title: Changes of several brain receptor complexes in the cerebral cortex of patients with Alzheimer disease: probable new potential pharmaceutical targets.
abstract: Although Alzheimer disease (AD) has been linked to defects in major brain receptors, studies thus far have been limited to the determination of receptor subunits or specific ligand binding studies. However, the availability of current technology enables the determination and quantification of brain receptor complexes. Thus, we examined levels of native receptor complexes in the brains of patients with AD. Cortical tissue was obtained from control subjects (n = 12 females and 12 males) and patients with AD (n = 12 females and 12 males) within a 3-h postmortem time period. The tissues were kept frozen until further biochemical analyses. Membrane proteins were extracted and subsequently enriched by ultracentrifugation using a sucrose gradient. Membrane proteins were then electrophoresed onto native gels and immunoblotted using antibodies against individual brain receptors. We found that the levels were comparable for complexes containing GluR2, GluR3 and GluR4 as well as 5-HT1A. Moreover, the levels of complexes containing muscarinic AChR M1, NR1 and GluR1 were significantly increased in male patients with AD. Nicotinic AChRs 4 and 7 as well as dopaminergic receptors D1 and D2 were also increased in males and females with AD. These findings reveal a pattern of altered receptor complex levels that may contribute to the deterioration of the concerted activity of these receptors and thus result in cognitive deficits observed in patients with AD. It should be emphasised that receptor complexes function as working units rather than individual subunits. Thus, the receptor deficits identified may be relevant for the design of experimental therapies. Therefore, specific pharmacological modulation of these receptors is within the pharmaceutical repertoire.
authors.affiliation: Department of Pediatrics, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
authors.forename: Soheil Keihan
authors.initials: SK
authors.lastname: Falsafi
authors.forename: Steffen
authors.initials: S
authors.lastname: Roßner
authors.forename: Maryam
authors.initials: M
authors.lastname: Ghafari
authors.forename: Michael
authors.initials: M
authors.lastname: Groessl
authors.forename: Markus
authors.initials: M
authors.lastname: Morawski
authors.forename: Christopher
authors.initials: C
authors.lastname: Gerner
authors.forename: Gert
authors.initials: G
authors.lastname: Lubec
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012727:Sex Characteristics
chemical_list: D011956:Receptors, Cell Surface