RT Journal Article
SR Electronic
T1 Leveraging selective hippocampal vulnerability among Alzheimer’s disease subtypes reveals a novel tau binding partner SERPINA5
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.12.18.423469
DO 10.1101/2020.12.18.423469
A1 Angela M. Crist
A1 Kelly M. Hinkle
A1 Xue Wang
A1 Christina M. Moloney
A1 Billie J. Matchett
A1 Sydney A. Labuzan
A1 Isabelle Frankenhauser
A1 Nkem O. Azu
A1 Amanda M. Liesinger
A1 Elizabeth R. Lesser
A1 Daniel J. Serie
A1 Zachary S. Quicksall
A1 Tulsi A. Patel
A1 Troy P. Carnwath
A1 Michael DeTure
A1 Xiaojia Tang
A1 Ronald C. Petersen
A1 Ranjan Duara
A1 Neill R. Graff-Radford
A1 Mariet Allen
A1 Minerva M. Carrasquillo
A1 Hu Li
A1 Owen A. Ross
A1 Nilufer Ertekin-Taner
A1 Dennis W. Dickson
A1 Yan W. Asmann
A1 Rickey E. Carter
A1 Melissa E. Murray
YR 2020
UL http://biorxiv.org/content/early/2020/12/20/2020.12.18.423469.abstract
AB Selective vulnerability is a central concept to the myriad of devastating neurodegenerative disorders. Although hippocampus and cortex are selectively vulnerable in Alzheimer’s disease (AD), the degree of involvement lies along a spectrum that we previously defined as AD subtypes revealing distinct clinical correlates. To operationalize heterogeneity of disease spectrum, we classified corticolimbic patterns of neurofibrillary tangles to capture extreme and representative phenotypes. We combined bulk RNA sequencing with digital pathology to examine hippocampal vulnerability in AD. Using a multidisciplinary approach, we uncovered disease-relevant hippocampal gene expression changes. Biological relevance was prioritized using machine learning and several levels of human validation. This resulted in five genes highly predictive of neuropathologically diagnosed AD: SERPINA5, RYBP, SLC38A2, FEM1B, and PYDC1. Deeper investigation revealed SERPINA5 to be a novel tau binding partner that may represent a “tipping point” in the dynamic maturity of neurofibrillary tangles. Our study highlights the importance of embracing heterogeneity of the human brain to yield promising gene candidates as exampled by SERPINA5.Competing Interest StatementR.C.P. is a consultant for Hoffman-La Roche, Merck, Biogen, Eisai. R.C.P. is on the Data safety and monitoring board for Genentech. N.G.R. takes part in multi-center studies funded by Lilly, Biogen and Abbvie. M.E.M is a consultant for AVID Radiopharmaceuticals.ADAlzheimer’s DiseaseANOVAAnalysis of varianceAUCArea under the curveAβAmyloid-βBpBasepairsBMEbeta-MercaptoethanolCIConfidence intervalDAB3,3′-DiaminobenzidineDAPI4′,6-diamidino-2-phenylindoleFCFold changeFDRFalse discovery rateGOGene ontologyHpSp ADHippocampal sparing subtype of Alzheimer’s DiseaseH&EHematoxylin and eosinLimbic ADLimbic predominant subtype of Alzheimer’s DiseaseMSBBMount Sinai VA Medical Center Brain BankMMSEMini mental state examNFTNeurofibrillary tangleOROdds ratioPBSPhosphate-buffered salinePMSFphenylmethylsulfonyl fluorideRINRNA integrity numberRNA-SeqRNA sequencingROCreceiver operating characteristicTBSTtris-buffered saline with Tween-20Thio-SThioflavin-STypical ADTypical Alzheimer’s Disease