title: The misfolded pro-inflammatory protein S100A9 disrupts memory via neurochemical remodelling instigating an Alzheimer's disease-like cognitive deficit.
abstract: Memory deficits may develop from a variety of neuropathologies including Alzheimer's disease dementia. During neurodegenerative conditions there are contributory factors such as neuroinflammation and amyloidogenesis involved in memory impairment. In the present study, dual properties of S100A9 protein as a pro-inflammatory and amyloidogenic agent were explored in the passive avoidance memory task along with neurochemical assays in the prefrontal cortex and hippocampus of aged mice. S100A9 oligomers and fibrils were generated in vitro and verified by AFM, Thioflavin T and A11 antibody binding. Native S100A9 as well as S100A9 oligomers and fibrils or their combination were administered intranasally over 14 days followed by behavioral and neurochemical analysis. Both oligomers and fibrils evoked amnestic activity which correlated with disrupted prefrontal cortical and hippocampal dopaminergic neurochemistry. The oligomer-fibril combination produced similar but weaker neurochemistry to the fibrils administered alone but without passive avoidance amnesia. Native S100A9 did not modify memory task performance even though it generated a general and consistent decrease in monoamine levels (DA, 5-HT and NA) and increased metabolic marker ratios of DA and 5-HT turnover (DOPAC/DA, HVA/DA and 5-HIAA) in the prefrontal cortex. These results provide insight into a novel pathogenetic mechanism underlying amnesia in a fear-aggravated memory task based on amyloidogenesis of a pro-inflammatory factor leading to disrupted brain neurochemistry in the aged brain. The data further suggests that amyloid species of S100A9 create deleterious effects principally on the dopaminergic system and this novel finding might be potentially exploited during dementia management through a neuroprotective strategy.
authors.affiliation: Federal State Budgetary Scientific Institution, "P. K. Anokhin Research Institute of Normal Physiology", Moscow, Russia.
authors.forename: Marina A
authors.initials: MA
authors.lastname: Gruden
authors.affiliation: Federal State Budgetary Scientific Institution, "Research Institute of General Pathology and Pathophysiology", Moscow, Russia.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Davydova
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, SE-90187, Sweden.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Federal State Budgetary Scientific Institution, "V. V. Zakusov Research Institute of Pharmacology, Moscow, Russia.
authors.forename: Victor B
authors.initials: VB
authors.lastname: Narkevich
authors.affiliation: Federal State Budgetary Scientific Institution, "Research Institute of General Pathology and Pathophysiology", Moscow, Russia.
authors.forename: Valentina G
authors.initials: VG
authors.lastname: Fomina
authors.affiliation: Federal State Budgetary Scientific Institution, "V. V. Zakusov Research Institute of Pharmacology, Moscow, Russia.
authors.forename: Vladimir S
authors.initials: VS
authors.lastname: Kudrin
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, SE-90187, Sweden.
authors.forename: Ludmilla A
authors.initials: LA
authors.lastname: Morozova-Roche
authors.affiliation: Cardiff School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff CF10 3NB, UK. Electronic address: sewell@cardiff.ac.uk.
authors.forename: Robert D E
authors.initials: RD
authors.lastname: Sewell
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D040502:Calgranulin B / Q000737:chemistry* / Q000633:toxicity*; D003072:Cognition Disorders / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D006624:Hippocampus / Q000737:chemistry / Q000187:drug effects; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced*; D051379:Mice; D008810:Mice, Inbred C57BL; D018625:Microscopy, Atomic Force; D060172:Morpholinos / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000378:metabolism; D017397:Prefrontal Cortex / Q000737:chemistry / Q000187:drug effects; D066329:Protein Aggregates / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D013997:Time Factors
chemical_list: D040502:Calgranulin B; D060172:Morpholinos; D018377:Neurotransmitter Agents; D066329:Protein Aggregates; C576329:S100A9 protein, mouse
keywords: Alzheimer’s disease; Amyloid; Memory; Neuroinflammation; Neurotransmitters; Passive avoidance task; S100A9