Antibodies against Extracellular Domains of alpha4 and alpha7 Subunits Alter the Levels of Nicotinic Receptors in the Mouse Brain and Affect Memory: Possible Relevance to Alzheimer's Pathology

作者：Lykhmus Olena; Koval Lyudmyla; Skok Maryna^*; Zouridakis Marios; Zisimopoulou Paraskevi; Tzartos Socrates; Tsetlin Victor; Granon Sylvie; Changeux Jean Pierre; Komisarenko Sergiy; Cloez Tayarani Isabelle

来源：Journal of Alzheimer's Disease, 2011, 24(4): 693-704.

DOI：10.3233/JAD-2011-101842

• Alzheimer's disease
• antibodies
• brain
• episodic memory
• ligand binding
• nicotinic acetylcholine receptor

Nicotinic acetylcholine receptors (nAChRs) of alpha 4 beta 2 and alpha 7 subtypes expressed in the brain neurons are involved in regulating memory and cognition. Their level is decreased upon several neurodegenerative disorders including Alzheimer's disease (AD), although the reasons for such a decrease are not completely understood. To test whether the nAChR-specific antibodies can affect the brain nAChRs and influence the behavior, we either immunized mice with recombinant extracellular domains of alpha 4 and alpha 7 subunits alpha 4(1-209) and alpha 7(1-208), or injected them with alpha 7(1-208)-specific antibodies. A decrease of alpha 4 beta 2- and alpha 7-nAChRs accompanied with an increase of alpha 4 beta 4-nAChRs in brain membranes of immunized mice was observed. Both alpha 4(1-209)- and alpha 7(1-208)-specific antibodies were detected in the brain membrane lysates of immunized mice. Antibody injection resulted in brain nAChR decrease only if mice were co-injected intraperitoneally with bacterial lipopolysaccharide. Brain sections of immunized mice were analyzed for the binding of [I-125]-alpha-bungarotoxin and [I-125]-epibatidine. A decrease in alpha-bungarotoxin binding in striatum (nucleus accumbens and caudate putamen) accompanied with an increase of epibatidine binding in the forebrain and caudate putamen was observed in mice immunized with either alpha 4 or alpha 7 nAChR domains compared to those immunized with BSA. Mice immunized with alpha 7(1-208) demonstrated significantly worse episodic memory measured in a novel object recognition task compared to non-immunized animals but did not differ from the controls in locomotor or anxiety-related tests. These results suggest that nAChR-specific antibodies are able to penetrate the brain upon inflammation with resulting decreases of brain nAChRs and worsening episodic memory.

• 出版日期2011