Synaptic proteins associated with cognitive performance and neuropathology in older humans revealed by multiplexed fractionated proteomics

•Proteomics linked 123 proteins to AD pathology and cognitive performance•Proteins involved in glucose metabolism are altered in cognitive impairment•Frail individuals show pathway dysregulation in absence of AD pathology Alzheimer's disease (AD) is defined by the presence of abundant amyloid-β...

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Bibliographic Details
Published in:Neurobiology of aging Vol. 105; no. C; pp. 99 - 114
Main Authors: Carlyle, Becky C., Kandigian, Savannah E., Kreuzer, Johannes, Das, Sudeshna, Trombetta, Bianca A., Kuo, Yikai, Bennett, David A., Schneider, Julie A., Petyuk, Vladislav A., Kitchen, Robert R., Morris, Robert, Nairn, Angus C., Hyman, Bradley T., Haas, Wilhelm, Arnold, Steven E.
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01.09.2021
Elsevier
Subjects:
60 APPLIED LIFE SCIENCES
Aged
Aged, 80 and over
Aging
Aging - pathology
Aging - psychology
Alzheimer Disease - diagnosis
Alzheimer Disease - genetics
Alzheimer Disease - pathology
Alzheimer Disease - psychology
Alzheimer's disease
Angular gyrus
Chromatography, Liquid
Cognition
Cognition - physiology
Cognitive resilience
Female
Geriatrics & Gerontology
Glycolysis
Humans
Independent Living
Male
Mass Spectrometry
Neuroproteomics
Neurosciences & Neurology
Parietal Lobe - metabolism
Phosphorylation
Proteasome Endopeptidase Complex - metabolism
Proteomics - methods
Serotonin - metabolism
Synapses - metabolism
Synapses - pathology
FDG-PET
LC-MS3
Neuroproteomics
AD
Angular gyrus
SPS-MS3
GSEA
SPE
Cognition
ROSMAP
MS1, MS2, MS3
Aβ
MMSE
Cognitive resilience
Aging
TMT11
m/z
BA39
bRPLC
Alzheimer's disease
AGC
HPLC
ISSN:0197-4580, 1558-1497, 1558-1497
Online Access:Get full text
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Description
Summary:•Proteomics linked 123 proteins to AD pathology and cognitive performance•Proteins involved in glucose metabolism are altered in cognitive impairment•Frail individuals show pathway dysregulation in absence of AD pathology Alzheimer's disease (AD) is defined by the presence of abundant amyloid-β (Aβ) and tau neuropathology. While this neuropathology is necessary for AD diagnosis, it is not sufficient for causing cognitive impairment. Up to one third of community dwelling older adults harbor intermediate to high levels of AD neuropathology at death yet demonstrate no significant cognitive impairment. Conversely, there are individuals who exhibit dementia with no gross explanatory neuropathology. In prior studies, synapse loss correlated with cognitive impairment. To understand how synaptic composition changes in relation to neuropathology and cognition, multiplexed liquid chromatography mass-spectrometry was used to quantify enriched synaptic proteins from the parietal association cortex of 100 subjects with contrasting levels of AD pathology and cognitive performance. 123 unique proteins were significantly associated with diagnostic category. Functional analysis showed enrichment of serotonin release and oxidative phosphorylation categories in normal (cognitively unimpaired, low neuropathology) and "resilient" (unimpaired despite AD pathology) individuals. In contrast, frail individuals, (low pathology, impaired cognition) showed a metabolic shift towards glycolysis and increased presence of proteasome subunits.
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USDOE
AC05-76RL01830
Becky C. Carlyle: Conceptualization, Methodology, Formal analysis, Investigation, Data curation, Writing – original draft, Visualization. Savannah E. Kandigian: Investigation, Writing – review & editing. Johannes Kreuzer: Investigation. Sudeshna Das: Supervision. Bianca A. Trombetta: Validation, Writing – review & editing. Yikai Kuo: Formal analysis, Visualization, Data curation. David A. Bennett: Resources, Writing – review & editing, Conceptualization. Julie A. Schneider: Resources, Conceptualization. Vladislav A. Petyuk: Writing – review & editing, Supervision. Robert R. Kitchen: Formal analysis, Data curation, Supervision, Resources. Robert Morris: Data curation. Angus C. Nairn: Writing – review & editing, Supervision. Bradley T. Hyman: Writing – review & editing, Supervision, Resources. Wilhelm Haas: Resources, Data curation, Writing – review & editing, Funding acquisition. Steven E. Arnold: Conceptualization, Resources, Data curation, Writing – review & editing, Funding acquisition.
CRediT authorship contribution statement
ISSN:0197-4580
1558-1497
1558-1497
DOI:10.1016/j.neurobiolaging.2021.04.012