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Cited by 417Alzheimer's disease research and treatmentsCholinesterase and Neurodegenerative DiseasesDementia and Cognitive Impairment Research

M1 Receptors Play a Central Role in Modulating AD-like Pathology in Transgenic Mice

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Caccamo, Antonella, Oddo, Salvatore, Billings, Lauren M., Green, Kim N., Martinez-Coria, Hilda, Fisher, Abraham, LaFerla, Frank M.·2006·Neuron
DOI 10.1016/j.neuron.2006.01.020
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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.

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  • Chronic administration of M1 receptor agonists reduce brain Aβ levels and plaque load.

    “Chronic administration of M1 receptor agonists reduce brain Aβ levels and plaque load (11–13).”

    From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [11]

    The Results report that chronic treatment with the M1 agonist AF267B reduced Aβ1-42 levels and extracellular Aβ staining in the cortex and hippocampus of 3xTg-AD mice, supporting the claim for that treatment and model. The claim is broader than these findings: Aβ1-40 levels did not fall, amygdala Aβ staining did not change, and the study tested one agonist rather than M1 agonists generally. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Synaptic activity regulates Aβ levels through neurotransmitter-activated second messenger signaling pathways that alter APP processing into Aβ.

    “Synaptic activity is known to regulate Aβ levels through a presynaptic mechanism that is dependent on APP endocytosis and cleavage (4, 5) and through neurotransmitter-activated second messenger signaling pathways that alter APP processing into Aβ (7, 11, 12, 31).”

    From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [11]

    The Results report that activating M1 cholinergic receptors with AF267B changes PKC and ERK1/2 activity and suggest that these pathways alter APP processing and Aβ pathology. This supports the cited signaling mechanism, but the study used a receptor agonist in transgenic mice; it did not directly show that synaptic activity regulates Aβ through that mechanism. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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  1. [1]1. Allinson, T.M. ∙ Parkin, E.T. ∙ Turner, A.J. ... ADAMs family members as amyloid precursor protein alpha-secretases J. Neurosci. Res. 2003; 74:342-352 Crossref Scopus (393) PubMed Google Scholar
  2. [2]2. Bigl, V. ∙ Rossner, S. Amyloid precursor protein processing in vivo–insights from a chemically-induced constitutive overactivation of protein kinase C in Guinea pig brain Curr. Med. Chem. 2003; 10:871-882 Crossref Scopus (12) PubMed Google Scholar
  3. [4]4. Buxbaum, J.D. ∙ Oishi, M. ∙ Chen, H.I. ... Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer beta/A4 amyloid protein precursor Proc. Natl. Acad. Sci. USA. 1992; 89:10075-10078 Crossref Scopus (525) PubMed Google Scholar
  4. [5]5. Buxbaum, J.D. ∙ Liu, K.N. ∙ Luo, Y. ... Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated alpha-secretase cleavage of the Alzheimer amyloid protein precursor J. Biol. Chem. 1998; 273:27765-27767 Crossref Scopus (852) PubMed Google Scholar
  5. [6]6. Cuajungco, M.P. ∙ Faget, K.Y. ∙ Huang, X. ... Metal chelation as a potential therapy for Alzheimer's disease Ann. N Y Acad. Sci. 2000; 920:292-304 Crossref Scopus (191) PubMed Google Scholar
  6. [7]7. Davies, P. ∙ Maloney, A.J. Selective loss of central cholinergic neurons in Alzheimer's disease Lancet. 1976; 2:1403 Crossref Scopus (2962) PubMed Google Scholar
  7. [9]9. Eglen, R.M. ∙ Choppin, A. ∙ Watson, N. Therapeutic opportunities from muscarinic receptor research Trends Pharmacol. Sci. 2001; 22:409-414 Full Text Full Text (PDF) Scopus (160) PubMed Google Scholar
  8. [10]10. Forlenza, O.V. ∙ Spink, J.M. ∙ Dayanandan, R. ... Muscarinic agonists reduce tau phosphorylation in non-neuronal cells via GSK-3beta inhibition and in neurons J. Neural Transm. 2000; 107:1201-1212 Crossref Scopus (78) PubMed Google Scholar
  9. [11]11. Giachetti, A. ∙ Giraldo, E. ∙ Ladinsky, H. ... Binding and functional profiles of the selective M1 muscarinic receptor antagonists trihexyphenidyl and dicyclomine Br. J. Pharmacol. 1986; 89:83-90 Crossref Scopus (84) PubMed Google Scholar
  10. [13]13. Haring, R. ∙ Fisher, A. ∙ Marciano, D. ... Mitogen-activated protein kinase-dependent and protein kinase C-dependent pathways link the m1 muscarinic receptor to beta-amyloid precursor protein secretion J. Neurochem. 1998; 71:2094-2103 Crossref Scopus (126) PubMed Google Scholar
  11. [14]14. Ibach, B. ∙ Haen, E. Acetylcholinesterase inhibition in Alzheimer's Disease Curr. Pharm. Des. 2004; 10:231-251 Crossref Scopus (178) PubMed Google Scholar
  12. [15]15. Jankowsky, J.L. ∙ Savonenko, A. ∙ Schilling, G. ... Transgenic mouse models of neurodegenerative disease: opportunities for therapeutic development Curr. Neurol. Neurosci. Rep. 2002; 2:457-464 Crossref Scopus (53) PubMed Google Scholar
  13. [16]16. Janus, C. ∙ Phinney, A.L. ∙ Chishti, M.A. ... New developments in animal models of Alzheimer's disease Curr. Neurol. Neurosci. Rep. 2001; 1:451-457 Crossref Scopus (36) PubMed Google Scholar
  14. [17]17. Karkkainen, I. ∙ Rybnikova, E. ∙ Pelto-Huikko, M. ... Metalloprotease-disintegrin (ADAM) genes are widely and differentially expressed in the adult CNS Mol. Cell. Neurosci. 2000; 15:547-560 Crossref Scopus (114) PubMed Google Scholar
  15. [18]18. Kitazawa, M. ∙ Oddo, S. ∙ Yamasaki, T.R. ... Lipopolysaccharide-induced inflammation exacerbates tau pathology by a cyclin-dependent kinase 5-mediated pathway in a transgenic model of Alzheimer's disease J. Neurosci. 2005; 25:8843-8853 Crossref Scopus (587) PubMed Google Scholar
  16. [19]19. Lammich, S. ∙ Kojro, E. ∙ Postina, R. ... Constitutive and regulated alpha-secretase cleavage of Alzheimer's amyloid precursor protein by a disintegrin metalloprotease Proc. Natl. Acad. Sci. USA. 1999; 96:3922-3927 Crossref Scopus (1011) PubMed Google Scholar
  17. [20]20. Levey, A.I. ∙ Kitt, C.A. ∙ Simonds, W.F. ... Identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype-specific antibodies J. Neurosci. 1991; 11:3218-3226 Crossref PubMed Google Scholar
  18. [21]21. McGaugh, J.L. ∙ McIntyre, C.K. ∙ Power, A.E. Amygdala modulation of memory consolidation: interaction with other brain systems Neurobiol. Learn. Mem. 2002; 78:539-552 Crossref Scopus (234) PubMed Google Scholar
  19. [22]22. Muir, J.L. Acetylcholine, aging, and Alzheimer's disease Pharmacol. Biochem. Behav. 1997; 56:687-696 Crossref Scopus (305) PubMed Google Scholar
  20. [23]23. Nitsch, R.M. ∙ Slack, B.E. ∙ Wurtman, R.J. ... Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors Science. 1992; 258:304-307 Crossref Scopus (855) PubMed Google Scholar
  21. [24]24. Nitsch, R.M. ∙ Slack, B.E. ∙ Farber, S.A. ... Receptor-coupled amyloid precursor protein processing Ann. N Y Acad. Sci. 1993; 695:122-127 Crossref Scopus (35) PubMed Google Scholar
  22. [25]25. Nordberg, A. ∙ Winblad, B. Reduced number of [3H]nicotine and [3H]acetylcholine binding sites in the frontal cortex of Alzheimer brains Neurosci. Lett. 1986; 72:115-119 Crossref Scopus (296) PubMed Google Scholar
  23. [26]26. Nordberg, A. ∙ Alafuzoff, I. ∙ Winblad, B. Nicotinic and muscarinic subtypes in the human brain: changes with aging and dementia J. Neurosci. Res. 1992; 31:103-111 Crossref Scopus (247) PubMed Google Scholar
  24. [27]27. Nordberg, A. ∙ Hellstrom-Lindahl, E. ∙ Lee, M. ... Chronic nicotine treatment reduces beta-amyloidosis in the brain of a mouse model of Alzheimer's disease (APPsw) J. Neurochem. 2002; 81:655-658 Crossref Scopus (202) PubMed Google Scholar
  25. [29]29. Oddo, S. ∙ Billings, L. ∙ Kesslak, J.P. ... Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome Neuron. 2004; 43:321-332 Full Text Full Text (PDF) Scopus (750) PubMed Google Scholar
  26. [31]31. Pinnix, I. ∙ Musunuru, U. ∙ Tun, H. ... A novel gamma-secretase assay based on detection of the putative C-terminal fragment-gamma of amyloid beta protein precursor J. Biol. Chem. 2001; 276:481-487 Crossref Scopus (133) PubMed Google Scholar
  27. [32]32. Postina, R. ∙ Schroeder, A. ∙ Dewachter, I. ... A disintegrin-metalloproteinase prevents amyloid plaque formation and hippocampal defects in an Alzheimer disease mouse model J. Clin. Invest. 2004; 113:1456-1464 Crossref Scopus (557) PubMed Google Scholar
  28. [33]33. Riekkinen, Jr., P. ∙ Schmidt, B.H. ∙ van der Staay, F.J. Animal models in the development of symptomatic and preventive drug therapies for Alzheimer's disease Ann. Med. 1998; 30:566-576 Crossref Scopus (13) PubMed Google Scholar
  29. [34]34. Rosenblum, K. ∙ Futter, M. ∙ Jones, M. ... ERKI/II regulation by the muscarinic acetylcholine receptors in neurons J. Neurosci. 2000; 20:977-985 Crossref PubMed Google Scholar
  30. [36]36. Selkoe, D.J. Alzheimer's disease: genes, proteins, and therapy Physiol. Rev. 2001; 81:741-766 Crossref Scopus (5381) PubMed Google Scholar
  31. [37]37. Skovronsky, D.M. ∙ Fath, S. ∙ Lee, V.M. ... Neuronal localization of the TNFalpha converting enzyme (TACE) in brain tissue and its correlation to amyloid plaques J. Neurobiol. 2001; 49:40-46 Crossref Scopus (76) PubMed Google Scholar
  32. [38]38. Spencer, Jr., D.G. ∙ Horvath, E. ∙ Traber, J. Direct autoradiographic determination of M1 and M2 muscarinic acetylcholine receptor distribution in the rat brain: relation to cholinergic nuclei and projections Brain Res. 1986; 380:59-68 Crossref Scopus (304) PubMed Google Scholar
  33. [39]39. Sugaya, K. ∙ Giacobini, E. ∙ Chiappinelli, V.A. Nicotinic acetylcholine receptor subtypes in human frontal cortex: changes in Alzheimer's disease J. Neurosci. Res. 1990; 27:349-359 Crossref Scopus (130) PubMed Google Scholar
  34. [40]40. Sugden, P.H. ∙ Clerk, A. Regulation of the ERK subgroup of MAP kinase cascades through G protein-coupled receptors Cell. Signal. 1997; 9:337-351 Crossref Scopus (286) PubMed Google Scholar
  35. [42]42. Wei, J. ∙ Walton, E.A. ∙ Milici, A. ... m1-m5 muscarinic receptor distribution in rat CNS by RT-PCR and HPLC J. Neurochem. 1994; 63:815-821 Crossref Scopus (181) PubMed Google Scholar
  36. [43]43. Whitehouse, P.J. ∙ Martino, A.M. ∙ Antuono, P.G. ... Nicotinic acetylcholine binding sites in Alzheimer's disease Brain Res. 1986; 371:146-151 Crossref Scopus (418) PubMed Google Scholar

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Authors
Caccamo, A., Oddo, S., Billings, L. M., Green, K. N., Martinez-Coria, H., Fisher, A., & LaFerla, F. M.
Affiliations
  • University of California, Irvine (US)
  • Israel Institute for Biological Research (IL)
Corresponding author
LaFerla, Frank M.
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2006-03
Volume
49
Issue
5
Pages
671-682
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2006.01.020
OpenAlex
W1977892449
Cited by
417
References
7
Citations by year
2026: 5 · 2025: 9 · 2024: 12 · 2023: 8 · 2022: 14 · 2021: 23 · 2020: 16 · 2019: 18 · 2018: 15 · 2017: 14 · 2016: 12 · 2015: 14 · 2014: 17 · 2013: 22 · 2012: 30
FWCI
25.91
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute on Aging (AG0212982)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
M1 muscarinic receptor, Alzheimer's disease, 3xTg-AD mice, amyloid-beta pathology, tau pathology, ADAM17, APP processing, non-amyloidogenic pathway, GSK3β, dicyclomine, cognitive impairment, muscarinic agonists
MeSH terms
Alzheimer Disease, Analysis of Variance, Animals, Antibodies, Monoclonal, Behavior, Animal, Brain, Cell Count, Cytoskeletal Proteins, Dicyclomine, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Escape Reaction, Humans, Immunohistochemistry, Memory Disorders, Mice, Transgenic, Nuclear Proteins, Piperidines, Protein Kinase C, Reaction Time, Spatial Behavior, Spiro Compounds, Thiazoles, Time Factors, Blotting, Western, Gene Expression, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, Muscarinic Antagonists, GTP-Binding Proteins, Receptor, Muscarinic M1, Mice, ADAM Proteins, Basigin

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