M1 receptors play a central role in modulating AD-like pathology in transgenic mice.
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.
Caccamo
Antonella
A
Department of Neurobiology and Behavior, University of California, Irvine, Irvine, California 92697, USA.
Oddo
Salvatore
S
Billings
Lauren M
LM
Green
Kim N
KN
Martinez-Coria
Hilda
H
Fisher
Abraham
A
LaFerla
Frank M
FM
D051722:ADAM Proteins / Q000378:metabolism; D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D051926:Basigin / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000473:pathology; D002452:Cell Count / Q000379:methods; D003598:Cytoskeletal Proteins; D004025:Dicyclomine / Q000008:administration & dosage; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D004924:Escape Reaction / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008569:Memory Disorders / Q000188:drug therapy; D051379:Mice; D008822:Mice, Transgenic / Q000502:physiology*; D018727:Muscarinic Antagonists / Q000008:administration & dosage; D009687:Nuclear Proteins; D010880:Piperidines / Q000008:administration & dosage; D011493:Protein Kinase C / Q000378:metabolism; D011930:Reaction Time / Q000187:drug effects; D043643:Receptor, Muscarinic M1 / Q000502:physiology*; D013037:Spatial Behavior / Q000187:drug effects; D013141:Spiro Compounds / Q000008:administration & dosage; D013844:Thiazoles / Q000008:administration & dosage; D013997:Time Factors; D016875:tau Proteins / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000911:Antibodies, Monoclonal; C497887:Bsg protein, mouse; D003598:Cytoskeletal Proteins; D018727:Muscarinic Antagonists; C512806:NIN protein, human; C099035:Nin protein, mouse; D009687:Nuclear Proteins; C085349:PHF-1 monoclonal antibody; D010880:Piperidines; D043643:Receptor, Muscarinic M1; D013141:Spiro Compounds; D013844:Thiazoles; D016875:tau Proteins; D051926:Basigin; D004025:Dicyclomine; C470586:(S)-2-ethyl-8-methyl-1-thia-4,8-diazaspiro(4.5)decan-3-one; D011493:Protein Kinase C; D051722:ADAM Proteins; D019204:GTP-Binding Proteins