Glycoproteome-Wide Discovery of Cortical Glycoproteins That May Provide Cognitive Resilience in Older Adults.

Autor:	Buchman AS; From the Rush Alzheimer's Disease Center (A.S.B., L.Y., A.R.Z., S.O., S.N., D.A.B.); Department of Neurological Sciences (A.S.B., L.Y., S.O., D.A.B.), Rush University Medical Center, Chicago, IL; Center for Translational and Computational Neuroimmunology (H.-U.K.), Department of Neurology, Columbia University Medical Center, New York; Department of Pathology (Neuropathology) (S.N.), Rush University Medical Center, Chicago, IL; Katz Institute for Nanoscale Science and Technology Ben Gurion University (N.T.), Beer Sheva; The de Botton Institute for Protein Profiling (H.L., D.M., Y.L.), Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel; Department of Neurology (N.S.), Emory University School of Medicine; Department of Biochemistry (N.S.), Emory University, Atlanta, GA; and Department of Neurology (M.S.B.), Rutgers Robert Wood Johnson Medical School and Rutgers Brain Health Institute, NJ., Yu L; From the Rush Alzheimer's Disease Center (A.S.B., L.Y., A.R.Z., S.O., S.N., D.A.B.); Department of Neurological Sciences (A.S.B., L.Y., S.O., D.A.B.), Rush University Medical Center, Chicago, IL; Center for Translational and Computational Neuroimmunology (H.-U.K.), Department of Neurology, Columbia University Medical Center, New York; Department of Pathology (Neuropathology) (S.N.), Rush University Medical Center, Chicago, IL; Katz Institute for Nanoscale Science and Technology Ben Gurion University (N.T.), Beer Sheva; The de Botton Institute for Protein Profiling (H.L., D.M., Y.L.), Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel; Department of Neurology (N.S.), Emory University School of Medicine; Department of Biochemistry (N.S.), Emory University, Atlanta, GA; and Department of Neurology (M.S.B.), Rutgers Robert Wood Johnson Medical School and Rutgers Brain Health Institute, NJ., Klein HU; From the Rush Alzheimer's Disease Center (A.S.B., L.Y., A.R.Z., S.O., S.N., D.A.B.); Department of Neurological Sciences (A.S.B., L.Y., S.O., D.A.B.), Rush University Medical Center, Chicago, IL; Center for Translational and Computational Neuroimmunology (H.-U.K.), Department of Neurology, Columbia University Medical Center, New York; Department of Pathology (Neuropathology) (S.N.), Rush University Medical Center, Chicago, IL; Katz Institute for Nanoscale Science and Technology Ben Gurion University (N.T.), Beer Sheva; The de Botton Institute for Protein Profiling (H.L., D.M., Y.L.), Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel; Department of Neurology (N.S.), Emory University School of Medicine; Department of Biochemistry (N.S.), Emory University, Atlanta, GA; and Department of Neurology (M.S.B.), Rutgers Robert Wood Johnson Medical School and Rutgers Brain Health Institute, NJ., Zammit AR; From the Rush Alzheimer's Disease Center (A.S.B., L.Y., A.R.Z., S.O., S.N., D.A.B.); Department of Neurological Sciences (A.S.B., L.Y., S.O., D.A.B.), Rush University Medical Center, Chicago, IL; Center for Translational and Computational Neuroimmunology (H.-U.K.), Department of Neurology, Columbia University Medical Center, New York; Department of Pathology (Neuropathology) (S.N.), Rush University Medical Center, Chicago, IL; Katz Institute for Nanoscale Science and Technology Ben Gurion University (N.T.), Beer Sheva; The de Botton Institute for Protein Profiling (H.L., D.M., Y.L.), Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel; Department of Neurology (N.S.), Emory University School of Medicine; Department of Biochemistry (N.S.), Emory University, Atlanta, GA; and Department of Neurology (M.S.B.), Rutgers Robert Wood Johnson Medical School and Rutgers Brain Health Institute, NJ., Oveisgharan S; From the Rush Alzheimer's Disease Center (A.S.B., L.Y., A.R.Z., S.O., S.N., D.A.B.); Department of Neurological Sciences (A.S.B., L.Y., S.O., D.A.B.), Rush University Medical Center, Chicago, IL; Center for Translational and Computational Neuroimmunology (H.-U.K.), Department of Neurology, Columbia University Medical Center, New York; Department of Pathology (Neuropathology) (S.N.), Rush University Medical Center, Chicago, IL; Katz Institute for Nanoscale Science and Technology Ben Gurion University (N.T.), Beer Sheva; The de Botton Institute for Protein Profiling (H.L., D.M., Y.L.), Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel; Department of Neurology (N.S.), Emory University School of Medicine; Department of Biochemistry (N.S.), Emory University, Atlanta, GA; and Department of Neurology (M.S.B.), Rutgers Robert Wood Johnson Medical School and Rutgers Brain Health Institute, NJ., Nag S; From the Rush Alzheimer's Disease Center (A.S.B., L.Y., A.R.Z., S.O., S.N., D.A.B.); Department of Neurological Sciences (A.S.B., L.Y., S.O., D.A.B.), Rush University Medical Center, Chicago, IL; Center for Translational and Computational Neuroimmunology (H.-U.K.), Department of Neurology, Columbia University Medical Center, New York; Department of Pathology (Neuropathology) (S.N.), Rush University Medical Center, Chicago, IL; Katz Institute for Nanoscale Science and Technology Ben Gurion University (N.T.), Beer Sheva; The de Botton Institute for Protein Profiling (H.L., D.M., Y.L.), Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel; Department of Neurology (N.S.), Emory University School of Medicine; Department of Biochemistry (N.S.), Emory University, Atlanta, GA; and Department of Neurology (M.S.B.), Rutgers Robert Wood Johnson Medical School and Rutgers Brain Health Institute, NJ., Tickotsky N; From the Rush Alzheimer's Disease Center (A.S.B., L.Y., A.R.Z., S.O., S.N., D.A.B.); Department of Neurological Sciences (A.S.B., L.Y., S.O., D.A.B.), Rush University Medical Center, Chicago, IL; Center for Translational and Computational Neuroimmunology (H.-U.K.), Department of Neurology, Columbia University Medical Center, New York; Department of Pathology (Neuropathology) (S.N.), Rush University Medical Center, Chicago, IL; Katz Institute for Nanoscale Science and Technology Ben Gurion University (N.T.), Beer Sheva; The de Botton Institute for Protein Profiling (H.L., D.M., Y.L.), Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel; Department of Neurology (N.S.), Emory University School of Medicine; Department of Biochemistry (N.S.), Emory University, Atlanta, GA; and Department of Neurology (M.S.B.), Rutgers Robert Wood Johnson Medical School and Rutgers Brain Health Institute, NJ., Levy H; From the Rush Alzheimer's Disease Center (A.S.B., L.Y., A.R.Z., S.O., S.N., D.A.B.); Department of Neurological Sciences (A.S.B., L.Y., S.O., D.A.B.), Rush University Medical Center, Chicago, IL; Center for Translational and Computational Neuroimmunology (H.-U.K.), Department of Neurology, Columbia University Medical Center, New York; Department of Pathology (Neuropathology) (S.N.), Rush University Medical Center, Chicago, IL; Katz Institute for Nanoscale Science and Technology Ben Gurion University (N.T.), Beer Sheva; The de Botton Institute for Protein Profiling (H.L., D.M., Y.L.), Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel; Department of Neurology (N.S.), Emory University School of Medicine; Department of Biochemistry (N.S.), Emory University, Atlanta, GA; and Department of Neurology (M.S.B.), Rutgers Robert Wood Johnson Medical School and Rutgers Brain Health Institute, NJ., Seyfried N; From the Rush Alzheimer's Disease Center (A.S.B., L.Y., A.R.Z., S.O., S.N., D.A.B.); Department of Neurological Sciences (A.S.B., L.Y., S.O., D.A.B.), Rush University Medical Center, Chicago, IL; Center for Translational and Computational Neuroimmunology (H.-U.K.), Department of Neurology, Columbia University Medical Center, New York; Department of Pathology (Neuropathology) (S.N.), Rush University Medical Center, Chicago, IL; Katz Institute for Nanoscale Science and Technology Ben Gurion University (N.T.), Beer Sheva; The de Botton Institute for Protein Profiling (H.L., D.M., Y.L.), Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel; Department of Neurology (N.S.), Emory University School of Medicine; Department of Biochemistry (N.S.), Emory University, Atlanta, GA; and Department of Neurology (M.S.B.), Rutgers Robert Wood Johnson Medical School and Rutgers Brain Health Institute, NJ., Morgenstern D; From the Rush Alzheimer's Disease Center (A.S.B., L.Y., A.R.Z., S.O., S.N., D.A.B.); Department of Neurological Sciences (A.S.B., L.Y., S.O., D.A.B.), Rush University Medical Center, Chicago, IL; Center for Translational and Computational Neuroimmunology (H.-U.K.), Department of Neurology, Columbia University Medical Center, New York; Department of Pathology (Neuropathology) (S.N.), Rush University Medical Center, Chicago, IL; Katz Institute for Nanoscale Science and Technology Ben Gurion University (N.T.), Beer Sheva; The de Botton Institute for Protein Profiling (H.L., D.M., Y.L.), Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel; Department of Neurology (N.S.), Emory University School of Medicine; Department of Biochemistry (N.S.), Emory University, Atlanta, GA; and Department of Neurology (M.S.B.), Rutgers Robert Wood Johnson Medical School and Rutgers Brain Health Institute, NJ., Levin Y; From the Rush Alzheimer's Disease Center (A.S.B., L.Y., A.R.Z., S.O., S.N., D.A.B.); Department of Neurological Sciences (A.S.B., L.Y., S.O., D.A.B.), Rush University Medical Center, Chicago, IL; Center for Translational and Computational Neuroimmunology (H.-U.K.), Department of Neurology, Columbia University Medical Center, New York; Department of Pathology (Neuropathology) (S.N.), Rush University Medical Center, Chicago, IL; Katz Institute for Nanoscale Science and Technology Ben Gurion University (N.T.), Beer Sheva; The de Botton Institute for Protein Profiling (H.L., D.M., Y.L.), Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel; Department of Neurology (N.S.), Emory University School of Medicine; Department of Biochemistry (N.S.), Emory University, Atlanta, GA; and Department of Neurology (M.S.B.), Rutgers Robert Wood Johnson Medical School and Rutgers Brain Health Institute, NJ., Schnaider Beeri M; From the Rush Alzheimer's Disease Center (A.S.B., L.Y., A.R.Z., S.O., S.N., D.A.B.); Department of Neurological Sciences (A.S.B., L.Y., S.O., D.A.B.), Rush University Medical Center, Chicago, IL; Center for Translational and Computational Neuroimmunology (H.-U.K.), Department of Neurology, Columbia University Medical Center, New York; Department of Pathology (Neuropathology) (S.N.), Rush University Medical Center, Chicago, IL; Katz Institute for Nanoscale Science and Technology Ben Gurion University (N.T.), Beer Sheva; The de Botton Institute for Protein Profiling (H.L., D.M., Y.L.), Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel; Department of Neurology (N.S.), Emory University School of Medicine; Department of Biochemistry (N.S.), Emory University, Atlanta, GA; and Department of Neurology (M.S.B.), Rutgers Robert Wood Johnson Medical School and Rutgers Brain Health Institute, NJ., Bennett DA; From the Rush Alzheimer's Disease Center (A.S.B., L.Y., A.R.Z., S.O., S.N., D.A.B.); Department of Neurological Sciences (A.S.B., L.Y., S.O., D.A.B.), Rush University Medical Center, Chicago, IL; Center for Translational and Computational Neuroimmunology (H.-U.K.), Department of Neurology, Columbia University Medical Center, New York; Department of Pathology (Neuropathology) (S.N.), Rush University Medical Center, Chicago, IL; Katz Institute for Nanoscale Science and Technology Ben Gurion University (N.T.), Beer Sheva; The de Botton Institute for Protein Profiling (H.L., D.M., Y.L.), Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot, Israel; Department of Neurology (N.S.), Emory University School of Medicine; Department of Biochemistry (N.S.), Emory University, Atlanta, GA; and Department of Neurology (M.S.B.), Rutgers Robert Wood Johnson Medical School and Rutgers Brain Health Institute, NJ.
Jazyk:	angličtina
Zdroj:	Neurology [Neurology] 2024 Apr 09; Vol. 102 (7), pp. e209223. Date of Electronic Publication: 2024 Mar 19.
DOI:	10.1212/WNL.0000000000209223
Abstrakt:	Background and Objectives: Molecular omics studies have identified proteins related to cognitive resilience but unrelated to Alzheimer disease and Alzheimer disease-related dementia (AD/ADRD) pathologies. Posttranslational modifications of proteins with glycans can modify protein function. In this study, we identified glycopeptiforms associated with cognitive resilience. Methods: We studied brains from adults with annual cognitive testing with postmortem indices of 10 AD/ADRD pathologies and proteome-wide data from dorsal lateral prefrontal cortex (DLPFC). We quantified 11, 012 glycopeptiforms from DLPFC using liquid chromatography with tandem mass spectrometry. We used linear mixed-effects models to identify glycopeptiforms associated with cognitive decline correcting for multiple comparisons ( p < 5 × 10 -6 ). Then, we regressed out the effect of AD/ADRD pathologies to identify glycopeptiforms that may provide cognitive resilience. Results: We studied 366 brains, average age at death 89 years, and 70% female with no cognitive impairment = 152, mild cognitive impairment = 93, and AD = 121 cognitive status at death. In models adjusting for age, sex and education, 11 glycopeptiforms were associated with cognitive decline. In further modeling, 8 of these glycopeptiforms remained associated with cognitive decline after adjusting for AD/ADRD pathologies: NPTX2a (Est., 0.030, SE, 0.005, p = 1 × 10 -4 ); NPTX2b (Est.,0.019, SE, 0.005, p = 2 × 10 -4 ) NECTIN1(Est., 0.029, SE, 0.009, p = 9 × 10 -4 ), NPTX2c (Est., 0.015, SE, 0.004, p = 9 × 10 -4 ), HSPB1 (Est., -0.021, SE, 0.006, p = 2 × 10 -4 ), PLTP (Est., -0.027, SE, 0.009, p = 4.2 × 10 -3 ), NAGK (Est., -0.027, SE, 0.008, p = 1.4 × 10 -3 ), and VAT1 (Est., -0.020, SE, 0.006, p = 1.1 × 10 -3 ). Higher levels of 4 resilience glycopeptiforms derived through glycosylation were associated with slower decline and higher levels of 4 derived through glycation were related to faster decline. Together, these 8 glycopeptiforms accounted for an additional 6% of cognitive decline over the 33% accounted for the 10 brain pathologies and demographics. All 8 resilience glycopeptiforms remained associated with cognitive decline after adjustments for the expression level of their corresponding protein. Exploratory gene ontology suggested that molecular mechanisms of glycopeptiforms associated with cognitive decline may involve metabolic pathways including pyruvate and NADH pathways and highlighted the importance of molecular mechanisms involved in glucose metabolism. Discussion: Glycopeptiforms in aging brains may provide cognitive resilience. Targeting these glycopeptiforms may lead to therapies that maintain cognition through resilience.
Databáze:	MEDLINE
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