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.
Highlights
Nicotinic acetylcholine receptors are ligand-gated ion channels mediating fast synaptic transmission in muscle and autonomic ganglia [1]
The decrease of the Nicotinic acetylcholine receptors (nAChRs) density in the brain neurons is observed upon Alzheimer disease (AD) [6], which is characterized by accumulation of oligomeric β-amyloids (Aβ) in the brain, memory impairments and loss of cognitive functions [7]
We looked for accumulation of glial fibrillary acidic protein (GFAP), a recognized marker of astrocyte activation [28] in the brain sections of experimental mice
Summary
Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels mediating fast synaptic transmission in muscle and autonomic ganglia [1]. Α7 nAChR-Specific Antibodies Induce Inflammation in the Brain control the release of several neurotransmitters, including dopamine, and influence cognition and memory, as well as establishment of nicotine dependence in smokers. NAChRs composed of α7 subunits are involved in regulating pro-inflammatory cytokines release in macrophages, brain astrocytes and microglia [2,3,4,5]. The decrease of the nAChR density in the brain neurons is observed upon Alzheimer disease (AD) [6], which is characterized by accumulation of oligomeric β-amyloids (Aβ) in the brain, memory impairments and loss of cognitive functions [7]. The AD is accompanied by neuroinflammation, which often precedes the development of cognitive symptoms [8]. In spite of numerous investigations performed during the last decade the reason for the cholinergic deficit upon AD and its relation to neuroinflammation are still poorly understood
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