An Expanded Narrative Review of Neurotransmitters on Alzheimer's Disease: The Role of Therapeutic Interventions on Neurotransmission

Overview

Journal Mol Neurobiol

Specialties Molecular Biology
Neurology

Date 2024 Jul 16

PMID 39012443

Authors

Enes Akyuz

Alina Arulsamy

Feyza Sule Aslan

Bugra Sarisozen

Beyzanur Guney

Abdulhekim Hekimoglu

Beyza Nur Yilmaz

Thaarvena Retinasamy

Mohd Farooq Shaikh

Affiliations

Soon will be listed here.

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease. The accumulation of amyloid-β (Aβ) plaques and tau neurofibrillary tangles are the key players responsible for the pathogenesis of the disease. The accumulation of Aβ plaques and tau affect the balance in chemical neurotransmitters in the brain. Thus, the current review examined the role of neurotransmitters in the pathogenesis of Alzheimer's disease and discusses the alterations in the neurochemical activity and cross talk with their receptors and transporters. In the presence of Aβ plaques and neurofibrillary tangles, changes may occur in the expression of neuronal receptors which in turn triggers excessive release of glutamate into the synaptic cleft contributing to cell death and neuronal damage. The GABAergic system may also be affected by AD pathology in a similar way. In addition, decreased receptors in the cholinergic system and dysfunction in the dopamine neurotransmission of AD pathology may also contribute to the damage to cognitive function. Moreover, the presence of deficiencies in noradrenergic neurons within the locus coeruleus in AD suggests that noradrenergic stimulation could be useful in addressing its pathophysiology. The regulation of melatonin, known for its effectiveness in enhancing cognitive function and preventing Aβ accumulation, along with the involvement of the serotonergic system and histaminergic system in cognition and memory, becomes remarkable for promoting neurotransmission in AD. Additionally, nitric oxide and adenosine-based therapeutic approaches play a protective role in AD by preventing neuroinflammation. Overall, neurotransmitter-based therapeutic strategies emerge as pivotal for addressing neurotransmitter homeostasis and neurotransmission in the context of AD. This review discussed the potential for neurotransmitter-based drugs to be effective in slowing and correcting the neurodegenerative processes in AD by targeting the neurochemical imbalance in the brain. Therefore, neurotransmitter-based drugs could serve as a future therapeutic strategy to tackle AD.

References

Kalev-Zylinska M, Morel-Kopp M, Ward C, Hearn J, Hamilton J, Bogdanova A . Ionotropic glutamate receptors in platelets: opposing effects and a unifying hypothesis. Platelets. 2020; 32(8):998-1008. DOI: 10.1080/09537104.2020.1852542. View

Medeiros R, Kitazawa M, Caccamo A, Baglietto-Vargas D, Estrada-Hernandez T, Cribbs D . Loss of muscarinic M1 receptor exacerbates Alzheimer's disease-like pathology and cognitive decline. Am J Pathol. 2011; 179(2):980-91. PMC: 3157199. DOI: 10.1016/j.ajpath.2011.04.041. View

Viana da Silva S, Haberl M, Zhang P, Bethge P, Lemos C, Goncalves N . Early synaptic deficits in the APP/PS1 mouse model of Alzheimer's disease involve neuronal adenosine A2A receptors. Nat Commun. 2016; 7:11915. PMC: 4915032. DOI: 10.1038/ncomms11915. View

Jand Y, Ghahremani M, Ghanbari A, Ejtemaei-Mehr S, Guillemin G, Ghazi-Khansari M . Melatonin ameliorates disease severity in a mouse model of multiple sclerosis by modulating the kynurenine pathway. Sci Rep. 2022; 12(1):15963. PMC: 9509376. DOI: 10.1038/s41598-022-20164-0. View

Sun Y, Zhang H, Zhang X, Wang W, Chen Y, Cai Z . Promotion of astrocyte-neuron glutamate-glutamine shuttle by SCFA contributes to the alleviation of Alzheimer's disease. Redox Biol. 2023; 62:102690. PMC: 10122027. DOI: 10.1016/j.redox.2023.102690. View

Dorheim M, Tracey W, Pollock J, Grammas P . Nitric oxide synthase activity is elevated in brain microvessels in Alzheimer's disease. Biochem Biophys Res Commun. 1994; 205(1):659-65. DOI: 10.1006/bbrc.1994.2716. View

Nous A, Engelborghs S, Smolders I . Melatonin levels in the Alzheimer's disease continuum: a systematic review. Alzheimers Res Ther. 2021; 13(1):52. PMC: 7903801. DOI: 10.1186/s13195-021-00788-6. View

Acquarone E, Argyrousi E, van den Berg M, Gulisano W, Fa M, Staniszewski A . Synaptic and memory dysfunction induced by tau oligomers is rescued by up-regulation of the nitric oxide cascade. Mol Neurodegener. 2019; 14(1):26. PMC: 6598340. DOI: 10.1186/s13024-019-0326-4. View

Szabo C, Ischiropoulos H, Radi R . Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Discov. 2007; 6(8):662-80. DOI: 10.1038/nrd2222. View

10.

Evans A, Ardestani P, Yi B, Park H, Lam R, Shamloo M . Beta-adrenergic receptor antagonism is proinflammatory and exacerbates neuroinflammation in a mouse model of Alzheimer's Disease. Neurobiol Dis. 2020; 146:105089. PMC: 7686098. DOI: 10.1016/j.nbd.2020.105089. View

11.

Arslan A . Extrasynaptic δ-subunit containing GABA receptors. J Integr Neurosci. 2021; 20(1):173-184. DOI: 10.31083/j.jin.2021.01.284. View

12.

Wang R, Reddy P . Role of Glutamate and NMDA Receptors in Alzheimer's Disease. J Alzheimers Dis. 2016; 57(4):1041-1048. PMC: 5791143. DOI: 10.3233/JAD-160763. View

13.

Flik G, Folgering J, Cremers T, Westerink B, Dremencov E . Interaction Between Brain Histamine and Serotonin, Norepinephrine, and Dopamine Systems: In Vivo Microdialysis and Electrophysiology Study. J Mol Neurosci. 2015; 56(2):320-8. DOI: 10.1007/s12031-015-0536-3. View

14.

De Ceglia R, Ledonne A, Litvin D, Lind B, Carriero G, Latagliata E . Specialized astrocytes mediate glutamatergic gliotransmission in the CNS. Nature. 2023; 622(7981):120-129. PMC: 10550825. DOI: 10.1038/s41586-023-06502-w. View

15.

Scammell T, Jackson A, Franks N, Wisden W, Dauvilliers Y . Histamine: neural circuits and new medications. Sleep. 2018; 42(1). PMC: 6335869. DOI: 10.1093/sleep/zsy183. View

16.

Wu H, Dunnett S, Ho Y, Chang R . The role of sleep deprivation and circadian rhythm disruption as risk factors of Alzheimer's disease. Front Neuroendocrinol. 2019; 54:100764. DOI: 10.1016/j.yfrne.2019.100764. View

17.

Ishibashi K, Miura Y, Toyohara J, Ishiwata K, Ishii K . Unchanged type 1 metabotropic glutamate receptor availability in patients with Alzheimer's disease: A study using C-ITMM positron emission tomography. Neuroimage Clin. 2019; 22:101783. PMC: 6434168. DOI: 10.1016/j.nicl.2019.101783. View

18.

Karpati A, Yoshikawa T, Naganuma F, Matsuzawa T, Kitano H, Yamada Y . Histamine H receptor on astrocytes and neurons controls distinct aspects of mouse behaviour. Sci Rep. 2019; 9(1):16451. PMC: 6848115. DOI: 10.1038/s41598-019-52623-6. View

19.

Salim S . Oxidative Stress and the Central Nervous System. J Pharmacol Exp Ther. 2016; 360(1):201-205. PMC: 5193071. DOI: 10.1124/jpet.116.237503. View

20.

Talantova M, Sanz-Blasco S, Zhang X, Xia P, Akhtar M, Okamoto S . Aβ induces astrocytic glutamate release, extrasynaptic NMDA receptor activation, and synaptic loss. Proc Natl Acad Sci U S A. 2013; 110(27):E2518-27. PMC: 3704025. DOI: 10.1073/pnas.1306832110. View