Neutralization of TNFSF10 ameliorates functional outcome in a murine model of Alzheimer’s disease

Abstract

Alzheimer's disease is one of the most common causes of death worldwide, with poor treatment options. A tissue landmark of Alzheimer's disease is accumulation of the anomalous protein amyloid-β in specific brain areas. Whether inflammation is an effect of amyloid-β on the Alzheimer's disease brain, or rather it represents a cause for formation of amyloid plaques and intracellular tangles remains a subject of debate. TNFSF10, a proapoptotic cytokine of the TNF superfamily, is a mediator of amyloid-β neurotoxicity. Here, we demonstrate that blocking TNFSF10 by administration of a neutralizing monoclonal antibody could attenuate the amyloid-β-induced neurotoxicity in a triple transgenic mouse model of Alzheimer's disease (3xTg-AD). The effects of TNFSF10 neutralization on either cognitive parameters, as well as on the expression of TNFSF10, amyloid-β, inflammatory mediators and GFAP were studied in the hippocampus of 3xTg-AD mice. Treatment with the TNFSF10 neutralizing antibody resulted in dramatic improvement of cognitive parameters, as assessed by the Morris water maze test and the novel object recognition test. These results were correlated with decreased protein expression of TNFSF10, amyloid-β, inflammatory mediators and GFAP in the hippocampus. Finally, neutralization of TNFSF10 results in functional improvement and restrained immune/inflammatory response in the brain of 3xTg-AD mice in vivo. Thus, it is plausible to regard the TNFSF10 system as a potential target for efficacious treatment of amyloid-related disorders.

Tumor necrosis factor‐related apoptosis‐inducing ligand reduces the expression of the neuroprotective Na+/Ca2+ exchanger isoform NCX3 in human neuroblastoma SH‐SY5Y cells

“…In fact, expression of TRAIL is increased in all these conditions, and associated with caspase activation, gliosis, and overexpression of an array of proinflammatory mediators [18]. Consistently, immunoneutralization of TRAIL results in decreased amyloid-b accumulation in the brain of 3xTg-AD mouse and reduced cognitive decline [19].…”

Rodent models for Alzheimer’s disease drug discovery

“…LTP and spatial memory impairment [50–53] were also evident. In our recent studies [54], 3XTg at 8–9 months of age showed an increase of Aβ42 levels and an increase of inflammatory mediators in the hippocampus, and an impairment of cognitive functions assessed by the MWM test and the NOR test. Increased age-related anxiety and fearfulness have been reported in some studies [55–57].…”

A Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease

“…TNF-α exerts a key role in this early proinflammatory process observed in preclinical AD as emerges from preclinical studies in animal models of AD (111)(112)(113)(114) as well as from human longitudinal studies (21,(113)(114)(115). TNF-α is chronically released during the course of AD pathology, likely by activated microglia, neurons, and astrocytes stimulated by increased levels of extracellular Aβ (111).…”