Deletion of M 1 Muscarinic Acetylcholine Receptors Increases Amyloid Pathology In Vitro and In Vivo
Open accessAbstract
Alzheimer's disease (AD) is a progressive neurological disorder that causes dementia and poses a major public health crisis as the population ages. Aberrant processing of the amyloid precursor protein (APP) is strongly implicated as a proximal event in AD pathophysiology, but the neurochemical signals that regulate APP processing in the brain are not completely understood. Activation of muscarinic acetylcholine receptors (mAChRs) has been shown to affect APP processing and AD pathology, but less is known about the roles of specific mAChR subtypes. In this study, we used M 1 mAChR knock-out mice (M 1 KO) to isolate the effects of the M 1 mAChR on APP processing in primary neurons and on the development of amyloid pathology in a transgenic mouse model of AD. We demonstrate that the loss of M 1 mAChRs increases amyloidogenic APP processing in neurons, as evidenced by decreased agonist-regulated shedding of the neuroprotective APP ectodomain APPsα and increased production of toxic Aβ peptides. Expression of M 1 mAChRs on the M 1 KO background rescued this phenotype, indicating that M 1 mAChRs are sufficient to modulate nonamyloidogenic APP processing. In APP Swe/Ind transgenic mice, the loss of M 1 mAChRs resulted in increased levels of brain Aβ and greater accumulation of amyloid plaque pathology. Analysis of APP metabolites in APP Swe/Ind brain tissue indicates that the loss of M 1 mAChRs increases amyloidogenic APP processing. These results indicate that the M 1 mAChR is an important regulator of amyloidogenesis in the brain and provide strong support for targeting the M 1 mAChR as a therapeutic candidate in AD.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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 [12]
The Introduction (page unavailable) reports that an M1-claimed agonist reduced amyloid pathology in an Alzheimer’s mouse model, supporting the plaque-load part of the claim. It does not establish that chronic M1 agonist administration reduced both brain Aβ levels and plaque load; the paper’s own in vivo results concern M1 receptor deletion, not agonist administration. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSynaptic 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 [12]
The Results (page not available) show that activating the M1 muscarinic receptor changes APP processing and Aβ secretion in cortical neuron cultures, supporting the neurotransmitter-receptor aspect of the claim. The Discussion (page not available) says the downstream mechanism requires further work; the paper does not establish that second-messenger pathways mediate the effect or directly test synaptic activity. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 36 · Cited by 137
Research works printed but not linked: 32
- Anagnostaras SG Murphy GG Hamilton SE Mitchell SL Rahnama NP Nathanson NM Silva AJ 2003 Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice Nat Neurosci 6 51 58 12483218
- Association As 2009 2009 Alzheimer's disease facts and figures Alzheimers Dement 5 234 270 19426951
- Beach TG Kuo YM Schwab C Walker DG Roher AE 2001a Reduction of cortical amyloid beta levels in guinea pig brain after systemic administration of physostigmine Neurosci Lett 310 21 24 11524148
- Beach TG Walker DG Potter PE Sue LI Fisher A 2001b Reduction of cerebrospinal fluid amyloid beta after systemic administration of M1 muscarinic agonists Brain Res 905 220 223 11423097
- Beach TG Potter PE Kuo YM Emmerling MR Durham RA Webster SD Walker DG Sue LI Scott S Layne KJ Roher AE 2000 Cholinergic deafferentation of the rabbit cortex: a new animal model of Abeta deposition Neurosci Lett 283 9 12 10729621
- Bell KF Zheng L Fahrenholz F Cuello AC 2008 ADAM-10 over-expression increases cortical synaptogenesis Neurobiol Aging 29 554 565 17187903
- Buckley NJ Bonner TI Brann MR 1988 Localization of a family of muscarinic receptor mRNAs in rat brain J Neurosci 8 4646 4652 3199198 PMC6569562
- Caccamo A Oddo S Billings LM Green KN Martinez-Coria H Fisher A Laferla FM 2006 M1 Receptors Play a Central Role in Modulating AD-like Pathology in Transgenic Mice Neuron 49 671 682 16504943
- DeLapp N Wu S Belagaje R Johnstone E Little S Shannon H Bymaster F Calligaro D Mitch C Whitesitt C Ward J Sheardown M Fink-Jensen A Jeppesen L Thomsen C Sauerberg P 1998 Effects of the M1 agonist xanomeline on processing of human beta-amyloid precursor protein (FAD, Swedish mutant) transfected into Chinese hamster ovary-m1 cells Biochem Biophys Res Commun 244 156 160 9514902
- Farber SA Nitsch RM Schulz JG Wurtman RJ 1995 Regulated secretion of beta-amyloid precursor protein in rat brain J Neurosci 15 7442 7451 7472496 PMC6578089
- Gralle M Botelho MG Wouters FS 2009 Neuroprotective secreted amyloid precursor protein acts by disrupting amyloid precursor protein dimers J Biol Chem PMC2685684 19336403
- Haring R Gurwitz D Barg J Pinkas-Kramarski R Heldman E Pittel Z Wengier A Meshulam H Marciano D Karton Y 1994 Amyloid precursor protein secretion via muscarinic receptors: reduced desensitization using the M1-selective agonist AF102B Biochem Biophys Res Commun 203 652 658 8074717
- Hebert LE Scherr PA Bienias JL Bennett DA Evans DA 2003 Alzheimer disease in the US population: prevalence estimates using the 2000 census Arch Neurol 60 1119 1122 12925369
- Hock C Maddalena A Raschig A Muller-Spahn F Eschweiler G Hager K Heuser I Hampel H Muller-Thomsen T Oertel W Wienrich M Signorell A Gonzalez-Agosti C Nitsch RM 2003 Treatment with the selective muscarinic m1 agonist talsaclidine decreases cerebrospinal fluid levels of A beta 42 in patients with Alzheimer's disease Amyloid 10 1 6 12762134
- Jones CK Brady AE Davis AA Xiang Z Bubser M Tantawy MN Kane AS Bridges TM Kennedy JP Bradley SR Peterson TE Ansari MS Baldwin RM Kessler RM Deutch AY Lah JJ Levey AI Lindsley CW Conn PJ 2008 Novel selective allosteric activator of the M1 muscarinic acetylcholine receptor regulates amyloid processing and produces antipsychotic-like activity in rats J Neurosci 28 10422 10433 18842902 PMC2577155
- Kim SH Kim YK Jeong SJ Haass C Kim YH Suh YH 1997 Enhanced release of secreted form of Alzheimer's amyloid precursor protein from PC12 cells by nicotine Mol Pharmacol 52 430 436 9281605
- Laemmli UK 1970 Cleavage of structural proteins during the assembly of the head of bacteriophage T4 Nature 227 680 685 5432063
- Lenzken SC Lanni C Govoni S Lucchelli A Schettini G Racchi M 2007 Nicotinic component of galantamine in the regulation of amyloid precursor protein processing Chem Biol Interact 165 138 145 17196952
- Levey AI Kitt CA Simonds WF Price DL Brann MR 1991 Identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype-specific antibodies J Neurosci 11 3218 3226 1941081 PMC6575445
- Levey AI Edmunds SM Koliatsos V Wiley RG Heilman CJ 1995 Expression of m1-m4 muscarinic acetylcholine receptor proteins in rat hippocampus and regulation by cholinergic innervation J Neurosci 15 4077 4092 7751967 PMC6578239
- Mattson MP Cheng B Culwell AR Esch FS Lieberburg I Rydel RE 1993 Evidence for excitoprotective and intraneuronal calcium-regulating roles for secreted forms of the beta-amyloid precursor protein Neuron 10 243 254 8094963
- Meziane H Dodart JC Mathis C Little S Clemens J Paul SM Ungerer A 1998 Memory-enhancing effects of secreted forms of the beta-amyloid precursor protein in normal and amnestic mice Proc Natl Acad Sci U S A 95 12683 12688 9770546 PMC22891
- Miyakawa T Yamada M Duttaroy A Wess J 2001 Hyperactivity and intact hippocampus-dependent learning in mice lacking the M1 muscarinic acetylcholine receptor J Neurosci 21 5239 5250 11438599 PMC6762828
- Mucke L Masliah E Yu GQ Mallory M Rockenstein EM Tatsuno G Hu K Kholodenko D Johnson-Wood K McConlogue L 2000 High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation J Neurosci 20 4050 4058 10818140 PMC6772621
- Nie H Li Z Lukas RJ Shen Y Song L Wang X Yin M 2008 Construction of SH-EP1-alpha4beta2-hAPP695 cell line and effects of nicotinic agonists on beta-amyloid in the cells Cell Mol Neurobiol 28 103 112 17912626 PMC11515028
- Nitsch RM Slack BE Wurtman RJ Growdon JH 1992 Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors Science 258 304 307 1411529
- Nitsch RM Deng M Tennis M Schoenfeld D Growdon JH 2000 The selective muscarinic M1 agonist AF102B decreases levels of total Abeta in cerebrospinal fluid of patients with Alzheimer's disease Ann Neurol 48 913 918 11117548
- Perry EK Kilford L Lees AJ Burn DJ Perry RH 2003 Increased Alzheimer pathology in Parkinson's disease related to antimuscarinic drugs Ann Neurol 54 235 238 12891676
- Selkoe DJ Yamazaki T Citron M Podlisny MB Koo EH Teplow DB Haass C 1996 The role of APP processing and trafficking pathways in the formation of amyloid beta-protein Ann N Y Acad Sci 777 57 64 8624127
- Thinakaran G Koo EH 2008 Amyloid precursor protein trafficking, processing, and function J Biol Chem 283 29615 29619 18650430 PMC2573065
- Walsh DM Klyubin I Shankar GM Townsend M Fadeeva JV Betts V Podlisny MB Cleary JP Ashe KH Rowan MJ Selkoe DJ 2005 The role of cell-derived oligomers of Abeta in Alzheimer's disease and avenues for therapeutic intervention Biochem Soc Trans 33 1087 1090 16246051
- Woodruff-Pak DS 2008 Animal models of Alzheimer's disease: therapeutic implications J Alzheimers Dis 15 507 521 19096153
- Authors
- Davis, A. A., Fritz, J. J., Wess, J., Lah, J. J., & Levey, A. I.
- Affiliations
- Emory University (US)
- National Institutes of Health (US)
- Corresponding author
- Levey, Allan I.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2010-03-24
- Volume
- 30
- Issue
- 12
- Pages
- 4190-4196
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2855655
- OpenAlex
- W2050330094
- Cited by
- 137
- References
- 36
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 9 · 2023: 4 · 2022: 10 · 2021: 8 · 2020: 7 · 2019: 1 · 2018: 9 · 2017: 9 · 2016: 10 · 2015: 7 · 2014: 13 · 2013: 10 · 2012: 11
- FWCI
- 8.88
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pharmaceutical Research and Manufacturers of America Foundation
- National Institutes of Health
- National Institute on Aging (F30AG029731)
- National Institute of General Medical Sciences (T32GM008169)
- National Institute of Neurological Disorders and Stroke (NS030454, R01NS030454)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- M1 muscarinic receptor, Alzheimer's disease, APP processing, amyloid-beta, amyloid plaques, therapeutic target
- MeSH terms
- ADAM10 Protein, Actins, Age Factors, Animals, Carbachol, Cells, Cultured, Cerebral Cortex, Embryo, Mammalian, Enzyme-Linked Immunosorbent Assay, Gene Expression Regulation, Humans, Male, Membrane Proteins, Mice, Transgenic, Neurons, Peptide Fragments, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Cholinergic Agonists, Receptor, Muscarinic M1, Mice, ADAM Proteins, Amyloid Precursor Protein Secretases
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
