The dopaminergic system and Alzheimer's disease

Abstract

Alzheimer's disease is a common neurodegenerative disorder in older adults. Despite its prevalence, its pathogenesis remains unclear. In addition to the most widely accepted causes, which include excessive amyloid-beta aggregation, tau hyperphosphorylation, and deficiency of the neurotransmitter acetylcholine, numerous studies have shown that the dopaminergic system is also closely associated with the occurrence and development of this condition. Dopamine is a crucial catecholaminergic neurotransmitter in the human body. Dopamine-associated treatments, such as drugs that target dopamine receptor D and dopamine analogs, can improve cognitive function and alleviate psychiatric symptoms as well as ameliorate other clinical manifestations. However, therapeutics targeting the dopaminergic system are associated with various adverse reactions, such as addiction and exacerbation of cognitive impairment. This review summarizes the role of the dopaminergic system in the pathology of Alzheimer's disease, focusing on currently available dopamine-based therapies for this disorder and the common side effects associated with dopamine-related drugs. The aim of this review is to provide insights into the potential connections between the dopaminergic system and Alzheimer's disease, thus helping to clarify the mechanisms underlying the condition and exploring more effective therapeutic options.

Figure 1

Dopamine receptors and associated signaling pathways. Dopamine binds to D1-like receptors, which are coupled to Gs, and promotes the activation of adenylate cyclase, increasing cAMP levels and leading to increased PKA activity. PKA phosphorylates downstream targets such as CREB, DARPP-32, glutamate receptors, and GABA receptors. Driven by NMDA receptor agonism, dopamine binds to D1-like receptors and activates DARPP-32, thereby suppressing PP1 activity, which leads to the phosphorylation of downstream MEK and ERK. The binding of dopamine to D2-like receptors, which are coupled to Gi, leads to reduced PKA activity and, consequently, the suppression of phosphorylation of downstream targets. The binding of dopamine to DRD1-DRD2 heterodimer receptor and DRD5, wich are both coupled to Gq, increases PLC activity, which promotes the hydrolysis of PIP2 to IP3 and DAG, resulting in increased intracellular calcium concentrations and PKC activation. The activation of DRD2 leads to the dephosphorylation of Akt, which inhibits its downstream GSK-3 phosphorylation. Created with Procreate and Adobe Illustrator. Akt: Protein kinase B; cAMP: cyclic adenosine monophosphate; CREB: cAMP response element-binding protein; DAG: diacylglycerol; ERK: extracellular signal-regulated kinase; GABAR: gamma-aminobutyric acid receptor; GSK-3β: glycogen synthase kinase 3 beta; IP3: inositol 1,4,5-trisphosphate; JNK: c-Jun N-terminal kinase; MEK: mitogen-activated protein kinase kinase; NMDA: N-methyl-D-aspartate receptor; PKA: protein kinase A; PKC: protein kinase C; PLC: phospholipase C; PP2A: protein phosphatase 2A; STAT3: signal transducer and activator of transcription 3.

Figure 2

Vulnerability of dopaminergic neurons. Dopamine autoxidation can lead to the formation of the toxic products dopamine quinone and ROS. The presence of dopamine quinone and its metabolites can lead to the modification of biological macromolecules, such as proteins, resulting in cellular dysfunction. Dopamine quinone can also be further converted to NM, the excessive accumulation of which can lead to neurotoxicity. With the onset of neuronal degeneration, MAO-B becomes the main enzyme involved in dopamine metabolism, leading to the massive production of ROS and toxic metabolites. Toxic metabolites can then induce the abnormal covalent modification of tau protein. Created with Procreate and Adobe Illustrator. DA: Dopamine; DOPEGAL: 3,4-dihydroxy-phenylglycolaldehyde; MAO-B: monoamine oxidase-B; NM: neuromelanin; ROS: reactive oxygen species.

Figure 3

Mechanisms of action of dopamine receptor-targeted drugs. Galantamine stimulates dopamine release at DRD1 through nACh receptors via allosteric regulations. SKF38393 increases the phosphorylation of CREB, enhances BDNF levels, and reduces BACE1 and Aβ1–42 levels. The phosphorylation of CREB can also promote Bcl-2 expression and reduce cell apoptosis. A-68930 can activate DRD1 and inhibit NLRP3 inflammasome-dependent neuroinflammation through the AMPK/autophagy signaling pathway. Bromocriptine can activate DRD2 receptors and promote the dephosphorylation of JNK by PP2A, thus inhibiting the JNK-mediated transcription of proinflammatory factors and activation of the NLRP3 inflammasome in microglia. Sinomenine can promote the activation and nuclear translocation of DRYAB by activating DRD2 on the astrocyte membrane and inhibiting STAT3 phosphorylation and the expression of downstream proinflammatory factors. Pramipexole can inhibit oxidative stress through the activation of the CREB/RCAN1 and Nrf2/HO-1 pathways. Created with Procreate and Adobe Illustrator. AMPK: AMP-activated protein kinase; BACE1: beta-site amyloid precursor protein cleaving enzyme 1; Bcl-2: B cell lymphoma-2; BDNF: brain-derived neurotrophic factor; CREB: cAMP response element-binding protein; CRYAB: alpha-crystallin B chain; HO-1: heme oxygenase-1; JNK: c-Jun N-terminal kinase; nAChR: nicotinic acetylcholine receptor; NLRP3: NLR-family pyrin domain-containing protein 3; Nrf2: nuclear factor erythroid 2-related factor 2; PP2A: protein phosphatase 2A; RCAN: regulator of calcineurin; STAT3: signal transducer and activator of transcription 3.

Figure 4

Timeline of research findings relating to the role of dopamine in AD. 5-HT: serotonin; ACh: acetylcholine; AD: Alzheimer’s disease; Aβ: amyloid-beta; BACE1: β-site amyloid precursor protein cleaving enzyme 1; BDNF: brain-derived neurotrophic factor; GABA: gamma-aminobutyric acid; nACh: nicotinic acetylcholine; NLRP3: NLR-family pyrin domain-containing protein 3; NM: neuromelanin.