Antioxidant and Neuroprotective Effects of Caffeine against Alzheimer's and Parkinson's Disease: Insight into the Role of Nrf-2 and A2AR Signaling

Abstract

This paper reviews the results of studies conducted on the role of caffeine in the management of different neurological disorders, such as Parkinson's disease (PD) and Alzheimer's disease (AD). To highlight the potential role of caffeine in managing different neurodegenerative diseases, we identified studies by searching PubMed, Web of Science, and Google Scholar by scrutinizing the lists of pertinent publications. According to the collected overall findings, caffeine may reduce the elevated oxidative stress; inhibit the activation of adenosine A2A, thereby regulating the accumulation of Aβ; reduce the hyperphosphorylation of tau; and reduce the accumulation of misfolded proteins, such as α-synuclein, in Alzheimer's and Parkinson's diseases. The studies have suggested that caffeine has promising protective effects against different neurodegenerative diseases and that these effects may be used to tackle the neurological diseases and/or their consequences. Here, we review the ongoing research on the role of caffeine in the management of different neurodegenerative disorders, focusing on AD and PD. The current findings suggest that caffeine produces potent antioxidant, inflammatory, and anti-apoptotic effects against different models of neurodegenerative disease, including AD, PD, and other neurodegenerative disorders. Caffeine has shown strong antagonistic effects against the adenosine A2A receptor, which is a microglial receptor, and strong agonistic effects against nuclear-related factor-2 (Nrf-2), thereby regulating the cellular homeostasis at the brain by reducing oxidative stress, neuroinflammation, regulating the accumulation of α-synuclein in PD and tau hyperphosphorylation, amyloidogenesis, and synaptic deficits in AD, which are the cardinal features of these neurodegenerative diseases.

Keywords: Alzheimer’s disease; Parkinson’s disease; antioxidant effects; caffeine; neurodegeneration; neuroprotective effects.

Figure 1

A simple illustration showing the role of reactive oxygen species (ROS) in neurodegenerative diseases. ROS may be produced from different sources, causing the mitochondrial dysfunction, oxidation of proteins, lipid peroxidation, and DNA denaturation, leading to neurodegeneration. The red arrow shows the processing. Red pointing arrow is showing the inducing effects.

Figure 2

Role of A2A receptor in the execution of Alzheimer’s disease (AD) pathology. A diagram highlighting the role of microglial receptor A2A in the hyperphosphorylation of tau, accumulation of amyloid-beta, and neuroinflammation in AD pathology. The upregulation of the A2A receptor is responsible for AD pathology, and inhibition of the A2A receptor may reduce the hyperphosphorylation of tau, reduce amyloid-beta, and cause neuroinflammation. The reduction in hyperphosphorylation of tau and accumulation of amyloid-beta neuroinflammation rescue cognitive dysfunction and memory impairment. , used for inhibition, the pointing arrow is used for induction.

Figure 3

Role of caffeine in the management of neurodegeneration. The rescuing effects of caffeine against neurotoxins and age-related neurodegeneration. Caffeine suppresses the expression of the A2A receptor and upregulates the expression of nuclear factor erythroid 2-related factor 2 (Nrf-2), thereby regulating the inflammatory mediators (phospho-c-Jun n-terminal kinase (p-JNK), phospho-nuclear factor-kappa B (p-NF-kB)), apoptotic markers (cytochrome C, and caspase-3), synaptic dysfunctions, and neurodegeneration. Green arrows are used for the beneficial effects of caffeine. The arrows with white background are showing the inducing effects.

Figure 4

Role of A2A receptor and Nrf-2 in the pathophysiology of PD. MPTP, 6-OHDA, α-synuclein, and other PD-inducing toxins induce oxidative stress, consequently downregulating the expression of Nrf-2 and upregulating the expression of the A2A receptor. Elevated oxidative stress and the activation of the A2A receptor trigger neuroinflammation and dopaminergic neurodegeneration. , used for inhibition, the pointing arrow is used for the induction.

Figure 5

Effects of caffeine against Parkinson’s disease (PD)-like pathological changes in the mouse brain. Reduced expression of Nrf-2 and activated level of A2A receptor in a mouse model of PD. Caffeine shows regulatory effects against A2A and Nrf-2, thereby rescuing the mice against neurodegeneration and memory impairment. , used for inhibition, the pointing arrow is used for the induction.