title: Hippocampal extracellular matrix levels and stochasticity in synaptic protein expression increase with age and are associated with age-dependent cognitive decline.
abstract: Age-related cognitive decline is a serious health concern in our aging society. Decreased cognitive function observed during healthy brain aging is most likely caused by changes in brain connectivity and synaptic dysfunction in particular brain regions. Here we show that aged C57BL/6J wild-type mice have hippocampus-dependent spatial memory impairments. To identify the molecular mechanisms that are relevant to these memory deficits, we investigated the temporal profile of mouse hippocampal synaptic proteome changes at 20, 40, 50, 60, 70, 80, 90, and 100 weeks of age. Extracellular matrix proteins were the only group of proteins that showed robust and progressive up-regulation over time. This was confirmed by immunoblotting and histochemical analysis, which indicated that the increased levels of hippocampal extracellular matrix might limit synaptic plasticity as a potential cause of age-related cognitive decline. In addition, we observed that stochasticity in synaptic protein expression increased with age, in particular for proteins that were previously linked with various neurodegenerative diseases, whereas low variance in expression was observed for proteins that play a basal role in neuronal function and synaptic neurotransmission. Together, our findings show that both specific changes and increased variance in synaptic protein expression are associated with aging and may underlie reduced synaptic plasticity and impaired cognitive performance in old age.
authors.affiliation: From the ‡Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, De Boelelaan 1085, 1081HV Amsterdam, The Netherlands;
authors.forename: Marlene J
authors.initials: MJ
authors.lastname: Végh
authors.affiliation: §Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 Avenue des Hauts Fourneaux, L-4362 Esch-sur-Alzette, Luxembourg;
authors.forename: Antonio
authors.initials: A
authors.lastname: Rausell
authors.affiliation: From the ‡Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, De Boelelaan 1085, 1081HV Amsterdam, The Netherlands; ¶Sylics (Synaptologics BV), PO Box 71033, 1008BA Amsterdam, The Netherlands.
authors.forename: Maarten
authors.initials: M
authors.lastname: Loos
authors.affiliation: From the ‡Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, De Boelelaan 1085, 1081HV Amsterdam, The Netherlands;
authors.forename: Céline M
authors.initials: CM
authors.lastname: Heldring
authors.affiliation: §Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 Avenue des Hauts Fourneaux, L-4362 Esch-sur-Alzette, Luxembourg;
authors.forename: Wiktor
authors.initials: W
authors.lastname: Jurkowski
authors.affiliation: From the ‡Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, De Boelelaan 1085, 1081HV Amsterdam, The Netherlands;
authors.forename: Pim
authors.initials: P
authors.lastname: van Nierop
authors.affiliation: From the ‡Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, De Boelelaan 1085, 1081HV Amsterdam, The Netherlands;
authors.forename: Iryna
authors.initials: I
authors.lastname: Paliukhovich
authors.affiliation: From the ‡Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, De Boelelaan 1085, 1081HV Amsterdam, The Netherlands;
authors.forename: Ka Wan
authors.initials: KW
authors.lastname: Li
authors.affiliation: §Luxembourg Centre for Systems Biomedicine, University of Luxembourg, 7 Avenue des Hauts Fourneaux, L-4362 Esch-sur-Alzette, Luxembourg;
authors.forename: Antonio
authors.initials: A
authors.lastname: del Sol
authors.affiliation: From the ‡Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, De Boelelaan 1085, 1081HV Amsterdam, The Netherlands;
authors.forename: August B
authors.initials: AB
authors.lastname: Smit
authors.affiliation: From the ‡Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, De Boelelaan 1085, 1081HV Amsterdam, The Netherlands;
authors.forename: Sabine
authors.initials: S
authors.lastname: Spijker
authors.affiliation: From the ‡Center for Neurogenomics and Cognitive Research, Neuroscience Campus Amsterdam, VU University, De Boelelaan 1085, 1081HV Amsterdam, The Netherlands; ronald.van.kesteren@vu.nl.
authors.forename: Ronald E
authors.initials: RE
authors.lastname: van Kesteren
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D003071:Cognition / Q000502:physiology; D060825:Cognitive Dysfunction / Q000503:physiopathology*; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000502:physiology*; D008297:Male; D018782:Maze Learning / Q000502:physiology*; D008569:Memory Disorders / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019636:Neurodegenerative Diseases / Q000378:metabolism / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000502:physiology; D020543:Proteome / Q000032:analysis; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013269:Stochastic Processes; D053719:Tandem Mass Spectrometry
chemical_list: D016326:Extracellular Matrix Proteins; D020543:Proteome