title: Prostate stem cell antigen interacts with nicotinic acetylcholine receptors and is affected in Alzheimer's disease.
abstract: Alzheimer's disease (AD) is a neurodegenerative disorder involving impaired cholinergic neurotransmission and dysregulation of nicotinic acetylcholine receptors (nAChRs). Ly-6/neurotoxin (Lynx) proteins have been shown to modulate cognition and neural plasticity by binding to nAChR subtypes and modulating their function. Hence, changes in nAChR regulatory proteins such as Lynx proteins could underlie the dysregulation of nAChRs in AD. Using Western blotting, we detected bands corresponding to the Lynx proteins prostate stem cell antigen (PSCA) and Lypd6 in human cortex indicating that both proteins are present in the human brain. We further showed that PSCA forms stable complexes with the α4 nAChR subunit and decreases nicotine-induced extracellular-signal regulated kinase phosphorylation in PC12 cells. In addition, we analyzed protein levels of PSCA and Lypd6 in postmortem tissue of medial frontal gyrus from AD patients and found significantly increased PSCA levels (approximately 70%). In contrast, no changes in Lypd6 levels were detected. In concordance with our findings in AD patients, PSCA levels were increased in the frontal cortex of triple transgenic mice with an AD-like pathology harboring human transgenes that cause both age-dependent β-amyloidosis and tauopathy, whereas Tg2576 mice, which display β-amyloidosis only, had unchanged PSCA levels compared to wild-type animals. These findings identify PSCA as a nAChR-binding protein in the human brain that is affected in AD, suggesting that PSCA-nAChR interactions may be involved in the cognitive dysfunction observed in AD.
authors: Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors: Majbrit M
authors: MM
authors: Jensen
authors: Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors: Maria
authors: M
authors: Arvaniti
authors: Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors: Jens D
authors: JD
authors: Mikkelsen
authors: Department of Neurology, University of Leipzig, Leipzig, Germany.
authors: Dominik
authors: D
authors: Michalski
authors: Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; Epilepsy Clinic, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors: Lars H
authors: LH
authors: Pinborg
authors: Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany.
authors: Wolfgang
authors: W
authors: Härtig
authors: Neurobiology Research Unit, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. Electronic address: morten.s.thomsen@sund.ku.dk.
authors: Morten S
authors: MS
authors: Thomsen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000378:metabolism*; D003072:Cognition Disorders / Q000235:genetics* / Q000378:metabolism; D005625:Frontal Lobe / Q000378:metabolism; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000378:metabolism*; D016716:PC12 Cells; D011485:Protein Binding; D060066:Protein Interaction Maps / Q000502:physiology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000950:Antigens, Ly; D000951:Antigens, Neoplasm; D058851:GPI-Linked Proteins; C549815:LYPD6 protein, human; D009363:Neoplasm Proteins; C110843:PSCA protein, human; D011978:Receptors, Nicotinic
keywords: Alzheimer's disease; Frontal cortex; Lynx; Lypd6; Nicotinic acetylcholine receptor; PSCA