TABLE 1.

Muscarinic acetylcholine receptors reported to be involved in Alzheimer’s disease.

GPCRs	Subtype	Agent	Subject	Second messenger	Mode of action	References
M1 receptors	M1 or M3 mAChR	Carbachol (A)	Cell	↑ PKC	↑ sAPP ↓ Aβ	Nitsch et al., 1992
			Cell	↑ PKC	↑ sAPP ↓ Aβ	Buxbaum et al., 1992
			Cell	↑ PKC	↑ sAPP ↓ Aβ	Hung et al., 1993
			Cell	↑ PKC ↓ GSK-3β	↓ Tau	Forlenza et al., 2000
			Cell and rat	ND	↑ sAPP ↓ Aβ	Qiu et al., 2003
			Cell	↑ PKC	↑ ADAM17 and sAPPα	Cisse et al., 2011
	M1 mAChR	77-LH-28-1 (A)	Mouse	ND	↑ AMPAR and p-GluA1Ser845 ↑ PSD-95 and cognition	Zhao L. X. et al., 2019
		AF102B (A)	Mouse	ND	↑ Cognition	Fisher et al., 1991
			Cell	ND	↓ Tau	Sadot et al., 1996
			Human	ND	↓ Aβ	Nitsch et al., 2000
			Mouse	↑ PKC and ERK1/2	↑ ADAM17 ↓ Aβ	Welt et al., 2015
		AF150 (S) (A)	Mouse	ND	↓ Tau	Genis et al., 1999
		AF267B (A)	Cell	↑ PKC ↓ GSK-3β	↑ Wnt and β-catenin ↓ Aβ neurotoxicity	Farias et al., 2004
			Mouse	↑ PKC and ERK1/2 ↓ GSK-3β	↑ ADAM17 and cognition ↓ Aβ and tau	Caccamo et al., 2006
		AF710B (A)	Mouse	↓ GSK-3β	↓ BACE1, p25/CDK5, Aβ40/42, amyloid plaques, tau and neuroinflammation ↑ Cognition	Fisher A. et al., 2016
			Rat	ND	↓ Aβ42 and neuroinflammation ↑ synaptic plasticity and cognition	Hall H. et al., 2018
		EUK1001 (A)	Mouse	ND	↓ Tau ↑ Cognition	Wang D. et al., 2011
			Cell and mouse	ND	↓ Aβ42 ↑ sAPPα and cognition	Li Z. et al., 2017
		BQCA (PAM)	Mouse	ND	↑ sAPPα and cognition	Shirey et al., 2009
			Mouse	ND	↑ Cognition	Puri et al., 2015
		Talsaclidine (A)	Human	ND	↓ Aβ42	Hock et al., 2003
		TBPB (A)	Cell	ND	↑ sAPPα↓ Aβ40	Jones et al., 2008
		VU0364572 (A)	Mouse	ND	↓ oAβ, Aβ40/42 ↑ Cognition	Lebois et al., 2017
		VU0486846 (PAM)	Mouse	ND	↓ BACE1, oAβ, amyloid plaques, and neuronal loss ↑ ADAM10, anxiety-like behavior and cognition	Abd-Elrahman et al., 2021
M2 receptors		Methoctramine (AN)	Mouse	ND	↓ sAPPβ and Aβ	Cheng et al., 2010
			Mouse	↑ PKC ↓ GSK-3β	↑ ACh ↓ Tau	Zhang et al., 2014

77-LH-28-1, 1-[3-(4-butylpiperidin-1-yl)propyl]-1,2,3,4-tetrahydroquinolin-2-one; A, agonist; Aβ, amyloid-β; ACh, acetylcholine; ADAM, a disintegrin and metalloprotease; AF102B, cevimeline; AF150(S), 1-methylpiperidine-4-spiro-(2′-methylthiazoline); AF267B, (2S)-2-Ethyl-8-methyl-1-thia-4,8-diazaspiro[4.5]decan-3-one; AF710B, 1-(2,8-Dimethyl-1-thia-3,8-diazaspiro[4.5]dec-3-yl)-3-(1H-indol-3-yl)propan-1-one; AMPAR,α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors; AN, antagonist; APP,β-amyloid precursor protein; BACE1,β-secretase; BQCA, benzylquinolone carboxylic acid; CDK5, cyclin-dependent kinase 5; ERK, extracellular regulated protein kinases; EUK1001, 3−[3−(3−florophenyl−2−propyn−1−ylthio)−1,2,5−thiadiazol-4-yl]-1,2,5,6-tetrahydro−1− methylpyridine oxalate; GSK-3β, glycogen synthase kinase-3β; mAChR, muscarinic acetylcholine receptor; ND, not determined; oAβ, Aβ oligomer; PAM, positive allosteric modulator; PKC, protein kinase C; PSD-95, postsynaptic density protein-95; sAPP, soluble amyloid precursor protein; sAPPα, soluble amino-terminal ectodomain of APP; sAPPβ, solubleβ fragment of APP; TBPB, 1-(1′-2-methylbenzyl)-1,4′-bipiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one; VU0364572, trifluoroacetate salt; VU0486846,(R)-4-(4-(1H-Pyrazol-1-yl)benzyl)-N-((1S,2S)-2-hydroxycyclohexyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide.