Tumor Necrosis Factor and Alzheimer's Disease: A Cause and Consequence Relationship

Abstract

Tumor necrosis factor and alzheimer's disease: a cause and consequence relationship Tumor necrosis factor alpha (TNF) was discovered more than a century ago as endotoxin-induced glycoprotein, which causes haemorrhagic necrosis of sarcomas. Originally described as a circulating factor that causes necrosis of tumours,it now appears that TNF has diverse and critical roles to play in the pathogenic progression of a number of chronic inflammatory disorders, including rheumatoid arthritis, Crohn's disease, psoriasis, Alzheimer's disease, ischemic stroke, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. A pivotal role has emerged for TNF as an important contributor to Alzheimer's disease pathology, as TNF appears to modulate several neuropathological mechanisms in Alzheimer's disease. Evidence for the involvement of TNF in Alzheimer's disease pathology and neuronal loss comes from studies of TNF over-expression, TNF localization studies, multiple relationships between TNF and amyloid β-peptide (Aβ), interactions between TNF and the microtubule-associated tau protein, TNF-mediated apoptotic cell death, and association of TNF with several neurotransmitters linked to Alzheimer's pathology. This review presents TNF as a neuromodulator in pathological progression of Alzheimer's disease by linking it with several endogenous mediators and advocates its status as a current therapeutic target in the quest to find a cure for Alzheimer's disease.

Dopamine Burden Triggers Neurodegeneration via Production and Release of TNF-α from Astrocytes in Minimal Hepatic Encephalopathy

“…TNF-α was originally identified as a factor that leads to the rapid necrosis of transplantable tumors in mice [38]. TNF-α is a pleiotropic cytokine regulating numerous physiological and pathological processes, including differentiation, inflammation, and cell death [39]. In pathological conditions, astrocytes and mainly microglia release large amounts of TNF-α; de novo production of this cytokine is an important component of the so-called neuroinflammatory response that is associated with several neurological disorders [13,[40][41][42].…”

Mathematical model on Alzheimer’s disease

“…Macrophages have a major role in A β clearance [12, 20], but activated microglia are poorly phagocytic for A β compared to peripheral macrophages [21]. M 1 and macrophages are neurotoxic; they produce proinflammatory cytokines TNF- α , IL-6, IL-12 and IL-1 β [20, 22, 23]. M 2 microglias and peripheral macrophages produce anti-inflammatory cytokines IL-10, IL-13, IL-4 and TGF- β [20].…”

Synergistic Effect of Galantamine Carried on a Novel Nano-Drug Delivery System on Induced Lung Disorders in Alzheimer’s Disease

“…[38] Inhibition of TNF alpha has been shown to decrease amyloid plaques and tau phosphorylation in the mouse brain, processes associated with dementia. [37,39] Several studies indicate that a neuroimmune reaction, associated with inflammatory mechanisms, can contribute in Alzheimer's disease (AD) to cell damage and neurodegeneration, [38] These results clearly demonstrate that dementia patients show a generalized increment of ILß-1 production in the CNS, with maximum response in those brain regions where AD neuropathology is most prominent. This overall increase in cytokine production might represent an early event in the activation of a neuroimmune cascade leading to cell death and neurodegeneration in brain regions where a primary cause (e.g., genetic, toxic, vascular) facilitates the induction of resting microglia for firing brain immune function.…”

“…[37] Activation of the TNF receptor 1 is required for neuronal cell death as a toxic consequence of beta amyloid protein. TNF alpha inhibits learning by inhibiting long term potentiation, a process critical for memory.…”

“…This overall increase in cytokine production might represent an early event in the activation of a neuroimmune cascade leading to cell death and neurodegeneration in brain regions where a primary cause (e.g., genetic, toxic, vascular) facilitates the induction of resting microglia for firing brain immune function. [37,38,40,41] 5-OH tryptamine performance as a tissue hormone, neurotransmitter and neuromodulator. [42,43] It is one of the most important neurotransmitters in the central nervous system (CNS) regulating multiple physiological functions such as body temperature, appetite, sleep, mood and pain.…”