TABLE 3.
Serotonergic receptors reported to be involved in Alzheimer’s disease.
| GPCRs | Subtype | Agent | Subject | Second messenger | Mode of action | References |
| 5-HT1R | 5-HT1AR | 8-OH-DPAT (A) | Cell | ↑ PI3K and Akt ↓ GSK-3β | ↓ Tau | Wang et al., 2016 |
| NAD-299 (AN) | Rat | ND | ↓ Amyloid plaques and neuronal loss ↑ BDNF and cognition | Afshar et al., 2018 | ||
| Rat | ND | ↓ Oxidative stress and neuronal loss | Afshar et al., 2019 | |||
| Rat | ND | ↓ Neuronal apoptosis | Shahidi et al., 2019a | |||
| WAY-100635 (AN) | Mouse | ↓ NF-κB | ↓ Neuroinflammation ↑ Cognition and neuronal survival | Wang et al., 2020 | ||
| 5-HT1BR | EG (A) | Cell | ↑ ERK1/2 | ↓ Neuroinflammation and neural death | Yang et al., 2021 | |
| 5-HT2R | 5-HT2AR | Desloratadine (AN) | Mouse | ↑ cAMP, PKA, CREB, and Sirt1 | ↓ Amyloid plaques and neuroinflammation | Lu et al., 2021 |
| Pimavanserin or M100907 (IA) | Mouse | ↑ ERK | ↓ Aβ↑α-secretase and cognition | Yuede et al., 2021 | ||
| TCB-2 (A) | Rat | ND | ↓ Amyloid plaques and neuronal loss ↑ BDNF and cognition | Afshar et al., 2018 | ||
| Rat | ND | ↓ Oxidative stress and neuronal loss | Afshar et al., 2019 | |||
| Rat | ND | ↓ Neuronal apoptosis | Shahidi et al., 2019a | |||
| 5-HT2CR | Dexnorfenfluramine (A) | Guinea pig | ND | ↑ sAPP ↓ Aβ | Arjona et al., 2002 | |
| RO-60-0175 (A) | Cell | ND | ↑ NEP | Tian et al., 2015 | ||
| 5-HT4R | BIMU8 (A) | Rat | ND | ↓ Neuronal apoptosis ↑ Synaptic plasticity and cognition | Hashemi-Firouzi et al., 2021 | |
| ML10302 (A) | Mouse | ND | ↑ sAPPα | Cachard-Chastel et al., 2007 | ||
| Mouse | ND | ↑ sAPPα | Russo et al., 2009 | |||
| Prucalopride (A) | Cell | ↑ PKA | ↑ sAPPα | Robert et al., 2001 | ||
| Mouse | ND | ↑ sAPPα | Cachard-Chastel et al., 2007 | |||
| RS-67333 (A) | Cell and mouse | ND | ↑ sAPPα and neuron survival ↓ Aβ | Cho and Hu, 2007 | ||
| Cell and mouse | ND | ↑ sAPPα, CTFα, and MMP-9 ↓ Aβ40 and amyloid plaques | Hashimoto et al., 2012 | |||
| Mouse | ND | ↑ sAPPα and cognition ↓ Aβ40/42, amyloid plaques and neuroinflammation | Giannoni et al., 2013 | |||
| Mouse | ND | ↓ Amyloid plaques and neuroinflammation ↑ Cognition | Baranger et al., 2017 | |||
| SSP-002392 (A) | Cell and mouse | ↑ cAMP | ↓ Aβ, BACE1, ADAM17, nicastrin, and neuroinflammation | Tesseur et al., 2013 | ||
| 5-HT6R | SB-258585 (AN) | Cell and mouse | ↑β-arrestin2 and CDK5 | ↓ Aβ | Li X. et al., 2017 | |
| Rat | ND | ↓ Neuronal apoptosis ↑ Cognition | Hashemi-Firouzi et al., 2018 | |||
| Rat | ND | ↑ Neuronal plasticity and cognition | Shahidi et al., 2019b | |||
| EMD-386088 (A) or SB-399885 (AN) | Cell | ND | ↓ Aβ neurotoxicity, oxidative stress and apoptosis ↑ Neurite outgrowth | Bokare et al., 2017 | ||
| SB-271046 (AN) | Mouse | ND | ↓γ-secretase, Aβ and neuroinflammation ↑ Cognition | Yun et al., 2015 | ||
| Cell and mouse | ND | ↑ Neuronal cilia morphology and cognition | Hu et al., 2017 | |||
| 5-HT7R | AS-19 (A) | Rat | ND | ↑ Synaptic function ↓ Neuronal apoptosis | Hashemi-Firouzi et al., 2017 | |
| Rat | ND | ↓ Amyloid plaques and neuronal apoptosis ↑ Synaptic function and cognition | Shahidi et al., 2018 |
8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide; A, agonist; Aβ, amyloid-β; ADAM, a disintegrin and metalloprotease; AN, antagonist; Akt, protein kinase B; APP,β-amyloid precursor protein; AS-19, (2S)-(+)-5-(1,3,5-TriMethylpyrazol-4-yl)-2-(diMethylaMino)tetralin; BDNF, brain-derived neurotrophic factor; BACE1,β-secretase; BIMU8, (endo-N-8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2,3-dehydro-2-oxo-3-(prop-2-yl)-1H-benzimid-azole-1-carboxamide; cAMP, cyclic adenosine monophosphate; CDK5, cyclin-dependent kinase 5; CREB, cAMP-response element binding protein; CTFα, C-terminal fragmentα; EG, emodin-8-O-β-d-glucopyranoside; EMD-386088, 5-chloro-2-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole hydrochloride; ERK, extracellular regulated protein kinases; GSK-3β, glycogen synthase kinase-3β; M100907, (R)-(+)-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine methanol; IA, inverse agonist; ML10302, 2-piperidinoethyl 4-amino-5-chloro-2-methoxybenzoate; MMP-9, matrix metalloprotein 9; NAD-299, (R)-3-N,N-dicyclobutylamino-8 fluoro-3,4-dihydro-3H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate; ND, not determined; NEP, neprilysin; NF-κB, nuclear factor kappa-B; PKA, cyclic-AMP dependent protein kinase A; PI3K, phosphatidylinositol 3-kinase; RO-60-0175, (S)-2-(chloro-5-fluoro-indol-l-yl)-1-methylethylamine fumarate; RS-67333, 1-(4-Amino-5-chloro-2-methoxyphenyl)-3-[1-butyl-4-piperidinyl]-1-propanone hydrochloride; sAPPα, soluble amino-terminal ectodomain of APP; SB-258585, 4-Iodo-N-[4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-benzen esulphonamide; SB-271046, 5-Chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenesulfon-amide; SB-399885, N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide; SIRT 1, silent mating type information regulation 2 homolog-1; SSP-002392, (4-amino-5-chloro-2,3-dihydro-benzofuran-7-carboxylic acid [3-hydroxy-1-(3-methoxy-propyl)-piperidin-4ylmethyl]-amide); TCB-2, (7R)-3-bromo-2, 5-dimethoxy-bicyclo[4.2.0]octa-1,3,5-trien-7-yl]methanamine; WAY-100635, [O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2- pyridinyl)cyclohexanecarboxamide trihydrochloride.