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Ruggiero, M.;  Calvello, R.;  Porro, C.;  Messina, G.;  Cianciulli, A.;  Panaro, M.A. Caffeine in Neurodegenerative Diseases. Encyclopedia. Available online: https://encyclopedia.pub/entry/32474 (accessed on 24 April 2024).
Ruggiero M,  Calvello R,  Porro C,  Messina G,  Cianciulli A,  Panaro MA. Caffeine in Neurodegenerative Diseases. Encyclopedia. Available at: https://encyclopedia.pub/entry/32474. Accessed April 24, 2024.
Ruggiero, Melania, Rosa Calvello, Chiara Porro, Giovanni Messina, Antonia Cianciulli, Maria Antonietta Panaro. "Caffeine in Neurodegenerative Diseases" Encyclopedia, https://encyclopedia.pub/entry/32474 (accessed April 24, 2024).
Ruggiero, M.,  Calvello, R.,  Porro, C.,  Messina, G.,  Cianciulli, A., & Panaro, M.A. (2022, November 02). Caffeine in Neurodegenerative Diseases. In Encyclopedia. https://encyclopedia.pub/entry/32474
Ruggiero, Melania, et al. "Caffeine in Neurodegenerative Diseases." Encyclopedia. Web. 02 November, 2022.
Caffeine in Neurodegenerative Diseases
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There has been considerable research showing that coffee consumption seems to be beneficial to human health, as it contains a mixture of different bioactive compounds such as chlorogenic acids, caffeic acid, alkaloids, diterpenes and polyphenols. Neurodegenerative diseases (NDs) are debilitating, and non-curable diseases associated with impaired central, peripheral and muscle nervous systems. Several studies demonstrate that neuroinflammation mediated by glial cells—such as microglia and astrocytes—is a critical factor contributing to neurodegeneration that causes the dysfunction of brain homeostasis, resulting in a progressive loss of structure, function, and number of neuronal cells. This happens over time and leads to brain damage and physical impairment. The most known chronic NDs are represented by Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD). According to epidemiological studies, regular coffee consumption is associated with a lower risk of neurodegenerative diseases. 

caffeine neurodegenerative diseases neuroinflammation

1. Introduction

Neuroinflammation represents a defense mechanism aimed to protect the brain by removing or disrupting noxious agents and microorganisms [1]. Although this host mechanism seems to determine beneficial effects—by removing cellular debris and promoting tissue repair as well as preserving the brain integrity—prolonged and sustained inflammation may result in some circumstances that are detrimental, causing damage to nervous tissue, thereby leading to neuron death and developing neurodegenerative diseases. [2][3]. Neuroinflammation is the inflammatory response described in the brain and involves some glial cells, named microglia and astrocytes, which actively participate to innate immune response in the central nervous system (CNS). However, if microglia and astrocytes remain activated for too long, they become responsible for a persistent inflammatory response, which can cause neurodegenerative disorders [2].
Within the last two decades, significant advances regarding the role that microglial cells play in the development of CNS diseases have been reached, these advances demonstrate how microglia activation is a trademark of a wide array of neurodegenerative diseases, such as Alzheimer ‘s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), as well as other brain diseases including amyotrophic lateral sclerosis (ASL) and Huntington’s disease (HD) due to the dysregulation of the defenee function and neuroinflammation [4][5].
Therefore, the deletion of negative effects associated with microglial activation have emerged as a possible therapeutic strategy to counteract the neuroinflammation-associated neurodegeneration [6][7].
Unfortunately, until now, no drug has been described capable to block or slow the progression of neurodegenerative pathologies, thus, actually a high number of investigations focalize the attention to search for natural bioactive compounds that could have beneficial effects on brain disorders, without affecting healthy cells.

2. Neuroprotective Effect of Caffeine in AD

AD is the most common form of dementia. This disorder, typical of elderly, is a neurodegenerative syndrome characterized by a slow and permanent loss of cognitive function. Memory loss, language issues, personality changes, lack of initiative, confusion, disorientation and the loss of logic and judgment are the most common symptoms of AD. Experts think that hereditary and environmental variables, as well as a particular style and, in some cases, familiarity with the condition, all contribute to the development of AD. The evidence on the pathophysiology of this form of dementia is clear: The cerebral extracellular deposition of diffuse and neuritic senile plaques is made by Aβ peptides, as well as the intracellular aggregation of flame-shaped neurofibrillary tangles (NFTs) that are made up of hyperphosphorylated aggregates of the microtubule-associated tau protein selectively mediate large-scale neuronal loss.
The tau-hyperphosphorylated protein and beta-amyloid (specifically the variant Aβ42) are proteins produced by the brain, the latter of which the brain is unable to eliminate. Both of these proteins then accumulate and start damaging neurons many years before memory disturbances appear [8][9]. Cell death begins in a region of the brain called the hippocampus. The hippocampus, located in the temporal lobe, is primarily involved in learning and memory processes. Subsequently, cell death extends to the involvement of the entire brain and leads to additional cognitive and functional difficulties that are observed in people with AD [10].
The mechanism behind the production of amyloid plaques and neurofibrillary tangles remains unknown. What is known is that they involve the damage and death of brain cells, resulting in memory difficulties and behavioral changes. Further, hypotheses include the presence of beta-amyloid oligomers which, like the amyloid plaques, are also potentially neurotoxic. Furthermore, the abnormal release of neurotransmitters, such as glutamate, also contributes to neuronal death and inflammatory processes within the brain. The neuro-inflammatory process is similarly involved in the complex cascade of processes that cause AD and subsequent symptoms. This process is therefore implicated both in the pathogenesis of AD and in its progression [8].
Currently, there have not been described efficient pharmacological approaches capable of reversing cognitive impairment and typical decline associated with AD.
Previous studies report that caffeine could prevent the Aβ aggregation through hydrophobic contacts with monomers or small aggregates [11].
Successive investigations demonstrated detectable effects of caffeine on Aβ fibrillization only when it was used at higher doses (10-fold molar excess caffeine). These surprising discrepancies probably reflect the different experimental conditions, being the prior existing study, which employed truncated Aβ16-22, instead of Aβ1-40 used in the other investigations, thus, highlighting the complexity of both assay conditions and aggregation processes. For example, changes in the pH solution, buffer composition, as well as differences of Aβ or tau concentrations, may lead to variations in the experimental outcomes [12]. The reported results have been conducted in in vitro models; therefore, it is possible that the same effect may not be reproduced in in vivo system. In this regard, Costa et al. reported that caffeine treatment in aged mice results in a significantly higher recognition and memory capacity than in age-matched control mice; this action may be due to a neuroprotective effect linked to the upregulation of the brain-derived neurotrophic factor (BDNF) or that of the tyrosine kinase receptor (TrkB) at hippocampal level [13]. Confirming these observations, Arendash et al. showed that aged transgenic AD mice fed an equivalent of 5 cups of coffee per day, in humans, had lower levels of β-amyloid in the hippocampus because of the suppression of both β-secretase (BACE1) and presenilin 1 (PS1) γ-secretase. Furthermore, these authors have shown, regarding the mechanism of action, that the suppression of caffeine by BACE1 involves the cRaf-1/NF-kB pathway [14]. Finally, aged APPsw mice showed improvement in memory capacity and a reversion of AD pathology, thus, suggesting a possible therapeutic role for caffeine in determined AD cases [15].
Some studies emphasized that the intake of caffeine prevents memory impairment in animal models of AD. Dall’Igna et al., in fact, demonstrated that combined acute (30 mg/kg) and prolonged (1 mg/mL) treatments of caffeine prevented cognitive dysfunction induced by 25–35 fragments of β-amyloid in mice, an effect mimicked by selective A2A receptor antagonists. The same outcome was also obtained through subchronic (4 days) treatment with daily injections of caffeine (30 mg/kg) [16]. Other authors observed, in mice, that caffeine consumption at higher non-toxic doses improved the performance of β-amyloid-induced spatial memory resulting from the blockade of the A2A receptor. However, the same neuroprotective effect was also observed combining caffeine-prolonged treatment with the acute administration of caffeine This treatment, in fact, seems to be able to improve the behavioral effects resulting from the blocking of the A2A receptor, while causing tolerance to the effects of the A1 receptor blockade [17]. In another study, Canas et al. showed that the pharmacological or genetic blockade of the A2A receptor prevents the synaptotoxicity induced by Aβ1-42 and the consequent memory deficit through a p38—MAPK (mitogen-activated protein kinase)-dependent pathway. This provides a molecular basis for the benefits of caffeine consumption in AD [18]. Furthermore, in an experimental model of sporadic AD, it was shown that caffeine consumption prevented streptozotocin (STZ) -induced behavioral modifications and neurodegeneration in the hippocampus, as well as upregulation of the A2A receptor [19].
An analytical study of the risk factors for AD, conducted on a group of 1023 people aged 65 and over, found that coffee consumption is associated with a 31% reduction risk of disease incidence [20]. This result has also been described by Eskelinen and collaborators who evaluated the association between coffee consumption in middle age and the risk of AD/dementia in old age over a 21-year follow-up. Consequently, moderate coffee users (3–5 cups/24 h) were shown to have a lower risk of AD/dementia than low coffee users (0–2 cups/24 h), thus, suggesting that regular coffee/caffeine can be beneficial for both AD and dementia [21].

3. Neuroprotective Effect of Caffeine in PD

About 1% of people over the age of 60 worldwide are severely affected by PD, which is the second most common neurodegenerative disease and is caused by dopaminergic neuronal loss of the SNpc. PD is a neurological disorder in which the first symptoms are not progressively evident, so, as a consequence, patients often lack adequate timely treatment [22][23]. PD produces both motor and non-motor impairment. Motor strength appears after the loss of 50–70% of nervous system cells and includes rigidity, bradykinesia, resting tremors and inadequate postural reflexes. Non-motor symptoms include abnormalities of mood, cognitive function, sleep, autonomy, dementia and changes in smell and memory. This condition is recognized to be etiologically caused by both environmental (90–95%) and genetic (5–10%) causes [24].
Many causative factors associated with PD have been identified so far, such as dopamine metabolism, impaired mitophagy, electron transport chain dysfunction, the induction of aberrant neuroinflammation, oxidative stress, activation of microglia, the formation of Lewy bodies and aging. Lewy bodies are mainly given by the deposition of α-syn encoded by the SNCA gene that plays a pivotal role in the pathogenesis of PD. The abnormal accumulation of soluble monomers of α-syn leads to oligomers formation and fibrils as a central event in the early stages of PD [25].
Many metabolic activities required by the organism result in oxidative stress [26]. On the other side, it has the potential to be harmful and detrimental to the body. Oxidative alterations, such as a reduction in the antioxidant defense system or the activation of glial cells, which are a source of oxidative stress, are crucial in the pathophysiology of PD because the generation of reactive oxygen species during the progression of PD damages the substantia nigra by lipid peroxidation, protein oxidation and DNA oxidation. Changes in the antioxidant defense system appear to be the cause of this condition. As a result, it is recognized that oxidative stress and inflammation are two essential variables that contribute to nervous system damage [27][28].
Currently, therapeutic treatments involve the administration of drugs that alleviate symptoms. As a result, new treatments are required, not just to arrest its development, but also to prevent it. For these reasons, natural substances with neuroprotective effects, including coffee, have gained attention. Caffeine has neuroprotective qualities, which may be connected to its antioxidant characteristics [29]. Caffeine can also reduce lipid peroxidation by lowering the generation of reactive oxygen species such as hydroxyl radicals and hydrogen. It can also serve as an antioxidant by increasing glutathione S-transferase activity. Specifically, the high activity of monoamine oxidase-B (MAO-B), present in PD catalyzes the oxidation of dopamine, thereby generating H2O2. In this way, increased oxidative stress is responsible for the loss of dopaminergic neurons. Caffeine, on the other hand, has recently been demonstrated to have neuroprotective benefits by blocking MAO-B, which may favor an increase in dopamine levels and so ameliorate motor symptoms [30]. Moreover, it seems that caffeine can also protect dopaminergic neurons by the activation of some antioxidant signaling molecules, such as the erythroid-related nuclear factor 2/Keap1 and the coactivator 1α of the receptor, activating the proliferation of gamma peroxisomes, promoting the activation of transcription factors, which are involved in the biogenesis of mitochondria, as well as in antioxidant and anti-inflammatory pathways [31].
Furthermore, the caffeine neuroprotective effect is also supported by animal studies, showing that this molecule confers neuroprotection against dopaminergic neurodegeneration both in neurotoxin PD models, where mitochondrial toxins (MPTP, 6-OHDA and rotenone) are used, and in an α-syn transmission mouse model through the intracerebral injection of α-Syn fibers [32][33][34]. It is worth noting that in a chronic MPTP infusion model of PD, caffeine can give protection against dopamine neurodegeneration even after the neurodegenerative process has started (i.e., 14 days after MPTP infusion) [35]. In addition, a recent study revealed that coffee might protect against α-syn-induced pathological alterations in an A53T animal model of PD and that this effect could be related with increased autophagy activity [33]. Importantly, the pharmacological blockade or genetic deletion of the adenosine A2AR—the main pharmacological target of caffeine in the brain—seems to protect against dopaminergic neurodegeneration in PD animal models [36]. This observation suggests that caffeine protective effects are probably due to its action on this receptor. Moreover, A2AR modulated α-syn aggregation and toxicity in SHSY5Y cells, as well as A2AR blockade, and was able to rescue synaptic and cognitive deficits in α-syn transgenic mouse model of PD, thereby showing that caffeine consumption can lower the risk of developing PD and supporting the clinical potential of caffeine and A2AR antagonists as a disease-modifying drug target for this condition [37][38].
In recent decades, several studies have been conducted to evaluate the effects of caffeine as a nutraceutical compound in PD. In a double-blind, controlled phase 2/3 complete study (NCT00459420), in fact, the effects of caffeine in idiopathic PD patients were evaluated. The main aim was to evaluate caffeine efficacies for excessive daily sleepiness in PD. All the participants continued to take their PD medication and were asked to drink caffeinated beverages. Caffeine was well tolerated and had no negative side effects. Despite an improvement in motor manifestations, it was seen that caffeine seems to have no effect on excessive daytime somnolence in PD patients [39]. The potential motor benefits, due to caffeine consumption, were better explored in a larger long-term trial (NCT01738178). In this trial, patients affected by idiopathic PD received 200 mg caffeine. In comparison to the control group, caffeine administration resulted in no adverse events. According to the findings, caffeine did not improve motor function in PD patients, so future study is necessary to determine the epidemiological linkages between caffeine use and a reduced incidence of PD. Several prospective studies were carried out in order to reveal the favorable benefits of caffeine in PD [40]. A prospective investigation was, in fact, performed to assess the potential link between caffeine intake and the risk of PD in men and women. This concluded that low levels of coffee drinking lowered the risk of PD in men more than in women [41].
Another study conducted on a large cohort of men and women revealed that caffeine consumption reduced the risk of developing PD in both sexes [42]. In this regard, recent reports showed that caffeine consumption was lower in PD patients compared to healthy subjects, and a high caffeine level was associated with a lower risk of idiopathic PD in a sex-independent way. As a result, habitual caffeine consumption may benefit humans by lowering the risk of PD [43].
In a large cohort of 8004 Japanese American males who were tracked for 30 years, the relationship between regular caffeine use and a decreased risk of PD was also explored. During this investigation, Ross et al. discovered a decreased risk of PD proportionate to coffee usage. Furthermore, non-coffee users had a fivefold increased risk of PD compared to those who drank 28 ounces or more per day [44].
Therefore, numerous supports emerge from the literature for the neuroprotective value of caffeine intake in patients with PD. The possible mechanism of action responsible for the protective effect of caffeine remains poorly studied. This mechanism should certainly be investigated in order to better understand the therapeutic potential of caffeine-based therapies in PD.

4. Neuroprotective Effect of Caffeine in MS

MS is degenerative disorder of the CNS characterized by chronic inflammation. Presumed to be autoimmune and characterized by demyelinating processes, MS occurs in the white and grey matter of the CNS and affects people of all ethnicities, ages and sexes. It is estimated that it affects approximately 400 000 people in the United States and 2.5 million people worldwide. The reason behind the development of MS has not been discovered yet, but it has been largely reported that not only genetic causes, but also environmental factors, may contribute to its development. [45][46]. MS causes inflammation and demyelination, thus, resulting in lesions in the white and grey matter. The symptoms of this pathology are caused by a decrease in conductance and/or blockage, together with axonal injury and neuron death. Moreover, symptoms may include eye problems, numbness, brain stem symptoms, bladder dysfunction, ataxia, paresis and a slowly increasing cognitive disability, depending on the lesions position [47][48].
Given the availability of 15 officially authorized disease-modifying therapies, the majority of MS patients keep suffering disability accrual and chronic symptoms, underlining the need for additional therapies. Unfortunately, MS is not a curable disease, but it is known that its course may be very positively influenced by medication [49].
Research has shown that the anti-inflammatory effect of caffeine can be involved in reducing the likelihood of developing MS, but the mechanism responsible for this is still unclear. In reference to MS, the neuroprotective properties of caffeine can suppress inflammation and assist with symptoms such as constipation and cognitive fog [50].
The protective effect of caffeine in MS has mainly been evaluated in clinical studies. In particular, in recent years, a study revealed a significant association between high consumption of coffee and a decreased risk for MS; in fact, a cross-sectional survey showed that coffee consumption, at least in the relapsing form of MS, has positive effects on the progression and disease course, when comparing daily coffee drinkers to the non-daily coffee drinkers [51]. An experimental study was conducted, in addition, to determine whether chronic caffeine treatment has any neuroprotective effects on the course of disease in an animal model of MS. In this regard, an EAE rat model, distinguished by widespread tissue inflammation and a chronic disease course, was used, and it was demonstrated that the incidence of EAE was reduced in rats treated with caffeine. The same study also showed that the disease was mitigated at histological, neurochemical and behavioral levels when compared to rats given only water [52].
Another study in EAE supports that caffeine intake is associated with a lower risk of developing MS. The caffeine protective effect appears to be due to an improvement in the integrity of the BBB, possibly via the caffeine-induced activation of adenosine 1A receptors (A1). Recently, two important case-control studies on coffee intake and MS indicated that coffee consumption was related with a lower possibility of developing MS in a dose-dependent way. Finally, a more recent study showed that coffee consumption may be a therapeutic approach for selected individuals with MS-related fatigue in the absence of a successful fatigue treatment [53][54][55].
Despite all these observations, few works about caffeine supplementation as a therapeutic modality for MS are present in the literature. In this respect, very recently, it was reported that caffeine, in an experimental autoimmune encephalomyelitis (EAE) animal model, is able to diminish NLRP3 inflammasome activation, thereby determining a neuroprotective effect by inducing autophagy and reducing both the infiltration of inflammatory cells and demyelination. In the same work, it was also shown that, in an in vitro model of neuroinflammation, caffeine was able to inhibit the activation of the NLRP3 inflammasome by promoting autophagy and by suppressing the mechanistic target of mTOR pathway [56].
Therefore, although the protective effect of caffeine is reported regarding MS, the cellular mechanism involved in the protective responses to the action of this molecule has not yet been investigated.

5. Neuroprotective Effect of Caffeine in ALS

ALS is an incurable and rapidly progressing neurodegenerative disease, which is characterized by a progressive degeneration of motor neurons in the spinal cord and motor cortex, resulting in skeletal muscle atrophy and leading to death by respiratory failure within 3–5 years of initial symptoms [57]. Although most cases of ALS are sporadic, the disease can occasionally also be caused by a single gene mutation, such as the Cu2+/Zn2+superoxide dismutase (SOD)-1 mutation [58].
Regarding the cellular level, instead, an excessive stimulation of glutamate receptors seems to lead to a large influx of calcium ions into the postsynaptic neuron, which results in oxidative stress, oxidative damage, inflammation and apoptosis [59].
Several studies suggested that caffeine seems to be able to play an important modulatory role in ALS via a variety of mechanisms. In this respect, the excitatory neurotransmitter glutamate has been suggested to play a role in ALS. It is known that chronic neuroinflammation is linked with an increase in extracellular glutamate levels. Drugs that limit glutamate effects on neuronal receptors have been shown to reduce, indirectly, the neuroinflammatory response of microglia cells. Interestingly, in fact, caffeine attenuated the number of activated microglia within the hippocampus of animals with LPS-induced and age-related inflammation [60]. Moreover, it was also reported that maternal caffeine intake during gestation is able to determine the downregulation of A1 and metabotropic glutamate receptors in the brain of both rat mothers and fetuses [61].
In addition, as previously reported for PD, it was also found that A2AR inhibition is beneficial in the SOD1G93A mouse model of ALS. A2AR is normally abundantly expressed in spinal cord cells, including motor neurons. A2AR levels in the spinal cord of G93A mice are higher than in wild-type mice, but daily A2AR antagonist treatment appears to be highly effective in increasing motor neuron survival, slowing the progressive loss of forelimb grip strength, delaying disease onset and, finally, extending overall survival [62].
Despite the observations reported above, a large longitudinal study revealed no connection between caffeine consumption and ALS risk, and, at the same time, the results do not support the hypothesis that caffeine consumption is associated with a decreased risk of ALS [63].

6. Neuroprotective Effect of Caffeine in HD

The inherited neurodegenerative disorder name HD is determined by expanded CAG repeats and it is characterized by cognitive and psychiatric disturbances, as well as by motor symptoms. HD is, in fact, a hyperkinetic disorder in which the main symptoms are represented by chorea (jerky, involuntary movements), tremor, dystonia, which manifests itself with abnormal muscle tone resulting in muscle spasm and abnormal posture, and prominent neuropsychiatric and cognitive changes [64]. During HD, the signs of neurodegeneration appear in several cerebral regions of the brain, but the primary neuropathological hallmark is represented by the atrophy of the striatum, with a particular involvement of striatopallidal neurons expressing dopamine receptors [65]. Chronic quinolinic acid (QA) lesions in rats are very similar to the neurodegeneration seen in HD [66]. QA intrastriatal administration can cause an overstimulation of NMDA receptor which, in turn, determines an influx of Ca2+ and that, eventually, leads to oxidative stress which can be responsible for the mitochondrial release of pro-apoptotic factors and cause neuron death. In this regard, it has been reported that during a treatment with caffeine for 7, 14 and 21 days, it completely restored motor function in male Sprague Dawley rats treated with QA. At the same time, the administration of caffeine also significantly reduced oxidative stress in rats treated with QA, thus, increasing endogenous antioxidant capacity and decreasing oxidative damage in a dose-dependent as well as time-dependent manner [67].
On the other hand, it was also reported that high dosages of caffeine, as well as the ablation of adenosine A2A receptor, seem to be detrimental in HD animal models [68].
Finally, one human study conducted in 80 HD male and female patients with an average age of 50 years, showed that caffeine consumption at >190 mg/d over a 10-year period was associated with an earlier age of onset of HD estimated in 1.6 years [64].
Therefore, also for HD, the caffeine effects and adenosine receptor antagonism seem to be highly dose dependent and definitely need further investigation.

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