title: Subacute ibuprofen treatment rescues the synaptic and cognitive deficits in advanced-aged mice.
abstract: Aging is accompanied by increased neuroinflammation, synaptic dysfunction, and cognitive deficits both in rodents and humans, yet the onset and progression of these deficits throughout the life span remain unknown. These aging-related deficits affect the quality of life and present challenges to our aging society. Here, we defined age-dependent and progressive impairments of synaptic and cognitive functions and showed that reducing astrocyte-related neuroinflammation through anti-inflammatory drug treatment in aged mice reverses these events. By comparing young (3 months), middle-aged (18 months), aged (24 months), and advanced-aged wild-type mice (30 months), we found that the levels of an astrocytic marker, glial fibrillary acidic protein, progressively increased after 18 months of age, which preceded the decreases of the synaptic marker PSD-95. Hippocampal long-term potentiation was also suppressed in an age-dependent manner, where significant deficits were observed after 24 months of age. Fear conditioning tests demonstrated that associative memory in the context and cued conditions was decreased starting at the ages of 18 and 30 months, respectively. When the mice were tested on hidden platform water maze, spatial learning memory was significantly impaired after 24 months of age. Importantly, subacute treatment with the anti-inflammatory drug ibuprofen suppressed astrocyte activation and restored synaptic plasticity and memory function in advanced-aged mice. These results support the critical contribution of aging-related inflammatory responses to hippocampal-dependent cognitive function and synaptic plasticity, in particular during advanced aging. Our findings provide strong evidence that suppression of neuroinflammation could be a promising treatment strategy to preserve cognition during aging.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Justin T
authors.initials: JT
authors.lastname: Rogers
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Liu
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Na
authors.initials: N
authors.lastname: Zhao
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Travis
authors.initials: T
authors.lastname: Putzke
authors.affiliation: Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, China.
authors.forename: Longyu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Shinohara
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Fryer
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kanekiyo
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, College of Medicine, Xiamen University, Xiamen, China; Neurobiology of Disease Graduate Program, Mayo Clinic College of Medicine, Jacksonville, FL, USA. Electronic address: bu.guojun@mayo.edu.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use*; D001253:Astrocytes / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D003071:Cognition / Q000187:drug effects* / Q000502:physiology*; D000066492:Cognitive Aging / Q000502:physiology* / Q000523:psychology*; D060825:Cognitive Dysfunction / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology; D004195:Disease Models, Animal; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006624:Hippocampus / Q000503:physiopathology; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology* / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D017774:Long-Term Potentiation; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D009473:Neuronal Plasticity / Q000187:drug effects*; D065853:Spatial Learning / Q000187:drug effects / Q000502:physiology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D005904:Glial Fibrillary Acidic Protein; D007052:Ibuprofen
keywords: Aging; Anti-inflammatory responses; Cognitive function; Ibuprofen; Synaptic plasticity