, presynapse, proteomics, proteostasis, synaptic dysfunction, synaptic vesicles",
author = "Hark, {Timothy J.} and Rao, {Nalini R.} and Charlotte Castillon and Tamara Basta and Samuel Smukowski and Huan Bao and Arun Upadhyay and Ewa Bomba-Warczak and Toshihiro Nomura and O'Toole, {Eileen T.} and Morgan, {Garry P.} and Laith Ali and Takashi Saito and Christelle Guillermier and Saido, {Takaomi C.} and Steinhauser, {Matthew L.} and Stowell, {Michael H.B.} and Chapman, {Edwin R.} and Anis Contractor and Savas, {Jeffrey N.}",
note = "Funding Information: This work was supported by the NIH , Mechanisms of Aging and Dementia T32AG20506 and F31AG059364 to T.J.H.; R01AG061787 , R01AG061865 , and R21NS107761 to J.N.S.; R01MH099114 to A.C.; MH061876 to E.R.C., who is an investigator of the Howard Hughes Medical Institute; AG061829 and the MCDB Neurodegenerative Disease Fund to M.H.B.S.; and the Cure Alzheimer{\textquoteright}s Fund and a pilot award from the CNADC of Northwestern Medicine to J.N.S. Funding Information: We thank Robert Vassar, Robert Kalb, Dimitri Krainc, and members of the Savas laboratory for insightful discussions. We thank Hongkai Wang for contributing to the Thioflavin S imaging. Some of the imaging in this article was derived from the Northwestern University Center for Advanced Microscopy, which is generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. Funding Information: We thank Robert Vassar, Robert Kalb, Dimitri Krainc, and members of the Savas laboratory for insightful discussions. We thank Hongkai Wang for contributing to the Thioflavin S imaging. Some of the imaging in this article was derived from the Northwestern University Center for Advanced Microscopy, which is generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. This work was supported by the NIH, Mechanisms of Aging and Dementia T32AG20506 and F31AG059364 to T.J.H.; R01AG061787, R01AG061865, and R21NS107761 to J.N.S.; R01MH099114 to A.C.; MH061876 to E.R.C. who is an investigator of the Howard Hughes Medical Institute; AG061829 and the MCDB Neurodegenerative Disease Fund to M.H.B.S.; and the Cure Alzheimer's Fund and a pilot award from the CNADC of Northwestern Medicine to J.N.S. T.J.H. M.L.S. M.H.B.S. E.R.C. A.C. and J.N.S. designed the experiments; T.J.H. performed the metabolic labeling, MS and bioinformatics, WB, IHC, and documented pathology; N.R.R. performed APP affinity purifications and MS/WBs analysis, TUBE purifications and WBs, ET data analysis, and intact SNARE analyses; C.C. and T.N. performed electrophysiology; T.B. E.T.O. and G.P.M. performed ET and analysis; C.G. and M.L.S. performed MIMS; H.B. and E.R.C. performed membrane fusion assays; L.A. performed detergent insoluble experiments; S.S. performed synaptosome purification and MS analysis; A.U. performed A? affinity purifications and dot blots; E.B.-W. contributed to ET analysis, intact SNARE, and membrane fusion assays; and T.J.H. and J.N.S. wrote the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2021",
month = feb,
day = "17",
doi = "10.1016/j.cels.2020.11.007",
language = "English (US)",
volume = "12",
pages = "141--158.e9",
journal = "Cell Systems",
issn = "2405-4712",
publisher = "Cell Press",
number = "2",
}