M1 receptors play a central role in modulating AD-like pathology in transgenic mice

Neuron
Antonella CaccamoFrank M LaFerla

Abstract

We investigated the therapeutic efficacy of the selective M1 muscarinic agonist AF267B in the 3xTg-AD model of Alzheimer disease. AF267B administration rescued the cognitive deficits in a spatial task but not contextual fear conditioning. The effect of AF267B on cognition predicted the neuropathological outcome, as both the Abeta and tau pathologies were reduced in the hippocampus and cortex, but not in the amygdala. The mechanism underlying the effect on the Abeta pathology was caused by the selective activation of ADAM17, thereby shifting APP processing toward the nonamyloidogenic pathway, whereas the reduction in tau pathology is mediated by decreased GSK3beta activity. We further demonstrate that administration of dicyclomine, an M1 antagonist, exacerbates the Abeta and tau pathologies. In conclusion, AF267B represents a peripherally administered low molecular weight compound to attenuate the major hallmarks of AD and to reverse deficits in cognition. Therefore, selective M1 agonists may be efficacious for the treatment of AD.

References

Nov 1, 1992·Proceedings of the National Academy of Sciences of the United States of America·J D BuxbaumP Greengard
Jan 1, 1992·Journal of Neuroscience Research·A NordbergB Winblad
Nov 1, 1990·Journal of Neuroscience Research·K SugayaV A Chiappinelli
Apr 16, 1986·Brain Research·P J WhitehouseK J Kellar
Oct 1, 1993·Proceedings of the National Academy of Sciences of the United States of America·A I LeveyB J Ciliax
Apr 1, 1997·Pharmacology, Biochemistry, and Behavior·J L Muir
Mar 31, 1999·Proceedings of the National Academy of Sciences of the United States of America·S LammichF Fahrenholz
Jun 22, 2000·Molecular and Cellular Neurosciences·I KärkkäinenA P Huovila
Jun 8, 2001·Life Sciences·E C HulmeJ Saldanha
Jul 5, 2001·Proceedings of the National Academy of Sciences of the United States of America·R B DeMattosD M Holtzman
Aug 2, 2001·Trends in Pharmacological Sciences·R M EglenN Watson
Mar 20, 2002·Current Neurology and Neuroscience Reports·C JanusD Westaway
Aug 10, 2002·Current Neurology and Neuroscience Reports·Joanna L JankowskyDavid R Borchelt
Nov 5, 2003·Journal of Neuroscience Research·Tobias M J AllinsonNigel M Hooper
Feb 3, 2004·Current Pharmaceutical Design·Bernd Ibach, Ekkehard Haen
Feb 12, 2005·Proceedings of the National Academy of Sciences of the United States of America·Salvatore OddoFrank M LaFerla
Sep 30, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Masashi KitazawaFrank M LaFerla

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Citations

Nov 20, 2012·Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology·Nibaldo C InestrosaMarco Fuenzalida
Jun 27, 2008·Molecular Neurobiology·Donna M Barten, Charles F Albright
Aug 1, 2008·Neuroscience Bulletin·Yi-Hui CuiXiao-Hua Cao
Jul 16, 2008·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Abraham Fisher
Jan 21, 2012·Expert Reviews in Molecular Medicine·Aarti N Patel, Jack H Jhamandas
Dec 8, 2006·Nature Medicine·Michael S Wolfe
Sep 23, 2011·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Alena V SavonenkoDon L Price
Oct 1, 2011·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Yoland SmithMahlon R DeLong
Sep 1, 2007·Nature Reviews. Drug Discovery·Jürgen WessDinesh Gautam
Feb 9, 2010·Nature Reviews. Neurology·Bart De StrooperTodd Golde
Oct 12, 2007·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Marina YamadaMasaaki Matsuoka
Jun 29, 2010·Molecular BioSystems·Gregory J DigbyP Jeffrey Conn
Jan 29, 2010·The New England Journal of Medicine·Henry W Querfurth, Frank M LaFerla
Jan 19, 2010·Proceedings of the National Academy of Sciences of the United States of America·Ariel KamslerSusumu Tonegawa
May 5, 2010·Proceedings of the National Academy of Sciences of the United States of America·Benoit PoulinAndrew B Tobin
Dec 29, 2010·Proceedings of the National Academy of Sciences of the United States of America·Yunmin DingUn Jung Kang
Aug 30, 2011·Proceedings of the National Academy of Sciences of the United States of America·John R CirritoYvette I Sheline
Oct 24, 2009·The Journal of Biological Chemistry·Thomas J NelsonDaniel L Alkon
Oct 24, 2009·The Journal of Biological Chemistry·Marie-Victoire Guillot-SestierFrédéric Checler
Nov 18, 2010·The Journal of Biological Chemistry·Cécile DelarasseJean M Kanellopoulos
Dec 21, 2011·The Journal of Biological Chemistry·Marie-Victoire Guillot-SestierFrédéric Checler
May 20, 2011·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Dorothea RatElzbieta Kojro
Nov 4, 2006·Science·Erik D Roberson, Lennart Mucke
Oct 19, 2006·Neuro-degenerative Diseases·Falk Fahrenholz, Rolf Postina
Jun 29, 2007·Neuro-degenerative Diseases·Daniele ZacchettiJacopo Meldolesi
Jun 4, 2008·Neuro-degenerative Diseases·Jean-Christophe CasselJohn C Dalrymple-Alford
Jun 22, 2011·Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology·Eva AlonsoLuis M Botana
Nov 9, 2010·BMC Neuroscience·Jeremy H ToynCharles F Albright
Jul 26, 2008·Molecular Neurodegeneration·Nibaldo C Inestrosa, Enrique M Toledo
Sep 12, 2013·PloS One·E Scott GrahamMike Dragunow
Jan 28, 2014·PloS One·Anna A PimenovaIna Tesseur
May 17, 2011·Reviews in the Neurosciences·Karim BordjiAlain Buisson
Aug 5, 2011·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Deborah K VergesJohn R Cirrito
Oct 10, 2008·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Carrie K JonesP Jeffrey Conn
Nov 13, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Jana K ShireyP Jeffrey Conn
Mar 26, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Albert A DavisAllan I Levey

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