title: α7 Nicotinic receptor agonist enhances cognition in aged 3xTg-AD mice with robust plaques and tangles.
abstract: Alzheimer disease (AD) is a progressive neurodegenerative disorder with associated memory loss, spatial disorientation, and other psychiatric problems. Cholinergic system dysfunction is an early and salient feature of AD, and enhancing cholinergic signaling with acetylcholinesterase inhibitors is currently the primary strategy for improving cognition. The beneficial effects of acetylcholinesterase inhibitors, however, are typically short-lived and accompanied by adverse effects. Recent evidence suggests that activating α7 nicotinic acetylcholine receptors (α7 nAChR) may facilitate the specific modulation of brain cholinergic signaling, leading to cognitive enhancement and possibly to amelioration of AD pathologic findings. In the present study, we determined the effect of long-term treatment with the selective α7 nAChR agonist A-582941 in aged 3xTg-AD mice with robust AD-like pathology, which is particularly significant not only because this is the only mouse model that co-develops amyloid plaques and neurofibrillary tangles but also because it enabled us to explore whether A-582941 is able to restore brain function after the severe damage associated with AD. Analysis of β-amyloid deposits, tau phosphorylation, and inflammatory cells revealed that, overall, pathologic findings were unchanged. Rather, α7 nAChR activation induced expression of c-Fos and brain-derived neurotrophic factor and phosphorylation of cyclic adenosine monophosphate response element binding and neurotrophic tyrosine receptor kinase type 2. More important, A-582941 completely restored cognition in aged 3xTg-AD mice to the level of that in age-matched nontransgenic mice. These novel findings indicate that activating α7 nAChR is a promising treatment for cognitive impairment in AD.
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California; Department of Neurobiology and Behavior, University of California, Irvine, California.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Medeiros
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California; Department of Neurobiology and Behavior, University of California, Irvine, California.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Castello
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California; Department of Neurobiology and Behavior, University of California, Irvine, California.
authors.forename: David
authors.initials: D
authors.lastname: Cheng
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California; Department of Neurobiology and Behavior, University of California, Irvine, California.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kitazawa
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California; Department of Neurobiology and Behavior, University of California, Irvine, California.
authors.forename: David
authors.initials: D
authors.lastname: Baglietto-Vargas
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California; Department of Neurobiology and Behavior, University of California, Irvine, California.
authors.forename: Kim N
authors.initials: KN
authors.lastname: Green
authors.affiliation: AbbVie Inc., North Chicago, Illinois.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Esbenshade
authors.affiliation: AbbVie Inc., North Chicago, Illinois.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Bitner
authors.affiliation: AbbVie Inc., North Chicago, Illinois.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Decker
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California; Department of Neurobiology and Behavior, University of California, Irvine, California. Electronic address: laferla@uci.edu.
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
mesh_terms: D000375:Aging / Q000473:pathology*; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D016229:Amyloid beta-Peptides; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003071:Cognition / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008297:Male; D008568:Memory / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D016874:Neurofibrillary Tangles / Q000187:drug effects / Q000473:pathology*; D018697:Nootropic Agents / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D011724:Pyridazines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists* / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: C524029:A-582941; D016229:Amyloid beta-Peptides; D018697:Nootropic Agents; D011724:Pyridazines; D011758:Pyrroles; D064569:alpha7 Nicotinic Acetylcholine Receptor; D016875:tau Proteins