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Published on: December 18, 2016
Association of AK4 Protein From Stem Cell-Derived Neurons With Cognitive Reserve: An Autopsy Study
Lei Yu1, Yi-Chen Hsieh2, Richard V Pearse2
1From the Rush Alzheimer's Disease Center (L.Y., Y.W., J.A.S., A.S.B., D.A.B.) and Department of Neurological Sciences (L.Y., Y.W., J.A.S., A.S.B., D.A.B.), Rush University Medical Center, Chicago, IL; Ann Romney Center for Neurologic Diseases (Y.H., R.V.P., T.L.P.), Department of Neurology, Brigham and Women's Hospital, Boston, MA; Harvard Medical School (Y.H., R.V.P., T.L.P.), Boston, MA; Pacific Northwest National Laboratory (V.A.P.), Richland, WA; Department of Pathology (J.A.S.), Rush University Medical Center, Chicago, IL; Department of Biochemistry (N.T.S.), Emory University, Atlanta, GA; and Center for Translational and Computational Neuroimmunology (P.L.D.), Department of Neurology & Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York. lei_yu@rush.edu.
Background And Objectives:
Identifying protein targets that provide cognitive reserve is a strategy to prevent and treat Alzheimer disease and Alzheimer disease related dementias (AD/ADRD). Previous studies using bulk human brain tissue reported 12 proteins associated with cognitive reserve. This study examined whether the same proteins from induced neurons (iNs) are associated with cognitive reserve of their human donors.
Methods:
Induced pluripotent stem cell (iPSC) lines were generated from cryopreserved peripheral blood mononuclear cells of older adults who were autopsied as part of the Religious Orders Study or Rush Memory and Aging Project. Neurons were induced from iPSCs using a standard neurogenin2 protocol. Tandem mass tag proteomics analyses were conducted on iNs day 21. Cognitive reserve of their human donors was measured as person-specific slopes of cognitive change not accounted for by common neuropathologies.
Results:
The 53 human donors died at a mean age of 91 years, all were non-Latino White, and 36 (67.9%) were female. Eighteen were diagnosed with Alzheimer dementia proximate to death, and 34 had pathologic AD diagnosis at autopsy. Approximately 60% of the donors had above-average cognitive reserve such that their cognition declined slower than an average person with comparable burdens of neuropathologies. Eight of the 12 candidate proteins were quantified in iNs proteomics analyses. Higher adenylate kinase 4 (AK4) expression in iNs was associated with lower cognitive reserve, consistent with the previous report for brain AK4 expression.
Discussion:
By replicating cortical protein associations with cognitive reserve in human iNs, these data provide a valuable molecular readout for studying complex clinical phenotypes such as cognitive reserve in a dish.
