TRAIL-R Deficient Mice Are Protected from Neurotoxic Effects of Amyloid-β

Abstract

TRAIL, a member of TNF superfamily, is a potent inducer of neuronal death. Neurotoxic effects of TRAIL appear mediated by its death receptor TRAIL-R2/DR5. To assess the role of TRAIL/TRAIL-R2 pathway in AD-related neurodegeneration, we studied the impact of the treatment with amyloid-β (Aβ) upon cell viability and inflammation in TRAIL-R-deficient mice (TRAIL-R−/−). Here, we demonstrate that the lack of TRAIL-R2 protects from death cultured TRAIL-R−/− mouse embryonic hippocampal cells after treatment with either Aβ1-42 or TRAIL. Consistently, stereotaxic injection of Aβ1-42 resulted in blunted caspase activation, as well as in reduction of JNK phosphorylation and increased AKT phosphorylation in TRAIL-R−/− mice. Moreover, the lack of TRAIL-R2 was associated with blunted constitutive p53 expression in mice that have undergone Aβ1-42 treatment, as well as in decrease of phosphorylated forms of tau and GSK3β proteins. Likewise, TRAIL-R2 appears essential to both TRAIL and Aβ-mediated neurotoxicity and inflammation. Indeed, hippocampi of TRAIL-R−/− mice challenged with Aβ1-42, showed a slight expression of microglial (Iba-1) and astrocytic (GFAP) markers along with attenuated levels of IL-1β, TNF-α, NOS2 and COX2. In conclusion, the bulk of these results demonstrate that the constitutive lack of TRAIL-R2 is associated with a substantial reduction of noxious effects of Aβ1-42, providing further evidence on the prominent role played by TRAIL in course of Aβ-related neurodegeneration and confirming that the TRAIL system represents a potential target for innovative AD therapy.

In major dysmood disorder, physiosomatic, chronic fatigue and fibromyalgia symptoms are driven by immune activation and increased immune-associated neurotoxicity

“…TRAIL signals apoptosis by binding to death receptors and activating the caspase pathway 67 . This cytokine has strong neurotoxic effects, even leading to neurodegeneration and neuronal death, mediated by the TRAIL-R2/DR5 receptor and caspase activation 68 . Recent evidence suggests, however, that TRAIL may modulate the IRS and T cell activation and shows anti-inflammatory effects 67 .…”

Identification of pyroptosis-related molecular clusters in alzheimer’s disease based on multiple machine learning models

“…When the central nervous system is in a state of chronic in ammation, CLIC1 protein increases sharply, so it is signi cantly highly expressed in the blood of AD patients, and it is expected to become a blood-dependent biomarkers [30]. The low expression of TNFRSF10B (TNF Receptor Superfamily Member 10b) can lead to the in ltration of resting CD4 + memory T cells and resting dendritic cells and indirectly participate in the occurrence and development of AD [31].…”

Microbiome Dysbiosis: A Pathological Mechanism at the Intersection of Obesity and Glaucoma

“…Glaucoma is a multifactorial neurodegenerative disease characterized by the death of retinal ganglion cells (RGCs). Biological mechanisms similar to those proposed for glaucoma and other neurodegenerative diseases involve the loss of particular nerves and the deposition of protein aggregates in specific anatomical areas [ 133 , 134 , 135 , 136 ]. Given that glaucoma and other neurodegenerative diseases have similar immune and neurodegenerative factors, the progressive neurodegeneration in glaucoma could be caused by microbial communication between the gut and the eye.…”