ReviewPost screenTargeting TNF: a therapeutic strategy for Alzheimer's disease
Introduction
Although current Alzheimer disease (AD) treatments are inadequate, there are many novel therapies that are currently undergoing rigorous exploration by the academic and pharmaceutical research communities. Inhibition of TNF and its mediated signal transduction pathway is one such potential target area.
TNF alpha (TNFα) is a key cytokine that was discovered approximately 25 years ago as a result of its ability to kill tumor cells in vitro and to cause hemorrhagic necrosis of tumors in animals. Subsequently, it was found that TNFα has a broad spectrum of biological activities, with a key role in a variety of pathological processes. In fact, TNFα is one of the most extensively investigated cytokines in various fields, and is one of the most widely used molecular targets for drugs. Here, we focus on what is known about TNFα, highlighting its biochemical characterization, biological role in diseases, and its involvement in the drug discovery process for neurodegenerative disorders such as AD. TNFα or the TNFα–TNFR complex is a two-faced molecule that not only has beneficial effects on anticancer mechanisms, but also has a destructive role in brain disorders such as AD.
Section snippets
The TNFα molecule and its biosynthesis
The human TNFα cDNA and gene have been cloned 1, 2. The gene is located on chromosome 6 between 6p21.1 and 6p21.3, which is within the human leukocyte antigen (HLA) class III region 3, 4, 5, 6, 7. This suggests that TNFα is an important mediator of inflammatory responses with multiple biological activities. TNFα comprises 157 nonglycosylated amino acids with a molecular weight of 17 kDa. It is synthesized as a membrane-bound pro-protein comprising 233 amino acids and is cleaved by a specific
TNF receptors and their signal transduction pathways
After TNFα is synthesized and released, it binds specific receptors to elicit biological effects by mechanisms that are still not fully understood. There are two receptor subtypes for TNFα: TNFRI (55 kDa, also known as p55TNFR) and TNFRII (75 kDa, also known as p75TNFR). The two TNFRs differ considerably in their amino acid sequences, with 24% homology in the extracellular region and approximately 10% homology in the intracellular domain. The two receptors are differentially expressed in various
Neurotoxicity of TNFα in the brain
TNFα has a crucial role in host immunity, preventing infection and the growth of malignant tumors 12, 13, 14. Recently, studies have shown that TNFα not only induces cytotoxic effects and apoptosis, but also has antiviral activity [15]. In the brain, activated microglia and astrocytes release TNFα that can be trophic or toxic, depending on the stage of neuronal development, target cells, and receptor subtypes. For example, TNFα protects fetal and postnatal neurons after glucose deprivation [16]
TNFα receptor signaling-related neuron death and neuroprotection
The TNFR superfamily contains several members with homologous DDs. As shown in Fig. 1, the DD is crucial in initiating signaling pathways after ligand binding. In the absence of a ligand, TNFRI (DD-containing) receptors remain inactive. Whereas TNFα expression in the brain is high during development, low during adulthood, and high in patients with AD, PD, multiple sclerosis, and stroke, studies identified a direct link between TNFRI activation and signal cascade-mediated neuron death in brains
TNF receptors and AD
Clinically, AD is characterized by dementia of insidious onset; pathologically, it is characterized by the presence of numerous neuritic plaques, neurofibrillary tangles, and neuronal loss 24, 25, 26. The plaques, comprising mainly Aβ peptide fragments, are derived from the processing of amyloid precursor protein (APP) by β- and γ-secretases. Interestingly, studies have shown that TNFRI is required for neuronal death induced by Aβ protein in the AD brain. However, whether TNF receptor subtypes
TNF receptor signaling, APP processing, and Aβ
In addition to mediating neuron survival and death, TNFR signaling is involved in APP processing, which affects Aβ production. For example, studies have identified a binding site for the transcription factor NF-κB, a component of the TNFRI signaling pathway, in the BACE1 promoter 29, 30, and showed that TNFα treatment results in increased BACE1 activity in vitro and that the TNFRI cascade is required for Aβ production in vivo [11]. Moreover, deletion of the TNFRI gene in APP23 transgenic mice
TNFα and genetics of AD
Pro-inflammatory cytokines, such as TNFα and acute-phase proteins, have an important role in AD neurodegeneration. It has been shown that common polymorphisms associated with TNFα upregulation are linked to AD. Data from family-based association tests have revealed an association between AD and the TNFα haplotype, as well as a significant increase in average age of disease onset among patients with AD carrying the haplotype associated with TNFA upregulation [31]. For example, the lowest age at
Current status of antiTNFα therapy in the clinic and possibly for AD
Anti-TNFα agents have been used worldwide in the clinic for nearly 20 years for the treatment of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn's disease, and so on, to reduce inflammation and stop disease progression (Table 1). However, there are few studies investigating the use of antiTNFα drugs in preventing or treating AD.
Infliximab (Remicade) is a chimeric bivalent immunoglobulin (Ig)-G1 monoclonal antibody comprising human-constant and murine-variable regions.
Investigation of thalidomide in humans
Thalidomide is a sedative-hypnotic and multiple myeloma medication [56]. The drug is a potent teratogen in rats, rabbits, and primates, including humans. This means that severe birth defects can result if the drug is taken during pregnancy. Thalidomide was primarily sold and prescribed during the late 1950s and early 1960s to pregnant women as an antiemetic to combat hyperemesis gravidarum and as a sleep aid. Given its significant teratogenicity [57], it has not been used since the 1960s,
Future molecular anti-TNFα candidates for the treatment of AD
Another agent that warrants consideration as a possible treatment for patients with dementia is lysofylline, a lysophosphatidic acid acyl transferase (LPAAT) inhibitor that has been shown to attenuate lipopolysaccharide-induced TNFα synthesis [61]. Lipopolysaccharide binds to a variety of serum proteins, most notably lipopolysaccharide-binding protein, which influences the macrophage-mediated proinflammatory response.
Inhibition of p38 MAP kinase might also be a useful therapeutic avenue for
Concluding remarks
In summary, agents that modulate TNFα production, such as inhibitors of LPAAT, p38 MAPK, NF-κB, and TACE or TNF receptor antagonists, could be potential future candidates for the treatment of AD and other neurodegenerative disorders.
Acknowledgements
We thank Esther Landhuis and Jun Konishita from Alzforum, for their help during the initial stage of the review article, and Allison Galbraith for editorial assistance during preparation of the manuscript. YS and RL are supported by NIHRO1AG032441, RO1AG025888, and Alzheimer Association Zenith Award, IIRG-0759510, IIRG09-61521, YS is also supported National Talent 1000 Plan of China. XC is supported by the grant (81100861) from the Natural Science Foundation of China, Special Research Fund
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