title: α7 Nicotinic acetylcholine receptor-specific antibody induces inflammation and amyloid β42 accumulation in the mouse brain to impair memory.
abstract: Nicotinic acetylcholine receptors (nAChRs) expressed in the brain are involved in regulating cognitive functions, as well as inflammatory reactions. Their density is decreased upon Alzheimer disease accompanied by accumulation of β-amyloid (Aβ42), memory deficit and neuroinflammation. Previously we found that α7 nAChR-specific antibody induced pro-inflammatory interleukin-6 production in U373 glioblastoma cells and that such antibodies were present in the blood of humans. We raised a hypothesis that α7 nAChR-specific antibody can cause neuroinflammation when penetrating the brain. To test this, C57Bl/6 mice were either immunized with extracellular domain of α7 nAChR subunit α7(1-208) or injected with bacterial lipopolysaccharide (LPS) for 5 months. We studied their behavior and the presence of α3, α4, α7, β2 and β4 nAChR subunits, Aβ40 and Aβ42 and activated astrocytes in the brain by sandwich ELISA and confocal microscopy. It was found that either LPS injections or immunizations with α7(1-208) resulted in region-specific decrease of α7 and α4β2 and increase of α3β4 nAChRs, accumulation of Aβ42 and activated astrocytes in the brain of mice and worsening of their episodic memory. Intravenously transferred α7 nAChR-specific-antibodies penetrated the brain parenchyma of mice pre-injected with LPS. Our data demonstrate that (1) neuroinflammation is sufficient to provoke the decrease of α7 and α4β2 nAChRs, Aβ42 accumulation and memory impairment in mice and (2) α7(1-208) nAChR-specific antibodies can cause inflammation within the brain resulting in the symptoms typical for Alzheimer disease.
authors: Palladin Institute of Biochemistry, Kyiv, Ukraine.
authors: Olena
authors: O
authors: Lykhmus
authors: Bogomoletz Institute of Physiology, Kyiv, Ukraine.
authors: Larysa
authors: L
authors: Voytenko
authors: Palladin Institute of Biochemistry, Kyiv, Ukraine.
authors: Lyudmyla
authors: L
authors: Koval
authors: Chebotaryov Institute of Gerontology, Kyiv, Ukraine.
authors: Sergiy
authors: S
authors: Mykhalskiy
authors: Chebotaryov Institute of Gerontology, Kyiv, Ukraine.
authors: Victor
authors: V
authors: Kholin
authors: Chebotaryov Institute of Gerontology, Kyiv, Ukraine.
authors: Kateryna
authors: K
authors: Peschana
authors: Hellenic Pasteur Institute, Athens, Greece.
authors: Marios
authors: M
authors: Zouridakis
authors: Hellenic Pasteur Institute, Athens, Greece.
authors: Socrates
authors: S
authors: Tzartos
authors: Palladin Institute of Biochemistry, Kyiv, Ukraine.
authors: Sergiy
authors: S
authors: Komisarenko
authors: Palladin Institute of Biochemistry, Kyiv, Ukraine.
authors: Maryna
authors: M
authors: Skok
mesh_terms: D000544:Alzheimer Disease / Q000276:immunology* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000276:immunology / Q000378:metabolism; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D001921:Brain / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D015850:Interleukin-6 / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity; D008569:Memory Disorders / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000276:immunology; D011978:Receptors, Nicotinic / Q000008:administration & dosage / Q000276:immunology*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D016229:Amyloid beta-Peptides; D000906:Antibodies; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403530:nicotinic receptor alpha3beta4; C403531:nicotinic receptor alpha4beta2