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Cited by 59Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Differential protein expression in the hippocampi of resilient individuals identified by digital spatial profiling

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Walker, Jamie M., Kazempour Dehkordi, Shiva, Fracassi, Anna, Vanschoiack, Alison, Pavenko, Anna, Taglialatela, Giulio, Woltjer, Randall, Richardson, Timothy E. +2 more·2022·Acta Neuropathologica Communications
DOI 10.1186/s40478-022-01324-9PMC PMC8842950
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Abstract

Clinical symptoms correlate with underlying neurodegenerative changes in the vast majority of people. However, an intriguing group of individuals demonstrate neuropathologic changes consistent with Alzheimer disease (AD) yet remain cognitively normal (termed "resilient"). Previous studies have reported less overall neuronal loss, less gliosis, and fewer comorbidities in these individuals. Herein, NanoString GeoMx™ Digital Spatial Profiler (DSP) technology was utilized to investigate protein expression differences comparing individuals with dementia and AD neuropathologic change to resilient individuals. DSP allows for spatial analysis of protein expression in multiple regions of interest (ROIs) on formalin-fixed paraffin-embedded sections. ROIs in this analysis were hippocampal neurofibrillary tangle (NFT)-bearing neurons, non-NFT-bearing neurons, and their immediate neuronal microenvironments. Analyses of 86 proteins associated with CNS cell-typing or known neurodegenerative changes in 168 ROIs from 14 individuals identified 11 proteins displaying differential expression in NFT-bearing neurons of the resilient when compared to the demented (including APP, IDH1, CD68, GFAP, SYP and Histone H3). In addition, IDH1, CD68, and SYP were differentially expressed in the environment of NFT-bearing neurons when comparing resilient to demented. IDH1 (which is upregulated under energetic and oxidative stress) and PINK1 (which is upregulated in response to mitochondrial dysfunction and oxidative stress) both displayed lower expression in the environment of NFT-bearing neurons in the resilient. Therefore, the resilient display less evidence of energetic and oxidative stress. Synaptophysin (SYP) was increased in the resilient, which likely indicates better maintenance of synapses and synaptic connections. Furthermore, neurofilament light chain (NEFL) and ubiquitin c-terminal hydrolase (Park5) were higher in the resilient in the environment of NFTs. These differences all suggest healthier intact axons, dendrites and synapses in the resilient. In conclusion, resilient individuals display protein expression patterns suggestive of an environment containing less energetic and oxidative stress, which in turn results in maintenance of neurons and their synaptic connections.

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Research works printed but not linked: 53

  1. [1]Aiello Bowles EJ Crane PK Walker RL Chubak J LaCroix AZ Anderson ML Rosenberg D Keene CD Larson EB Cognitive resilience to Alzheimer's disease pathology in the human brain J Alzheimers Dis 2019 68 1071 1083 10.3233/JAD-180942 30909217 PMC8357030 · DOI
  2. [2]Arenaza-Urquijo EM Przybelski SA Lesnick TL Graff-Radford J Machulda MM Knopman DS Schwarz CG Lowe VJ Mielke MM Petersen RC The metabolic brain signature of cognitive resilience in the 80+: beyond Alzheimer pathologies Brain 2019 142 1134 1147 10.1093/brain/awz037 30851100 PMC6439329 · DOI
  3. [3]Atai NA Renkema-Mills NA Bosman J Schmidt N Rijkeboer D Tigchelaar W Bosch KS Troost D Jonker A Bleeker FE Differential activity of NADPH-producing dehydrogenases renders rodents unsuitable models to study IDH1R132 mutation effects in human glioblastoma J Histochem Cytochem 2011 59 489 503 10.1369/0022155411400606 21527585 PMC3201175 · DOI
  4. [4]Attems J Jellinger K Neuropathological correlates of cerebral multimorbidity Curr Alzheimer Res 2013 10 569 577 10.2174/15672050113109990002 23627751 · DOI
  5. [5]Ayyadevara S Balasubramaniam M Parcon PA Barger SW Griffin WST Alla R Tackett AJ Mackintosh SG Petricoin E Zhou W Proteins that mediate protein aggregation and cytotoxicity distinguish Alzheimer's hippocampus from normal controls Aging Cell 2016 15 924 939 10.1111/acel.12501 27448508 PMC5013017 · DOI
  6. [6]Barroeta-Espar I Weinstock LD Perez-Nievas BG Meltzer AC Siao Tick Chong M Amaral AC Murray ME Moulder KL Morris JC Cairns NJ Distinct cytokine profiles in human brains resilient to Alzheimer's pathology Neurobiol Dis 2019 121 327 337 10.1016/j.nbd.2018.10.009 30336198 PMC6437670 · DOI · Paper page
  7. [8]Boyle PA Yu L Wilson RS Schneider JA Bennett DA Relation of neuropathology with cognitive decline among older persons without dementia Front Aging Neurosci 2013 5 50 10.3389/fnagi.2013.00050 24058343 PMC3766823 · DOI
  8. [9]Braak H Thal DR Ghebremedhin E Del Tredici K Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years J Neuropathol Exp Neurol 2011 70 960 969 10.1097/NEN.0b013e318232a379 22002422 · DOI · Paper page
  9. [11]Chow HM Shi M Cheng A Gao Y Chen G Song X So RWL Zhang J Herrup K Age-related hyperinsulinemia leads to insulin resistance in neurons and cell-cycle-induced senescence Nat Neurosci 2019 22 1806 1819 10.1038/s41593-019-0505-1 31636448 · DOI · Paper page
  10. [12]Counts SE Alldred MJ Che S Ginsberg SD Mufson EJ Synaptic gene dysregulation within hippocampal CA1 pyramidal neurons in mild cognitive impairment Neuropharmacology 2014 79 172 179 10.1016/j.neuropharm.2013.10.018 24445080 PMC3951099 · DOI
  11. [13]Dehkordi SK Walker J Sah E Bennett E Atrian F Frost B Woost B Bennett RE Orr TC Zhou Y Profiling senescent cells in human brains reveals neurons with CDKN2D/p19 and tau neuropathology Nat Aging 2021 10.1038/s43587-021-00142-3 PMC9075501 35531351 · DOI · Paper page
  12. [14]Drummond E Pires G MacMurray C Askenazi M Nayak S Bourdon M Safar J Ueberheide B Wisniewski T Phosphorylated tau interactome in the human Alzheimer's disease brain Brain 2020 143 2803 2817 10.1093/brain/awaa223 32812023 PMC7526722 · DOI · Paper page
  13. [15]Dumitrescu L Mahoney ER Mukherjee S Lee ML Bush WS Engelman CD Lu Q Fardo DW Trittschuh EH Mez J Genetic variants and functional pathways associated with resilience to Alzheimer's disease Brain 2020 143 2561 2575 10.1093/brain/awaa209 32844198 PMC7447518 · DOI
  14. [17]Evans DB Rank KB Bhattacharya K Thomsen DR Gurney ME Sharma SK Tau phosphorylation at serine 396 and serine 404 by human recombinant tau protein kinase II inhibits tau's ability to promote microtubule assembly J Biol Chem 2000 275 24977 24983 10.1074/jbc.M000808200 10818091 · DOI
  15. [19]Gong B Cao Z Zheng P Vitolo OV Liu S Staniszewski A Moolman D Zhang H Shelanski M Arancio O Ubiquitin hydrolase Uch-L1 rescues beta-amyloid-induced decreases in synaptic function and contextual memory Cell 2006 126 775 788 10.1016/j.cell.2006.06.046 16923396 · DOI
  16. [20]Gu Z Eils R Schlesner M Complex heatmaps reveal patterns and correlations in multidimensional genomic data Bioinformatics 2016 32 2847 2849 10.1093/bioinformatics/btw313 27207943 · DOI
  17. [21]Hayden KM Gaussoin SA Hunter JC Manson JE Sachs BC Shadyab AH Tindle HA Mossavar-Rahmani Y Mozhui K Snively BM Cognitive resilience among APOE epsilon4 carriers in the oldest old Int J Geriatr Psychiatry 2019 34 1833 1844 10.1002/gps.5199 31418472 PMC7143252 · DOI
  18. [24]Jellinger KA Attems J Challenges of multimorbidity of the aging brain: a critical update J Neural Transm (Vienna) 2015 122 505 521 10.1007/s00702-014-1288-x 25091618 · DOI · Paper page
  19. [26]Latimer CS Burke BT Liachko NF Currey HN Kilgore MD Gibbons LE Henriksen J Darvas M Domoto-Reilly K Jayadev S Resistance and resilience to Alzheimer's disease pathology are associated with reduced cortical pTau and absence of limbic-predominant age-related TDP-43 encephalopathy in a community-based cohort Acta Neuropathol Commun 2019 7 91 10.1186/s40478-019-0743-1 31174609 PMC6556006 · DOI
  20. [28]Maesako M Uemura K Kuzuya A Sasaki K Asada M Watanabe K Ando K Kubota M Akiyama H Takahashi R Gain of function by phosphorylation in Presenilin 1-mediated regulation of insulin signaling J Neurochem 2012 121 964 973 10.1111/j.1471-4159.2012.07741.x 22443192 · DOI
  21. [29]Mathys H Davila-Velderrain J Peng Z Gao F Mohammadi S Young JZ Menon M He L Abdurrob F Jiang X Single-cell transcriptomic analysis of Alzheimer’s disease Nature 2019 570 332 337 10.1038/s41586-019-1195-2 31042697 PMC6865822 · DOI · Paper page
  22. [30]McAleese KE Colloby SJ Thomas AJ Al-Sarraj S Ansorge O Neal J Roncaroli F Love S Francis PT Attems J Concomitant neurodegenerative pathologies contribute to the transition from mild cognitive impairment to dementia Alzheimers Dement 2021 17 1121 1133 10.1002/alz.12291 33663011 · DOI
  23. [31]Meakin PJ Harper AJ Hamilton DL Gallagher J McNeilly AD Burgess LA Vaanholt LM Bannon KA Latcham J Hussain I Reduction in BACE1 decreases body weight, protects against diet-induced obesity and enhances insulin sensitivity in mice Biochem J 2012 441 285 296 10.1042/BJ20110512 21880018 PMC3242510 · DOI
  24. [32]Meier SE Bell M Lyons DN Ingram A Chen J Gensel JC Zhu H Nelson PT Abisambra JF Identification of novel Tau interactions with endoplasmic reticulum proteins in Alzheimer's disease brain J Alzheimers Dis 2015 48 687 702 10.3233/JAD-150298 26402096 PMC4881838 · DOI
  25. [33]Merritt CR Ong GT Church SE Barker K Danaher P Geiss G Hoang M Jung J Liang Y McKay-Fleisch J Multiplex digital spatial profiling of proteins and RNA in fixed tissue Nat Biotechnol 2020 38 586 599 10.1038/s41587-020-0472-9 32393914 · DOI · Paper page
  26. [34]Mirsky IA Broh-Kahn RH The inactivation of insulin by tissue extracts; the distribution and properties of insulin inactivating extracts Arch Biochem 1949 20 1 9 18104389
  27. [35]Mirsky IA Simkin B Broh-Kahn RH The inactivation of insulin by tissue extracts. VI. The existence, distribution and properties of an insulinase inhibitor Arch Biochem 1950 28 415 423 14790783
  28. [36]Montine TJ Monsell SE Beach TG Bigio EH Bu Y Cairns NJ Frosch M Henriksen J Kofler J Kukull WA Multisite assessment of NIA-AA guidelines for the neuropathologic evaluation of Alzheimer's disease Alzheimers Dement 2016 12 164 169 10.1016/j.jalz.2015.07.492 26327235 PMC4562409 · DOI · Paper page
  29. [37]Musi N Valentine JM Sickora KR Baeuerle E Thompson CS Shen Q Orr ME Tau protein aggregation is associated with cellular senescence in the brain Aging Cell 2018 17 e12840 10.1111/acel.12840 30126037 PMC6260915 · DOI · Paper page
  30. [38]Myeku N Clelland CL Emrani S Kukushkin NV Yu WH Goldberg AL Duff KE Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling Nat Med 2016 22 46 53 10.1038/nm.4011 26692334 PMC4787271 · DOI · Paper page
  31. [39]Neddens J Temmel M Flunkert S Kerschbaumer B Hoeller C Loeffler T Niederkofler V Daum G Attems J Hutter-Paier B Phosphorylation of different tau sites during progression of Alzheimer's disease Acta Neuropathol Commun 2018 6 52 10.1186/s40478-018-0557-6 29958544 PMC6027763 · DOI · Paper page
  32. [40]O'Sullivan RJ Kubicek S Schreiber SL Karlseder J Reduced histone biosynthesis and chromatin changes arising from a damage signal at telomeres Nat Struct Mol Biol 2010 17 1218 1225 10.1038/nsmb.1897 20890289 PMC2951278 · DOI · Paper page
  33. [42]Paganini-Hill A Kawas CH Corrada MM Lifestyle factors and dementia in the oldest-old: the 90+ study Alzheimer Dis Assoc Disord 2016 30 21 26 10.1097/WAD.0000000000000087 25710250 PMC4561216 · DOI
  34. [44]Phongpreecha T, Gajera CR, Liu CC, Vijayaragavan K, Chang AL, Becker M, Fallahzadeh R, Fernandez R, Postupna N, Sherfield E, et al (2021) Single-synapse analyses of Alzheimer’s disease implicate pathologic tau, DJ1, CD47, and ApoE. bioRxiv. Doi:10.1101/2021.06.14.448240 PMC8673771 34910503 · DOI
  35. [45]Pine PS Munro SA Parsons JR McDaniel J Lucas AB Lozach J Myers TG Su Q Jacobs-Helber SM Salit M Evaluation of the External RNA Controls Consortium (ERCC) reference material using a modified Latin square design BMC Biotechnol 2016 16 54 10.1186/s12896-016-0281-x 27342544 PMC4921035 · DOI
  36. [46]Prokop S Miller KR Labra SR Pitkin RM Hoxha K Narasimhan S Changolkar L Rosenbloom A Lee VM Trojanowski JQ Impact of TREM2 risk variants on brain region-specific immune activation and plaque microenvironment in Alzheimer's disease patient brain samples Acta Neuropathol 2019 138 613 630 10.1007/s00401-019-02048-2 31350575 PMC6939638 · DOI · Paper page
  37. [47]Ramanan VK Lesnick TG Przybelski SA Heckman MG Knopman DS Graff-Radford J Lowe VJ Machulda MM Mielke MM Jack CR Jr.et al, Coping with brain amyloid: genetic heterogeneity and cognitive resilience to Alzheimer's pathophysiology Acta Neuropathol Commun 2021 9 48 10.1186/s40478-021-01154-1 33757599 PMC7986461 · DOI
  38. [48]Regalado-Reyes M Furcila D Hernandez F Avila J DeFelipe J Leon-Espinosa G Phospho-tau changes in the human CA1 during Alzheimer's disease progression J Alzheimers Dis 2019 69 277 288 10.3233/JAD-181263 30958368 PMC6598029 · DOI
  39. [49]Ritchie ME Phipson B Wu D Hu Y Law CW Shi W Smyth GK limma powers differential expression analyses for RNA-sequencing and microarray studies Nucleic Acids Res 2015 43 e47 10.1093/nar/gkv007 25605792 PMC4402510 · DOI · Paper page
  40. [50]Robinson JL Corrada MM Kovacs GG Dominique M Caswell C Xie SX Lee VM Kawas CH Trojanowski JQ Non-Alzheimer's contributions to dementia and cognitive resilience in The 90+ Study Acta Neuropathol 2018 136 377 388 10.1007/s00401-018-1872-5 29916037 PMC6534149 · DOI
  41. [51]Rogalski EJ Gefen T Shi J Samimi M Bigio E Weintraub S Geula C Mesulam MM Youthful memory capacity in old brains: anatomic and genetic clues from the Northwestern SuperAging Project J Cogn Neurosci 2013 25 29 36 10.1162/jocn_a_00300 23198888 PMC3541673 · DOI
  42. [52]Sekine S Youle RJ PINK1 import regulation; a fine system to convey mitochondrial stress to the cytosol BMC Biol 2018 16 2 10.1186/s12915-017-0470-7 29325568 PMC5795276 · DOI
  43. [53]Serrano-Pozo A Qian J Muzikansky A Monsell SE Montine TJ Frosch MP Betensky RA Hyman BT Thal amyloid stages do not significantly impact the correlation between neuropathological change and cognition in the Alzheimer disease continuum J Neuropathol Exp Neurol 2016 75 516 526 10.1093/jnen/nlw026 27105663 PMC6250207 · DOI
  44. [54]Singh A Allen D Fracassi A Tumurbaatar B Natarajan C Scaduto P Woltjer R Kayed R Limon A Krishnan B Functional integrity of synapses in the central nervous system of cognitively intact individuals with high Alzheimer's disease neuropathology is associated with absence of synaptic tau oligomers J Alzheimers Dis 2020 78 1661 1678 10.3233/JAD-200716 33185603 PMC7836055 · DOI · Paper page
  45. [55]Smyth GK Michaud J Scott HS Use of within-array replicate spots for assessing differential expression in microarray experiments Bioinformatics 2005 21 2067 2075 10.1093/bioinformatics/bti270 15657102 · DOI
  46. [56]Standeven KF Hess K Carter AM Rice GI Cordell PA Balmforth AJ Lu B Scott DJ Turner AJ Hooper NM Neprilysin, obesity and the metabolic syndrome Int J Obes (Lond) 2011 35 1031 1040 10.1038/ijo.2010.227 21042321 PMC3040694 · DOI
  47. [58]Tomlinson BE Blessed G Roth M Observations on the brains of non-demented old people J Neurol Sci 1968 7 331 356 10.1016/0022-510x(68)90154-8 5707082 · DOI · Paper page
  48. [59]Tundo GR Sbardella D Ciaccio C Bianculli A Orlandi A Desimio MG Arcuri G Coletta M Marini S Insulin-degrading enzyme (IDE): a novel heat shock-like protein J Biol Chem 2013 288 2281 2289 10.1074/jbc.M112.393108 23188819 PMC3554900 · DOI
  49. [60]Wahl DR Dresser J Wilder-Romans K Parsels JD Zhao SG Davis M Zhao L Kachman M Wernisch S Burant CF Glioblastoma therapy can be augmented by targeting IDH1-mediated NADPH biosynthesis Cancer Res 2017 77 960 970 10.1158/0008-5472.CAN-16-2008 27923831 PMC5726266 · DOI
  50. [61]Willard JR Barrow BM Zraika S Improved glycaemia in high-fat-fed neprilysin-deficient mice is associated with reduced DPP-4 activity and increased active GLP-1 levels Diabetologia 2017 60 701 708 10.1007/s00125-016-4172-4 27933334 PMC5342915 · DOI
  51. [62]Yarchoan M Toledo JB Lee EB Arvanitakis Z Kazi H Han LY Louneva N Lee VM Kim SF Trojanowski JQ Abnormal serine phosphorylation of insulin receptor substrate 1 is associated with tau pathology in Alzheimer's disease and tauopathies Acta Neuropathol 2014 128 679 689 10.1007/s00401-014-1328-5 25107476 PMC4304658 · DOI
  52. [63]Zolochevska O Bjorklund N Woltjer R Wiktorowicz JE Taglialatela G Postsynaptic proteome of non-demented individuals with Alzheimer's disease neuropathology J Alzheimers Dis 2018 65 659 682 10.3233/JAD-180179 30103319 PMC6130411 · DOI · Paper page
  53. [64]Zraika S Koh DS Barrow BM Lu B Kahn SE Andrikopoulos S Neprilysin deficiency protects against fat-induced insulin secretory dysfunction by maintaining calcium influx Diabetes 2013 62 1593 1601 10.2337/db11-1593 23328128 PMC3636612 · DOI

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Authors
Walker, J. M., Kazempour Dehkordi, S., Fracassi, A., Vanschoiack, A., Pavenko, A., Taglialatela, G., Woltjer, R., Richardson, T. E., Zare, H., & Orr, M. E.
Affiliations
  • The University of Texas at San Antonio Health Science Center (US)
  • The University of Texas Medical Branch at Galveston (US)
  • Nanostring Technologies (United States) (US)
  • Oregon Health & Science University (US)
  • W. G. (Bill) Hefner VA Medical Center (US)
Corresponding author
  • Walker, Jamie M.
  • Orr, Miranda E.
ORCID
Venue
Acta Neuropathologica Communications
Publisher
Springer Science and Business Media LLC
Published
2022-02-14
Volume
10
Issue
1
Pages
23-23
ISSN
2051-5960 (ISSN-L)
DOI
10.1186/s40478-022-01324-9
PMC
PMC8842950
OpenAlex
W4213207581
Cited by
59
References
10
Citations by year
2026: 1 · 2025: 11 · 2024: 33 · 2023: 10 · 2022: 4
FWCI
8.98
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Neuropathologica Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute on Aging (P30AG066546, R01AG068293, P30AG044271)
  • U.S. Department of Veterans Affairs (K2BX003804)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, cognitive resilience, hippocampus, neurofibrillary tangles, differentially expressed proteins, spatial proteomics, NanoString GeoMx, IDH1, oxidative stress, energy stress, PINK1, mitochondrial dysfunction, synaptophysin, synapse maintenance, neurofilament light chain, CD68, glial fibrillary acidic protein, APP, dementia
MeSH terms
Aged, Aged, 80 and over, Female, Hippocampus, Humans, Male, Middle Aged, Neurons, Synapses, Neurofibrillary Tangles, Proteomics, Disease Resistance

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