Research on the Role of Dopamine and Noradrenaline in Alzheimer’s

Disease and Their Changes in the Aging Brain

Guangmiao Jin

Department of Life Sciences, Imperial College London, SW7 2AZ, U.K.

Keywords: Alzheimer Disease (AD), Aging, Noradrenaline (NA), Dopamine (DA), Neurodegernative Diseases.

Abstract: Alzheimer’s disease (AD) particularly affects the aged generations on a global scale. Dopamine (DA) and

noradrenaline (NA) are the two essential components in regulating human behaviours, cognition and memory

formation. The correlation between the two neuromodulators and AD was intensively studied in this paper. A

wide range of genetically modified animal models were adopted in combination with monitoring methods.

Because AD occurs more frequently in older age, it is suspected that the aging might be a potential factor of

AD. in this review, abundant literatures regarding AD, NA, DA and aging were summarized to generate an

insight. Although the relationship between AD and the NA system remains vague, AD is a long-term affecting

disease and may not be induced simply by aging.

1 INTRODUCTION

According to Global Health Estimates of World

Health Organization (WHO) in 2019, Alzheimer’s

disease (AD) and other dementias rated sixth place

among all the diseases with the highest mortality rate,

causing 814,000 deaths annually. For high-income

countries, neurodegenerative diseases overtook

stroke and became the second most lethal disease

(World Health Organization. (2020). Past research

has identified that beta-amyloid (Aβ) plaque has

strong association with AD and is often regarded as a

histopathological hallmark (Jack 2013). Genetic

studies revealed that the presence of Aβ is frequently

associated with synaptic dysfunction, interrupting

neuronal connectivity and neuronal death in a region-

specific manner (Murphy, & LeVine 2010). AD onset

is often diagnosed in the older age. Similar to AD,

aging is accompanied by the changes in neural

circuits. To reveal the mechanism of how AD is

gradually developed and if there is similarity between

the two factors, some studies related to dopamine

(DA) and noradrenaline (NA) are listed, analysed and

compared. The review aims to guide readers to a more

comprehensive view of NA and DA functioning and

their potential roles in regulating AD and aging. As a

consequence, the clinical trials based on the two

neuromodulator might be attempted, benefiting the

AD patients. In the following text, dopaminergic and

noradrenergic systems with linkage to aging will be

discussed in more detail.

2 DA PATHWAY

Tyrosine is the precursor amino acid in DA

biosynthesis. Tyrosine hydroxylase (TH) catalyzes

the conversion of L-tyrosine to L-

dihydroxyphenylalanine (L-DOPA). Consequently,

the decarboxylation reaction catalyzed by DOPA

decarboxylase (DDAP) removes one molecule of

carbon dioxide from the L-DOPA molecule and

converts L-DOPA to dopamine (Pan, Kaminga, Wen,

Wu, Acheampong, & Liu 2019). Synthesized DA is

immediately transported out from the cytosol of the

dopaminergic neurons into the monoaminergic

synaptic vesicles by vesicular monoamine

transporters (VMAT-2). VMAT-2 is located at the

membrane of the vesicle. DA uptake into

monoaminergic vesicles prevents the accumulation of

free DA and the oxidation of DA to o-quinone, as

VMAT-2-coupled ATPase actively pumps protons

into the vesicles to build up a high proton gradient.

DA stored in the dopaminergic vesicle is released into

the synaptic cleft and binds onto the DA receptor on

the postsynaptic neuron membrane. DA remained in

the cleft is cleaved by a DA transporter which

Jin, G.

Research on the Role of Dopamine and Noradrenaline in Alzheimer’s Disease and Their Changes in the Aging Brain.

DOI: 10.5220/0011248100003438

In Proceedings of the 1st International Conference on Health Big Data and Intelligent Healthcare (ICHIH 2022), pages 221-227

ISBN: 978-989-758-596-8

221

localizes on the dopaminergic membrane (Segura-

Aguilar, Paris, Muñoz, Ferrari, Zecca, & Zucca

2014).

DA neuron loss has been a widely accepted

concept in explaining AD progression. Hippocampus

which controls the memory formation and voluntary

movement receives input from both cortical and

subcortical regions. Consistent with the observation,

hippocampal DA is released from the ventral

tegmental area (VTA) which contributes to the

subcortical input. Decreased levels of DA neurons

and DA receptors are often detected in AD patients’

brains, in agreement with the changes in the

midbrain-located DA system of Tg2576 mouse

model. Tg2576 mice were genetically modified to

overexpress mutated amyloid precursor proteins

(APPs). Also, DA is a well-recognized modulator for

hippocampal plasticity. The memory formation is

encoded by the binding of DA at the hippocampal DA

receptors (Nobili 2017). In addition, previous studies

applying the 18F - fluorodeoxyglucose Positron

Emission Tomography indicated that human neuronal

function loss occurs prior to the onset of AD.

Synaptic dysfunction is one of the early indicators,

marking the initiation of pathology. Spine loss in

mice harboring the human familial gene mutation is

positively correlated with the appearance of cognitive

impairment. Synaptic connectivity determines the

signal transmission efficiency, further impacting on

the learning and memory (Kashyap, Bapat, Das,

Gowaikar, Amritkar, Rangarajan, Ravindranath, &

Ambika 2019). In line with these finding, aging is

positively correlated with neuronal degeneration.

Noda et al. reported the age-dependent DA neuronal

loss and mitochondrial dysfunction in DA neurons of

C57BL/6 mice (Noda, Sato, Fukuda, Tada, & Hattori

2020). Wang et al. in 2019 also demonstrated that

normally aged rat brains contained fewer DA

neurons, as the number of TH positive neurons

declined significantly in 18-month and 28-month than

their younger counterparts which were 2- and 6-

month-old (Figure 1) (Wang, Zhou, Wang, Li, Liu, &

Zhang 2019).

Figure 1. The image shows the stained neurons using anti-TH in four age groups: 2-month, 6-month, 18-month and 28-month-

old. Quantitative counting is summarized as a bar chart in which *P < .05 compared with 2-month-old rats (Wang, Zhou,

Wang, Li, Liu, & Zhang 2019).

In neurons with high DA concentration, reactive

oxygen species (ROS) is often generated by DA

autoxidation, including superoxide anion radical

(O2•–) and hydrogen peroxide (H2O2) which

severely damages cellular activities (Linert,

Herlinger, Jameson, Kienzl, Jellinger, & Youdim

1996). ROS can bring a series of toxic consequences:

such as mitochondrial dysfunction, oxidative stress

and protein denaturation. Not only Aβ, ROS is also a

potential pathological factor that intertwines with Aβ

through numerous routes. Aβ complex binding to

metal ions such as Cu (I/II) and Zn (II) facilitates Aβ

aggregation and toxic oligomer formation. In

addition, the redox-active metal bound Aβ complex

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promotes the overproduction of ROS. Consequently,

ROS overproduction would impose detrimental

effects on nucleic acids, lipids and cellular organelles

(Han, Lee, Kim, Lee, Suh, Cho, Chae, & Lim 2018).

These factors can individually or mutually contribute

to oxidative transformation of DA, bridging the gap

between DA and AD pathology. DA is responsible for

long-term memory and motor activities, therefore,

Aβ-included DA system dysfunction, as well as

degeneration of AD-releasing neurons in VTA region

were commonly reported in AD-affected brains. In

conclusion, DA, along with its oxidative derivatives,

would have a potential role in oxidizing metal-bound

or metal-free Aβ oligomers and regulating Aβ

aggregation pathways (Nam, Derrick, Lee, Kang,

Han, Lee, Chung, & Lim 2018).

Despite that aging is reported to be a major risk

factor of AD, normal aging still overlaps with AD in

terms of pathology and postulated mechanisms. For

instance, neurofibrillary tangles (NFTs) and plaques

are frequently found in brains of neurologically

normal individuals in postmortem studies (Figure 2)

(Davis, Schmitt, Wekstein, & Markesbery 1999).

Besides, tau pathology which has been confined in

LC and entorhinal cortex (EC) is also detected in

many aged brains. The deposit of phosphorylated tau

was visualized by staining and identified via the

immunocytochemistry techniques. The severity of

AD develops with aging until the symptoms are

diagnosable (Braak, Thal, Ghebremedhin, & Del

Tredici 2011). In addition, oxidative balance in brains

is disrupted with aging, as the capacity of

synthesizing anti-oxidants decreases significantly.

Thus, ROS accumulates and inhibits the

metabolically important pathways, such as the

synthesis of DNA, lipids and proteins. Moreover,

inefficient oxidative phosphorylation in mitochondria

of older individuals might aggravate the oxidative

stress (Sutherland, Chami, Youssef, & Witting 2013).

The close association between aging, mitochondrial

dysfunction and oxidative burden in AD formation

would implicate that antioxidants would be a

potential medical target.

3 NA PATHWAY

Noradrenergic pathway initiates from the cell bodies

in LC and propagates towards different cerebral

regions, spinal cord, and other areas, such as the

amygdala, hippocampus, and hypothalamus (Moret,

& Briley 2011). Unlike GABA or glutamate which

binds to ionotropic receptors in fast action, NA is a

neuromodulator and mainly activates metabotropic

receptors (Ranjbar-Slamloo, & Fazlali 2020). NA is

synthesized from precursor amino acid tyrosine by a

series of steps. Dopamine-β-hydroxylase is one of the

critical enzymes which catalyze the conversion of

dopamine to NA. Once the step is completed, the

vesicle packs NA and transports it across the

membrane by VMAT2 into the synaptic cleft via

exocytosis. Otherwise, catechol-O-

methyltransferases (COMT) or monoamine oxidases

(MAO) can enzymatically digest the extracellular NA

molecules (Figure 3) (Gannon, & Wang 2019). The

release of noradrenaline is mediated by adrenoceptors

which could generate different effects. For instance,

activation of presynaptic α2-adrenoceptors (α2-ARs)

and β2-adrenoceptors (β2-ARs) respectively inhibits

and promotes NA release. Transporter facilitates the

recycling of NA into the presynaptic neuron. The

complexity of NA is regulated by the density or

distribution of different adrenoceptor subtypes

(Gareri, De Fazio, & De Sarro 2002).

Figure 2. The process of NA synthesized in the presynaptic neuron and different fates of NA (Reprinted from “NA synthesis

and export”, by BioRender.com (2021).

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As NA is mainly supplied from LC, the

degeneration of NA is marked as an early sign of

neurodegeneration. One of the most obvious changes

in the LC region is the decline in the number of NA

neurons. A significant NA neuron loss can lead to AD

progression (Holland, Robbins, & Rowe 2021). The

remaining NA neurons would initiate changes in

activity as a compensation. For instance, the mRNA

level of TH would increase in the remaining NA

neurons, since TH is involved in the rate-limiting

step. According to TH-immunoreactivity (TH-IR)

quantification, the number of TH-IR-positive neurons

reduced significantly in AD subjects (Figure 3). The

evidence further emphasizes the importance of NA in

maintaining the normal functioning of human brains.

Besides, NA negatively regulates the transcription of

pro-inflammatory genes in astrocytes and microglia

and the production of the cytokine and chemokine, as

well as controlling the microglial and phagocytosis

migration (McMillan, White, Franklin, Greenup,

Leverenz, Raskind, & Szot 2011).

Figure 3. Cell bodies are independently assessed as individual neurons. The number of TH-IR positive cells in AD is

significantly fewer than the control (Left histogram). TH-IR positive fiber score is an indicator of TH level. No clear difference

is observed between the two groups (Right histogram). The two results, in combination, would implicate a compensation

behaviour in AD-loss scenario (McMillan, White, Franklin, Greenup, Leverenz, Raskind, & Szot 2011).

In post-mortem studies of AD patients’ brains,

tissue separation and oligonucleotide probe which

targets at the AR of interest were performed

individually. It was found that various AR subtypes

undergo different changes. The expression level

ofα1A- and α2A-AR mRNA in the hippocampus

remains constant, whereas the expression level

ofα1D- and α2C-AR mRNA reduces profoundly

(Szot, White, Greenup, Leverenz, Peskind, &

Raskind 2006). Alterations in the AR are constantly

observed with the changes in receptor expression and

density, affecting sensitivity and amplitude of the NA

modulating abilities (Gannon, & Wang 2019).

Furthermore, AR subtypes were proved to be related

to the formation of Aβ. For instance, α2A-AR

activation interprets the interaction of APP with a

Vps10 family receptor which mediates the APP

sorting. Therefore, activation of inα2A-AR promotes

the amyloidogenic process (Chen, Peng, Che,

Gannon, Liu, Li, Bu, van Groen, Jiao, & Wang 2014).

Similarly, β2-AR up-regulates the γ-secretase

activity. Activated γ-secretase, along with β-

secretase, cleaves APP to produce Aβ. Thereby β2-

AR accelerates the pathology of AD by stimulating

more Aβ plaques formed in the brains (Ni, Zhao, Bao,

Zou, Teng, Wang, Song, Xiong, Bai, & Pei 2006).

The β2-AR also functions to influence the microglial

dynamics. Strikingly, the effect of β2-AR imposed on

microglia depends on the stress level. By comparing

mice during wakefulness and sleeping, β2-AR was

found to diminish the activity and clearance ability of

microglia for awake mice. In contrast, β2-AR

inhibitors down-regulate the stress-induced activities

of microglia (Mather 2021).

Even though a clear relationship between the

postmortem LC neuron count and aging has not been

established, several other indicators have implied the

decline in the LC-NA system. One of the indicators is

the decreased NA level with aging in some brain

regions, such as the cingulate gyrus, hippocampus,

hippocampus and hindbrain (Mather, Gutchess, &

Thomas 2019). Complementarily, NA level in

cerebrospinal fluid and blood grows with age

progression. Seals & Esler estimated that a 15-20%

increase per decade in plasma NA would be observed

over the adult range. More NA spillover into plasma

was reported in accord with aging (Seals, & Esler

2000). The degree of increase is even more obvious

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in AD patients than in healthily aged adults (Elrod,

Peskind, DiGiacomo, Brodkin, Veith, & Raskind

(1997). Strikingly, hyperactivation of LC-NA

systems would also occur in the early AD stage. LC

hyperactivation promotes the Ca2+ influx and

mitochondrial toxicity. Furthermore, the pacemaker

activity is interpreted, associated with an elevation in

bioenergetic demand which would potentially induce

a significant level of oxidative stress (Weinshenker

2018). Moreover, tau pathology continues to progress

in LC with aging. Increasing tau proteins are

hyperphosphorylated and integrate as oligomers. The

tubulin-binding affinity of hyperphosphorylated tau

decreases. Instead, tau proteins tend to aggregate.

Consistently, aggregated tau is often involved in the

initial phase of AD and other neurodegenerative

diseases (Iqbal, Liu, & Gong 2016). At least, by

current studies, clinical signs of AD are detectable in

an early age but can also be symptomless, since pre-

tangles and NFTs in nerves can exist for decades.

Although AD is not likely to be age-dependent, it

develops in a long-term mode and extends in old ages

(Braak, & Del Tredici 2011).

4 CONCLUSIONS

The article reviews the past investigations on the DA

and NA. In conclusion, DA and NA, being provided

from VTA and LC, are both crucial neuromodulators

in terms of modulating brain states and memory

formation. They influence the brain functioning from

several mechanisms: (1) reduction or lack of neurons

synthesizing DA or NA; (2) adding burden to

oxidative stress in the neurons; (3) variation in the

density and expression levels of different AR

subtypes. These findings provide new strategies for

designing drugs which target specifically at AD

patients in the hope that their brains’ normal functions

could be recovered. Although brain changes during

normal aging overlap partially with changes in AD

patients’ brain, there is still no clear evidence to prove

that aging is directly correlated to AD progress. But

instead, AD is more likely to affect an individual from

an early age until the symptoms reveal in a relatively

older age. Thus, it would be worth exploring if there

is any other factors correlated to aging.

REFERENCES

Braak, H. & Del Tredici, K. (2011) The pathological

process underlying Alzheimer's disease in individuals

under thirty. Acta Neuropathologica. 121 (2), 171-181.

Available from: doi: 10.1007/s00401-010-0789-4 [doi].

Braak, H., Thal, D. R., Ghebremedhin, E. & Del Tredici, K.

(2011) Stages of the Pathologic Process in Alzheimer

Disease: Age Categories From 1 to 100 Years. Journal

of Neuropathology & Experimental Neurology. 70

(11), 960-969. Available

from: https://doi.org/10.1097/NEN.0b013e318232a37

9. Available from: doi:

10.1097/NEN.0b013e318232a379. [Accessed

9/28/2021].

Chen, Y., Peng, Y., Che, P., Gannon, M., Liu, Y., Li, L.,

Bu, G., van Groen, T., Jiao, K. & Wang, Q. (2014)

α2A adrenergic receptor promotes amyloidogenesis

through disrupting APP-SorLA

interaction. Proceedings of the National Academy of

Sciences. 111 (48), 17296-17301. Available

from: http://www.pnas.org/content/111/48/17296.abstr

act. Available from: doi: 10.1073/pnas.1409513111.

Davis, D. G., Schmitt, F. A., Wekstein, D. R. &

Markesbery, W. R. (1999) Alzheimer Neuropathologic

Alterations in Aged Cognitively Normal

Subjects. Journal of Neuropathology & Experimental

Neurology. 58 (4), 376-388. Available

from: https://doi.org/10.1097/00005072-199904000-

00008. Available from: doi: 10.1097/00005072-

199904000-00008. [Accessed 9/30/2021].

Elrod, R., Peskind, E. R., DiGiacomo, L., Brodkin, K. I.,

Veith, R. C. & Raskind, M. A. (1997) Effects of

Alzheimer's disease severity on cerebrospinal fluid

norepinephrine concentration. The American Journal of

Psychiatry. 154 (1), 25-30. Available from: doi:

10.1176/ajp.154.1.25 [doi].

Gannon, M. & Wang, Q. (2019) Complex noradrenergic

dysfunction in Alzheimer's disease: Low

norepinephrine input is not always to blame. Brain

Research. 1702 12-16. Available

from: https://pubmed.ncbi.nlm.nih.gov/29307592 https

://www.ncbi.nlm.nih.gov/pmc/articles/PMC6855395/.

Available from: doi: 10.1016/j.brainres.2018.01.001.

Gareri, P., De Fazio, P. & De Sarro, G. (2002)

Neuropharmacology of depression in aging and age-

related diseases. Ageing Research Reviews. 1 (1), 113-

134. Available from: doi: S0047637401003700 [pii].

Han, J., Lee, H. J., Kim, K. Y., Lee, S. J. C., Suh, J., Cho,

J., Chae, J. & Lim, M. H. (2018) Tuning Structures and

Properties for Developing Novel Chemical Tools

toward Distinct Pathogenic Elements in Alzheimer’s

Disease. ACS Chemical Neuroscience. 9 (4), 800-808.

Available

from: https://doi.org/10.1021/acschemneuro.7b00454.

Available from: doi: 10.1021/acschemneuro.7b00454.

Holland, N., Robbins, T. W. & Rowe, J. B. (2021) The role

of noradrenaline in cognition and cognitive

disorders. Brain. 144 (8), 2243-2256. Available

from: https://doi.org/10.1093/brain/awab111.

Available from: doi: 10.1093/brain/awab111.

[Accessed 9/24/2021].

Iqbal, K., Liu, F. & Gong, C. (2016) Tau and

neurodegenerative disease: the story so far. Nature

Research on the Role of Dopamine and Noradrenaline in Alzheimer’s Disease and Their Changes in the Aging Brain

225

Reviews Neurology. 12 (1), 15-27. Available

from: https://doi.org/10.1038/nrneurol.2015.225.

Available from: doi: 10.1038/nrneurol.2015.225.

Jack, C. R., Knopman, D. S., Jagust, W. J., Petersen, R. C.,

Weiner, M. W., Aisen, P. S., Shaw, L. M., Vemuri, P.,

Wiste, H. J., Weigand, S. D., Lesnick, T. G., Pankratz,

V. S., Donohue, M. C. & Trojanowski, J. Q. (2013)

Tracking pathophysiological processes in Alzheimer's

disease: an updated hypothetical model of dynamic

biomarkers. The Lancet Neurology. 12 (2), 207-216.

Available

from: https://www.sciencedirect.com/science/article/pi

i/S1474442212702910. Available from:

doi: https://doi.org/10.1016/S1474-4422(12)70291-0.

Kashyap, G., Bapat, D., Das, D., Gowaikar, R., Amritkar,

R. E., Rangarajan, G., Ravindranath, V. & Ambika, G.

(2019) Synapse loss and progress of Alzheimer’s

disease -A network model. Scientific Reports. 9 (1),

6555.10.1038/s41598-019-43076-y.

Linert, W., Herlinger, E., Jameson, R. F., Kienzl, E.,

Jellinger, K. & Youdim, M. B. H. (1996) Dopamine, 6-

hydroxydopamine, iron, and dioxygen — their mutual

interactions and possible implication in the

development of Parkinson's disease. Biochimica Et

Biophysica Acta (BBA) - Molecular Basis of

Disease. 1316 (3), 160-168. Available

from: https://www.sciencedirect.com/science/article/pi

i/0925443996000208. Available from:

doi: https://doi.org/10.1016/0925-4439(96)00020-8.

Mather, M. (2021) Noradrenaline in the aging brain:

Promoting cognitive reserve or accelerating

Alzheimer's disease? Seminars in Cell &

Developmental Biology. 116 108-124. Available

from: https://www.sciencedirect.com/science/article/pi

i/S1084952121001221. Available from:

doi: https://doi.org/10.1016/j.semcdb.2021.05.013.

Mather, M., Gutchess, A. & Thomas, A. E. (2019) How

arousal-related neurotransmitter systems compensate

for age-related decline. The Cambridge Handbook of

Cognitive Aging: A Life Course Perspective.

McMillan, P. J., White, S. S., Franklin, A., Greenup, J. L.,

Leverenz, J. B., Raskind, M. A. & Szot, P. (2011)

Differential response of the central noradrenergic

nervous system to the loss of locus coeruleus neurons

in Parkinson's disease and Alzheimer's disease. Brain

Research. 1373 240-252. Available

from: https://www.sciencedirect.com/science/article/pi

i/S0006899310026545. Available from:

doi: https://doi.org/10.1016/j.brainres.2010.12.015.

Moret, C. & Briley, M. (2011) The importance of

norepinephrine in depression. Neuropsychiatric

Disease and Treatment. 7 9-13. Available

from: https://pubmed.ncbi.nlm.nih.gov/21750623 https

://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131098/.

Available from: doi: 10.2147/NDT.S19619.

Murphy, M. P. & LeVine, H., 3rd. (2010) Alzheimer's

disease and the amyloid-beta peptide. Journal of

Alzheimer's Disease: JAD. 19 (1), 311-323. Available

from: https://pubmed.ncbi.nlm.nih.gov/20061647 https

://www.ncbi.nlm.nih.gov/pmc/articles/PMC2813509/.

Available from: doi: 10.3233/JAD-2010-1221.

Nam, E., Derrick, J. S., Lee, S., Kang, J., Han, J., Lee, S. J.

C., Chung, S. W. & Lim, M. H. (2018) Regulatory

Activities of Dopamine and Its Derivatives toward

Metal-Free and Metal-Induced Amyloid-β

Aggregation, Oxidative Stress, and Inflammation in

Alzheimer’s Disease. ACS Chemical Neuroscience. 9

(11), 2655-2666. Available

from: https://doi.org/10.1021/acschemneuro.8b00122.

Available from: doi: 10.1021/acschemneuro.8b00122.

Ni, Y., Zhao, X., Bao, G., Zou, L., Teng, L., Wang, Z.,

Song, M., Xiong, J., Bai, Y. & Pei, G. (2006) Activation

of β2-adrenergic receptor stimulates γ-secretase activity

and accelerates amyloid plaque formation. Nature

Medicine. 12 (12), 1390-1396. Available

from: https://doi.org/10.1038/nm1485. Available from:

doi: 10.1038/nm1485.

Nobili, A., Latagliata, E. C., Viscomi, M. T., Cavallucci,

V., Cutuli, D., Giacovazzo, G., Krashia, P., Rizzo, F.

R., Marino, R., Federici, M., De Bartolo, P., Aversa, D.,

Dell’Acqua, M. C., Cordella, A., Sancandi, M., Keller,

F., Petrosini, L., Puglisi-Allegra, S., Mercuri, N. B.,

Coccurello, R., Berretta, N. & D’Amelio, M. (2017)

Dopamine neuronal loss contributes to memory and

reward dysfunction in a model of Alzheimer’s

disease. Nature Communications. 8 (1), 14727.

Available

from: https://doi.org/10.1038/ncomms14727.

Available from: doi: 10.1038/ncomms14727.

Noda, S., Sato, S., Fukuda, T., Tada, N. & Hattori, N.

(2020) Aging-related motor function and dopaminergic

neuronal loss in C57BL/6 mice. Molecular Brain. 13

(1), 46. Available

from: https://doi.org/10.1186/s13041-020-00585-6.

Available from: doi: 10.1186/s13041-020-00585-6.

Pan, X., Kaminga, A. C., Wen, S. W., Wu, X.,

Acheampong, K. & Liu, A. (2019) Dopamine and

Dopamine Receptors in Alzheimer's Disease: A

Systematic Review and Network Meta-

Analysis. Frontiers in Aging Neuroscience. 11 175.

Available

from: https://pubmed.ncbi.nlm.nih.gov/31354471 https

://www.ncbi.nlm.nih.gov/pmc/articles/PMC6637734/.

Available from: doi: 10.3389/fnagi.2019.00175.

Ranjbar-Slamloo, Y. & Fazlali, Z. (2020) Dopamine and

Noradrenaline in the Brain; Overlapping or Dissociate

Functions? Frontiers in Molecular Neuroscience. 12

334. Available

from: https://www.frontiersin.org/article/10.3389/fnm

ol.2019.00334.

Reprinted from “NA synthesis and export”, by

BioRender.com (2021). Retrieved from:

https://app.biorender.com/illustrations/602cf1f6c8e56

800a3c62566

Seals, D. R. & Esler, M. D. (2000) Human ageing and the

sympathoadrenal system. The Journal of

Physiology. 528 407-417. Available

from: https://pubmed.ncbi.nlm.nih.gov/11060120 https

://www.ncbi.nlm.nih.gov/pmc/articles/PMC2270159/.

ICHIH 2022 - International Conference on Health Big Data and Intelligent Healthcare

226

Available from: doi: 10.1111/j.1469-

7793.2000.00407.x.

Segura-Aguilar, J., Paris, I., Muñoz, P., Ferrari, E., Zecca,

L. & Zucca, F. A. (2014) Protective and toxic roles of

dopamine in Parkinson's disease. Journal of

Neurochemistry. 129 (6), 898-915. Available

from: https://doi.org/10.1111/jnc.12686. Available

from: doi: https://doi.org/10.1111/jnc.12686.

Sutherland, G. T., Chami, B., Youssef, P. & Witting, P. K.

(2013) Oxidative stress in Alzheimer's disease: Primary

villain or physiological by-product? Null. 18 (4), 134-

141. Available

from: https://doi.org/10.1179/1351000213Y.00000000

52. Available from: doi:

10.1179/1351000213Y.0000000052.

Szot, P., White, S. S., Greenup, J. L., Leverenz, J. B.,

Peskind, E. R. & Raskind, M. A. (2006) Compensatory

Changes in the Noradrenergic Nervous System in the

Locus Ceruleus and Hippocampus of Postmortem

Subjects with Alzheimer's Disease and Dementia with

Lewy Bodies. The Journal of Neuroscience. 26 (2),

467-478. Available

from: http://www.jneurosci.org/content/26/2/467.abstr

act. Available from: doi: 10.1523/JNEUROSCI.4265-

05.2006.

Wang, G., Zhou, Y., Wang, Y., Li, D., Liu, J. & Zhang, F.

(2019) Age-Associated Dopaminergic Neuron Loss and

Midbrain Glia Cell Phenotypic

Polarization. Neuroscience. 415 89-

96.https://doi.org/10.1016/j.neuroscience.2019.07.021.

Weinshenker, D. (2018) Long Road to Ruin: Noradrenergic

Dysfunction in Neurodegenerative Disease. Trends in

Neurosciences. 41 (4), 211-223. Available from: doi:

S0166-2236(18)30034-1 [pii].

World Health Organization. (2020) The top 10 causes of

death. https://www.who.int/news-room/fact-

sheets/detail/the-top-10-causes-of-

death#.YUio2eFUdhU.link [Accessed 20th September

2021]

Research on the Role of Dopamine and Noradrenaline in Alzheimer’s Disease and Their Changes in the Aging Brain

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