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Review
. 2023 Nov 13:17:1292858.
doi: 10.3389/fncel.2023.1292858. eCollection 2023.

_targeting dopamine transporter to ameliorate cognitive deficits in Alzheimer's disease

Ammara Shaikh  1 , Fairus Ahmad  1 , Seong Lin Teoh  1 , Jaya Kumar  2 , Mohamad Fairuz Yahaya  1
Affiliations
Review

_targeting dopamine transporter to ameliorate cognitive deficits in Alzheimer's disease

Ammara Shaikh et al. Front Cell Neurosci. .

Abstract

Alzheimer's disease (AD) is characterized by the pathologic deposition of amyloid and neurofibrillary tangles in the brain, leading to neuronal damage and defective synapses. These changes manifest as abnormalities in cognition and behavior. The functional deficits are also attributed to abnormalities in multiple neurotransmitter systems contributing to neuronal dysfunction. One such important system is the dopaminergic system. It plays a crucial role in modulating movement, cognition, and behavior while connecting various brain areas and influencing other neurotransmitter systems, making it relevant in neurodegenerative disorders like AD and Parkinson's disease (PD). Considering its significance, the dopaminergic system has emerged as a promising _target for alleviating movement and cognitive deficits in PD and AD, respectively. Extensive research has been conducted on dopaminergic neurons, receptors, and dopamine levels as critical factors in cognition and memory in AD. However, the exact nature of movement abnormalities and other features of extrapyramidal symptoms are not fully understood yet in AD. Recently, a previously overlooked element of the dopaminergic system, the dopamine transporter, has shown significant promise as a more effective _target for enhancing cognition while addressing dopaminergic system dysfunction in AD.

Keywords: Alzheimer's disease; cognition; dopamine; dopamine transporter; mesocorticolimbic pathway.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Regulation of dopamine metabolism and dopamine transporter surface expression in the synaptic cleft. Dopamine is formed from tyrosine and stored in the presynaptic vesicles to be released upon nerve stimulation. The secreted dopamine in the synaptic cleft is attached to the post-synaptic dopamine receptors to transmit the nerve impulse. Soon after achieving the desired effect, the dopamine transporter reuptake results in the termination of signals. The expression of the dopamine transporter is regulated by phosphorylation, followed by internalization through any of the three kinase pathways. The transporter then undergoes ubiquitination, which leads to either degradation by lysosomes or recycling back to the membrane. Created with BioRender.com.
Figure 2
Figure 2
Regulatory mechanism of various DAT inhibitors. The figure compares the mechanism of action of atypical DAT inhibitor (A), substrate-like DAT inhibitor (B), and DILAP (C). The atypical inhibitors bind DAT to block dopamine reuptake (A). The substrate-like inhibitors block dopamine influx while stimulating the DAT-mediated reverse transport of DAT into the synaptic cleft; they also decrease DAT availability by promoting its internalization (B). The DILAP inhibits DAT to increase synaptic dopamine, and their binding cause DAT translocation to the lysosomal membrane, which results in nuclear translocation of the dephosphorylated TFEB to increase expression of autophagic and lysosomal genes, ultimately leading to Aβ-plaques degradation by an unknown mechanism (C). Created with BioRender.com.
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References

    1. Aggarwal S., Liu X., Rice C., Menell P., Clark P. J., Paparoidamis N., et al. . (2019). Identification of a novel allosteric modulator of the human dopamine transporter. ACS Chem. Neurosci. 10, 3718–3730. 10.1021/acschemneuro.9b00262 - DOI - PMC - PubMed
    1. Ambrée O., Richter H., Sachser N., Lewejohann L., Dere E., Souza Silva M. A., et al. . (2009). Levodopa ameliorates learning and memory deficits in a murine model of Alzheimer's disease. Neurobiol. Aging 30, 1192–1204. 10.1016/j.neurobiolaging.2007.11.010 - DOI - PubMed
    1. Barbera L., Vedele F., Nobili A., Krashia P., Spoleti E., Latagliata E. C., et al. . (2021). Nilotinib restores memory function by preventing dopaminergic neuron degeneration in a mouse model of Alzheimer's disease. Progr. Neurobiol. 202, 102031. 10.1016/j.pneurobio.2021.102031 - DOI - PubMed
    1. Benoit-Marand M., Jaber M., Gonon F. (2000). Release and elimination of dopamine in vivo in mice lacking the dopamine transporter: functional consequences: dopamine release in mice lacking DA transporter. Eur. J. Neurosci. 12, 2985–2992. 10.1046/j.1460-9568.2000.00155.x - DOI - PubMed
    1. Bhatia A., Lenchner J. R., Saadabadi A. (2023). “Biochemistry, dopamine receptors,” in StatPearls (StatPearls Publishing: ). - PubMed

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The present work is supported by the study grants funded by Universiti Kebangsaan Malaysia Research University Grant, grant No. GUP-2021-038.

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