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α7 Nicotinic acetylcholine receptor-specific antibody induces inflammation and amyloid β42 accumulation in the mouse brain to impair memory.

Lykhmus O, Voytenko L, Koval L, Mykhalskiy S, Kholin V, Peschana K, Zouridakis M, Tzartos S, Komisarenko S, Skok M - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Palladin Institute of Biochemistry, Kyiv, Ukraine.

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.

No MeSH data available.


Related in: MedlinePlus

The GFAP-positive astrocytes (A) and the number of nucleated cells (B) in the brain sections of experimental mice studied by immunohistochemistry.A—Confocal microscopy images of the hippocampus CA1 (Hip), motor/somatosensory cortex (Crtx) or striatum (Str) of non-treated (Ctrl), α7(1–208)-immunized or LPS-injected mice stained with rabbit GFAP-specific antibody and developed with anti-rabbit Alexa 488 (green). Cell nuclei are stained with DAPI (blue). Bar corresponds to 50μm, actual for each fragment of the panel. B—The number of nucleated cells (DAPI-positive) in corresponding brain regions studied in all available sections (12 to 16 for each treatment for each region); *—p<0.05; **—p< 0.005.
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pone.0122706.g005: The GFAP-positive astrocytes (A) and the number of nucleated cells (B) in the brain sections of experimental mice studied by immunohistochemistry.A—Confocal microscopy images of the hippocampus CA1 (Hip), motor/somatosensory cortex (Crtx) or striatum (Str) of non-treated (Ctrl), α7(1–208)-immunized or LPS-injected mice stained with rabbit GFAP-specific antibody and developed with anti-rabbit Alexa 488 (green). Cell nuclei are stained with DAPI (blue). Bar corresponds to 50μm, actual for each fragment of the panel. B—The number of nucleated cells (DAPI-positive) in corresponding brain regions studied in all available sections (12 to 16 for each treatment for each region); *—p<0.05; **—p< 0.005.

Mentions: We looked for accumulation of glial fibrillary acidic protein (GFAP), a recognized marker of astrocyte activation [28] in the brain sections of experimental mice. As shown in Fig 5A, the GFAP-specific antibody stained small weakly activated astrocytes in the control cortex, hippocampus and striatum. Either immunizations with α7(1–208) or LPS injections resulted in intensive GFAP-specific staining and appearance of large GFAP-positive astrocytes in the motor/somatosensory cortex and striatum. The weakest astrocyte reaction was found in the hippocampus where α7 nAChRs were mostly decreased.


α7 Nicotinic acetylcholine receptor-specific antibody induces inflammation and amyloid β42 accumulation in the mouse brain to impair memory.

Lykhmus O, Voytenko L, Koval L, Mykhalskiy S, Kholin V, Peschana K, Zouridakis M, Tzartos S, Komisarenko S, Skok M - PLoS ONE (2015)

The GFAP-positive astrocytes (A) and the number of nucleated cells (B) in the brain sections of experimental mice studied by immunohistochemistry.A—Confocal microscopy images of the hippocampus CA1 (Hip), motor/somatosensory cortex (Crtx) or striatum (Str) of non-treated (Ctrl), α7(1–208)-immunized or LPS-injected mice stained with rabbit GFAP-specific antibody and developed with anti-rabbit Alexa 488 (green). Cell nuclei are stained with DAPI (blue). Bar corresponds to 50μm, actual for each fragment of the panel. B—The number of nucleated cells (DAPI-positive) in corresponding brain regions studied in all available sections (12 to 16 for each treatment for each region); *—p<0.05; **—p< 0.005.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4376778&req=5

pone.0122706.g005: The GFAP-positive astrocytes (A) and the number of nucleated cells (B) in the brain sections of experimental mice studied by immunohistochemistry.A—Confocal microscopy images of the hippocampus CA1 (Hip), motor/somatosensory cortex (Crtx) or striatum (Str) of non-treated (Ctrl), α7(1–208)-immunized or LPS-injected mice stained with rabbit GFAP-specific antibody and developed with anti-rabbit Alexa 488 (green). Cell nuclei are stained with DAPI (blue). Bar corresponds to 50μm, actual for each fragment of the panel. B—The number of nucleated cells (DAPI-positive) in corresponding brain regions studied in all available sections (12 to 16 for each treatment for each region); *—p<0.05; **—p< 0.005.
Mentions: We looked for accumulation of glial fibrillary acidic protein (GFAP), a recognized marker of astrocyte activation [28] in the brain sections of experimental mice. As shown in Fig 5A, the GFAP-specific antibody stained small weakly activated astrocytes in the control cortex, hippocampus and striatum. Either immunizations with α7(1–208) or LPS injections resulted in intensive GFAP-specific staining and appearance of large GFAP-positive astrocytes in the motor/somatosensory cortex and striatum. The weakest astrocyte reaction was found in the hippocampus where α7 nAChRs were mostly decreased.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Palladin Institute of Biochemistry, Kyiv, Ukraine.

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.

No MeSH data available.


Related in: MedlinePlus