title: Neuroinflammation impairs adaptive structural plasticity of dendritic spines in a preclinical model of Alzheimer's disease.
abstract: To successfully treat Alzheimer's disease (AD), pathophysiological events in preclinical stages need to be identified. Preclinical AD refers to the stages that exhibit amyloid deposition in the brain but have normal cognitive function, which are replicated in young adult APPswe/PS1deltaE9 (deltaE9) mice. By long-term in vivo two-photon microscopy, we demonstrate impaired adaptive spine plasticity in these transgenic mice illustrated by their failure to increase dendritic spine density and form novel neural connections when housed in enriched environment (EE). Decrease of amyloid plaques by reducing BACE1 activity restores the gain of spine density upon EE in deltaE9 mice, but not the remodeling of neural networks. On the other hand, anti-inflammatory treatment with pioglitazone or interleukin 1 receptor antagonist in deltaE9 mice successfully rescues the impairments in increasing spine density and remodeling of neural networks during EE. Our data suggest that neuroinflammation disrupts experience-dependent structural plasticity of dendritic spines in preclinical stages of AD.
authors.affiliation: Department for Translational Brain Research, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, Munich, Germany.|Munich Cluster of Systems Neurology (SyNergy), Ludwig-Maximilians-University Munich, Schillerstraße 44, 80336, Munich, Germany.|Graduate School of Systemic Neuroscience, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Chengyu
authors.initials: C
authors.lastname: Zou
authors.affiliation: Department for Translational Brain Research, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Ohli
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schüller
authors.affiliation: Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Mario M
authors.initials: MM
authors.lastname: Dorostkar
authors.affiliation: Department for Translational Brain Research, German Center for Neurodegenerative Diseases (DZNE), Munich, Germany. jochen.herms@med.uni-muenchen.de.|Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, Munich, Germany. jochen.herms@med.uni-muenchen.de.|Munich Cluster of Systems Neurology (SyNergy), Ludwig-Maximilians-University Munich, Schillerstraße 44, 80336, Munich, Germany. jochen.herms@med.uni-muenchen.de.
authors.forename: Jochen
authors.initials: J
authors.lastname: Herms
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism; D049229:Dendritic Spines / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015213:Neuroimmunomodulation / Q000187:drug effects / Q000276:immunology*; D009473:Neuronal Plasticity / Q000187:drug effects / Q000276:immunology*; D000077205:Pioglitazone; D017966:Pyramidal Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D053573:Receptors, Interleukin-1 Type I / Q000037:antagonists & inhibitors / Q000378:metabolism; D013003:Somatosensory Cortex / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D000893:Anti-Inflammatory Agents; D053573:Receptors, Interleukin-1 Type I; D045162:Thiazolidinediones; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D000077205:Pioglitazone
keywords: APPswe/PS1deltaE9 mice; Dendritic spines; Neuroinflammation; Preclinical AD; Structural plasticity