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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 level of Aβ40 and Aβ42 in the brain sections of experimental mice studied by immunohistochemistry.Confocal microscopy images of the hippocampus CA1 or motor/somatosensory cortex of non-treated (Ctrl), α7(1–208)-immunized or LPS-injected mice stained with biotinylated Aβ40- or Aβ42-specific antibodies and developed with Extravidin-Cy3 (red) and with α7-specific antibody developed with anti-rabbit Alexa 488 (green). Bar corresponds to 50μm, actual for each fragment of the panel.
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pone.0122706.g004: The level of Aβ40 and Aβ42 in the brain sections of experimental mice studied by immunohistochemistry.Confocal microscopy images of the hippocampus CA1 or motor/somatosensory cortex of non-treated (Ctrl), α7(1–208)-immunized or LPS-injected mice stained with biotinylated Aβ40- or Aβ42-specific antibodies and developed with Extravidin-Cy3 (red) and with α7-specific antibody developed with anti-rabbit Alexa 488 (green). Bar corresponds to 50μm, actual for each fragment of the panel.

Mentions: Aβ accumulations can also be identified immunohistochemically [27]. We observed the Aβ42 as local granules in pyramidal cell layer of the hippocampus and in the motor/somatosensory cortex of non-treated animals. In α7-immunized and LPS-injected mice the staining spread out and surrounded the cells in a diffuse way merging with that for α7 (Fig 4). The Aβ40 isoform was found out of pyramidal layer in the hippocampus, and its quantity increased after either α7 immunizations or LPS injections. In contrast, in the cortex, Aβ40-specific staining was initially merged with α7-specific one and obviously decreased after immunization, correlating with the data of Sandwich-ELISA (Fig 3A). No definite changes of Aβ were found in the striatum (data not shown).


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 level of Aβ40 and Aβ42 in the brain sections of experimental mice studied by immunohistochemistry.Confocal microscopy images of the hippocampus CA1 or motor/somatosensory cortex of non-treated (Ctrl), α7(1–208)-immunized or LPS-injected mice stained with biotinylated Aβ40- or Aβ42-specific antibodies and developed with Extravidin-Cy3 (red) and with α7-specific antibody developed with anti-rabbit Alexa 488 (green). Bar corresponds to 50μm, actual for each fragment of the panel.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0122706.g004: The level of Aβ40 and Aβ42 in the brain sections of experimental mice studied by immunohistochemistry.Confocal microscopy images of the hippocampus CA1 or motor/somatosensory cortex of non-treated (Ctrl), α7(1–208)-immunized or LPS-injected mice stained with biotinylated Aβ40- or Aβ42-specific antibodies and developed with Extravidin-Cy3 (red) and with α7-specific antibody developed with anti-rabbit Alexa 488 (green). Bar corresponds to 50μm, actual for each fragment of the panel.
Mentions: Aβ accumulations can also be identified immunohistochemically [27]. We observed the Aβ42 as local granules in pyramidal cell layer of the hippocampus and in the motor/somatosensory cortex of non-treated animals. In α7-immunized and LPS-injected mice the staining spread out and surrounded the cells in a diffuse way merging with that for α7 (Fig 4). The Aβ40 isoform was found out of pyramidal layer in the hippocampus, and its quantity increased after either α7 immunizations or LPS injections. In contrast, in the cortex, Aβ40-specific staining was initially merged with α7-specific one and obviously decreased after immunization, correlating with the data of Sandwich-ELISA (Fig 3A). No definite changes of Aβ were found in the striatum (data not shown).

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