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Review
. 2021 Jul 31:2021:9982954.
doi: 10.1155/2021/9982954. eCollection 2021.

Inflammation and Alzheimer's Disease: Mechanisms and Therapeutic Implications by Natural Products

Mashoque Ahmad Rather  1 , Andleeb Khan  2 , Saeed Alshahrani  2 , Hina Rashid  2 , Marwa Qadri  2 , Summya Rashid  3 , Rana M Alsaffar  3 , Mohammad Amjad Kamal #  4   5   6 , Muneeb U Rehman #  7
Affiliations
Review

Inflammation and Alzheimer's Disease: Mechanisms and Therapeutic Implications by Natural Products

Mashoque Ahmad Rather et al. Mediators Inflamm. .

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder with no clear causative event making the disease difficult to diagnose and treat. The pathological hallmarks of AD include amyloid plaques, neurofibrillary tangles, and widespread neuronal loss. Amyloid-beta has been extensively studied and targeted to develop an effective disease-modifying therapy, but the success rate in clinical practice is minimal. Recently, neuroinflammation has been focused on as the event in AD progression to be targeted for therapies. Various mechanistic pathways including cytokines and chemokines, complement system, oxidative stress, and cyclooxygenase pathways are linked to neuroinflammation in the AD brain. Many cells including microglia, astrocytes, and oligodendrocytes work together to protect the brain from injury. This review is focused to better understand the AD inflammatory and immunoregulatory processes to develop novel anti-inflammatory drugs to slow down the progression of AD.

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Conflict of interest statement

The authors declare that there is no conflict of interest regarding the publication of this paper.

Figures

Figure 1
Figure 1
Aβ fibrils lead to neuronal death, which include ROS generation, neurotoxicity, release of inflammatory cytokines, and activation of the complement system. Due to the accumulation of Aβ oligomers, neuronal degeneration may stimulate the microglial activation, which will initiate the liberation of proinflammatory mediators, neurotoxins, and free radicals but also play a pivotal role in the elimination of Aβ peptides. These peptides trigger oxidative stress and promote inflammatory processes in neurons, which enhance the production of Aβ peptides via increased APP expression. Activated MAPK (a mitogen-activated protein kinase) and NF-кB (nuclear factor kappa-light-chain-enhancer of activated B cells) lead to the production of proinflammatory cytokines, and their increased expansion promotes APP processing and disintegration of BBB (blood-brain barrier) and aggravates the phosphorylation of Tau protein and eventually leads to the formation of neurofibrillary tangles via the activation of p38-MAPK which leads to neuronal degeneration (created with http://BioRender.com/).
Figure 2
Figure 2
Inflammatory cytokines initiate the activation of the PI3K (phosphoinositide 3 kinase) pathway, phosphorylate the JAK-STAT (Janus kinases, signal transducer and activator of transcription proteins) factors, which activate the NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway and enhance the production of ROS leading to apoptosis. p38 MAPK (a mitogen-activated protein kinase) is involved in the AD mechanism which includes the cytokine activation of p38 MAPK in microglia, leads to the increased production of proinflammatory cytokines which initiates the inflammatory process, and the cytokines also initiate the activation of p28 MAPK in astrocytes and neurons, which further escalates the inflammation. All these events lead to hyperphosphorylation, inhibition of long-term potentiation, apoptosis and synaptic dysfunction. NF-кB is a regulated transcription factor, involved in the regulation of inflammation, cellular growth, immune function and apoptosis. Free radical production led to the activation of IKB which phosphorylates the NFкB inhibitor, initiates the proteasomal degradation of IKB (IkappaB kinase) and the liberation of NFкB which translocates into the nucleus and binds to the DNA responsive element. Together with the coadjuvant and other activators, the increased expression of proinflammatory cytokines is triggered and neuroinflammation is supported, which causes the degeneration of neurons and eventually leads to the progression of AD (created with http://BioRender.com/).
Figure 3
Figure 3
Other mechanisms driving neuroinflammation: increased oxidative stress either by excessive production and release of ROS (reactive oxygen species) of inflammatory mediators leading to the overproduction proinflammatory cytokines. Proinflammatory factors activate the glial cells and promote the process of neuroinflammation. Several antioxidants including SOD (superoxide dismutase), Cat (catalase), and GPx (glutathione peroxidase) may act as reducing agents in attenuating ROS production and diminish the inflammatory response. Activated glial cells under the influence of several proinflammatory cytokines trigger the complement system, and the released cytokines form T cells. Activated glial cells further promote the release and activation of inflammatory cytokines such as TNF-α (tumor necrosis factor), IL-1β (interleukin-1β), IL-6 (interleukin-6), NO (nitric oxide), COX-2 (cyclooxygenase-2), IFN-γ (interferon gamma), and chemokines which cause damage to the neurons and lead to their degeneration.
Figure 4
Figure 4
Role of inflammation on Tau pathology: inflammatory stimuli activate the microglial cells and trigger production of proinflammatory cytokines and Tau accumulation in the AD brain. Proinflammatory mediators such as TNF-α (tumor necrosis factor), IL-1β (interleukin-1β), and IL-6 (interleukin-6) could trigger neuroinflammation and tau pathology. Neuroinflammatory response activates a signaling cascade with the release and activation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), overproduction of proinflammatory cytokines, and the activation of neuronal receptors. Hyperphosphorylation of tau protein initiates the dissociation of microtubule. Soluble tau aggregates into pathological tau oligomers, forms tau filaments, and ultimately leads to the formation of neurofibrillary tangles, which promote the neuronal death (created with http://BioRender.com/).
Figure 5
Figure 5
Role of inflammation on Aβ pathology: Aβ stress leads to the production of ROS, and the inflammatory stimuli activate the microglial cells, which leads to the production of proinflammatory cytokines and causes the elevated levels of cytokines and accumulation of activated microglia. The promoter region of NFкB (nuclear factor kappa-light-chain-enhancer of activated B cells) has binding sites, which lead to the process of amyloidogensis and inflammation, and the activated NFкB initiates the production of proinflammatory cytokines, which triggers neuroinflammation. These mediators cause the excitation of the glial cells which further stimulate the production of Aβ burden and additional proinflammatory cytokines and ultimately leads to the death of neurons and AD pathology.
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