Targeting Tumor Necrosis Factor Alpha for Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) affects an estimated 44 million individuals worldwide, yet no therapeutic intervention is available to stop the progression of the dementia. Neuropathological hallmarks of AD are extracellular deposits of amyloid beta (Aβ) peptides into plaques, intraneuronal accumulation of hyperphosphorylated tau protein forming tangles, and chronic inflammation. A pivotal molecule in inflammation is the pro-inflammatory cytokine TNF-α. Several lines of evidence using genetic and pharmacological manipulations indicate that TNF-α signaling exacerbates both Aβ and tau pathologies in vivo. Interestingly, preventive and intervention anti-inflammatory strategies demonstrated a reduction in brain pathology and an amelioration of cognitive function in rodent models of AD. Phase I and IIa clinical trials suggest that TNF-α inhibitors might slow down cognitive decline and improve daily activities in AD patients. In the present review, we summarize the evidence pointing towards a beneficial role of anti-TNF-α therapies to prevent or slow the progression of AD. We also present possible physical and pharmacological interventions to modulate TNF-α signaling in AD subjects along with their limitations.

Inflammatory markers in Alzheimer’s disease and mild cognitive impairment: a meta-analysis and systematic review of 170 studies

“…Decreased levels of IL-8 in patients with AD were linked to descending reparative mechanism in the central nervous system (CNS) 7. The proinflammatory cytokine TNF-α and its receptors sTNFR1 and sTNFR2, which regulate numerous physiological processes in CNS, have been detected to exacerbate the main pathological changes of AD (both Aβ and tau pathologies) in vivo 25. Our meta-analyses proved notable variances in the peripheral concentrations of sTNFR1 and sTNFR2 between group comparisons, implying that these markers may be useful in helping to monitor disease progression.…”

Neuroprotective Effect of Different Doses of Vitamine D3 in Diabetic-Induced Alzheimer Rat Model

“…Furthermore, the neuropathological parameters of AD such as aggregation of phosphorylated tau protein, Aβ deposition, and activated microglial and astrocyte cell were all observed to be reduced by the inhibition of the TNF-α pathway. It's worth to mention that prevention of this signaling cascade inhibits the strong stimulation of microglial cells, keeping them in a state of moderate stimulation where they play a neuroprotective role by elevating of βAPP clearance [38].…”

Alveolar early progenitors in the aged human lung have increased expression of ACE2 accompanied with genes involved in beta-amyloid clearance: Indication of SARS-CoV-2 also using soluble ACE2 in aged-lungs to enter ACE2-negative cells

“…Further, the current analysis also showed that in older lungs, AEP and Macrophages both have TNFα levels significantly increased ( Figure 1G, Supplementary Figure S1F). Along with the gene expression signature described above, it is plausible aged baseline inflammation very likely be a result of the increased beta-amyloid load (Decourt et al, 2017). ADAM17 member of "A Disintegrin And Metalloprotease" (ADAM) family, also known as TNFα converter (TACE), mediates ACE2 shedding on the membrane in response to RAS mediated signaling (Lambert et al, 2005), was expressed in AEPs (Supplementary Figure S1G).…”