2. Academic Validation
  3. Stem cell-derived neurons reflect features of protein networks, neuropathology, and cognitive outcome of their aged human donors

Stem cell-derived neurons reflect features of protein networks, neuropathology, and cognitive outcome of their aged human donors

  • Neuron. 2021 Nov 3;109(21):3402-3420.e9. doi: 10.1016/j.neuron.2021.08.003.
Valentina N Lagomarsino 1,  Richard V Pearse 2nd 1,  Lei Liu 1,  Yi-Chen Hsieh 1,  Marty A Fernandez 1,  Elizabeth A Vinton 1,  Daniel Paull 2,  Daniel Felsky 3,  Shinya Tasaki 4,  Chris Gaiteri 4,  Badri Vardarajan 5,  Hyo Lee 1,  Christina R Muratore 1,  Courtney R Benoit 1,  Vicky Chou 1,  Seeley B Fancher 1,  Amy He 1,  Julie P Merchant 1,  Duc M Duong 6,  Hector Martinez 2,  Monica Zhou 2,  Fatmata Bah 1,  Maria A Vicent 1,  Jonathan M S Stricker 1,  Jishu Xu 4,  Eric B Dammer 6,  Allan I Levey 7,  Lori B Chibnik 8,  Vilas Menon 5,  Nicholas T Seyfried 9,  Philip L De Jager 5,  Scott Noggle 2,  Dennis J Selkoe 1,  David A Bennett 4,  Tracy L Young-Pearse 10
Affiliations

Affiliations

  • 1 Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • 2 New York Stem Cell Foundation Research Institute, New York, NY, USA.
  • 3 Krembil Centre for Neuroinformatics, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Psychiatry and Institute of Medical Science, University of Toronto, Toronto, ON, Canada.
  • 4 Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
  • 5 Center for Translational and Computational Neuroimmunology, Department of Neurology and the Taub Institute for the Study of Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA.
  • 6 Department of Biochemistry, Emory School of Medicine, Atlanta, GA, USA.
  • 7 Department of Neurology, Emory School of Medicine, Atlanta, GA, USA.
  • 8 Department of Neurology, Massachusetts General Hospital, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
  • 9 Department of Biochemistry, Emory School of Medicine, Atlanta, GA, USA; Department of Neurology, Emory School of Medicine, Atlanta, GA, USA.
  • 10 Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. Electronic address: [email protected].
PMID: 34473944 DOI: 10.1016/j.neuron.2021.08.003
Abstract

We have generated a controlled and manipulable resource that captures genetic risk for Alzheimer's disease: iPSC lines from 53 individuals coupled with RNA and proteomic profiling of both iPSC-derived neurons and brain tissue of the same individuals. Data collected for each person include genome sequencing, longitudinal cognitive scores, and quantitative neuropathology. The utility of this resource is exemplified here by analyses of neurons derived from these lines, revealing significant associations between specific Aβ and tau species and the levels of plaque and tangle deposition in the brain and, more importantly, with the trajectory of cognitive decline. Proteins and networks are identified that are associated with AD phenotypes in iPSC neurons, and relevant associations are validated in brain. The data presented establish this iPSC collection as a resource for investigating person-specific processes in the brain that can aid in identifying and validating molecular pathways underlying AD.

Keywords

Alzheimer’s; Aβ; LOAD; MAPT; PP1; PRS; genetics; iPSC; neuron; tau.

Figures
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