Targeting the miRNA-155/TNFSF10 network restrains inflammatory response in the retina in a mouse model of Alzheimer's disease.
Alzheimer Disease
/ genetics
Amyloid beta-Peptides
/ metabolism
Animals
Antibodies, Neutralizing
/ pharmacology
Base Sequence
Calcium-Binding Proteins
/ metabolism
Cyclooxygenase 2
/ metabolism
Disease Models, Animal
Down-Regulation
/ drug effects
Gene Expression Profiling
Gene Expression Regulation
Gene Regulatory Networks
Glial Fibrillary Acidic Protein
/ metabolism
Gliosis
/ complications
Inflammation
/ complications
Interleukin-10
/ metabolism
Mice, Transgenic
MicroRNAs
/ genetics
Microfilament Proteins
/ metabolism
Microglia
/ drug effects
Phosphorylation
/ drug effects
Receptors, TNF-Related Apoptosis-Inducing Ligand
/ genetics
Retina
/ pathology
Retinal Pigment Epithelium
/ drug effects
Signal Transduction
/ genetics
Suppressor of Cytokine Signaling 1 Protein
/ metabolism
TNF-Related Apoptosis-Inducing Ligand
/ metabolism
Tumor Necrosis Factor-alpha
/ metabolism
tau Proteins
/ metabolism
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
05 10 2021
05 10 2021
Historique:
received:
02
03
2021
accepted:
15
09
2021
revised:
25
08
2021
entrez:
6
10
2021
pubmed:
7
10
2021
medline:
4
2
2022
Statut:
epublish
Résumé
Age-related disorders, such as Alzheimer's disease (AD) and age-related macular degeneration (AMD) share common features such as amyloid-β (Aβ) protein accumulation. Retinal deposition of Aβ aggregates in AMD patients has suggested a potential link between AMD and AD. In the present study, we analyzed the expression pattern of a focused set of miRNAs, previously found to be involved in both AD and AMD, in the retina of a triple transgenic mouse model of AD (3xTg-AD) at different time-points. Several miRNAs were differentially expressed in the retina of 3xTg-AD mice, compared to the retina of age-matched wild-type (WT) mice. In particular, bioinformatic analysis revealed that miR-155 had a central role in miRNA-gene network stability, regulating several pathways, including apoptotic and inflammatory signaling pathways modulated by TNF-related apoptosis-inducing ligand (TNFSF10). We showed that chronic treatment of 3xTg-AD mice with an anti-TNFSF10 monoclonal antibody was able to inhibit the retinal expression of miR-155, which inversely correlated with the expression of its molecular target SOCS-1. Moreover, the fine-tuned mechanism related to TNFSF10 immunoneutralization was tightly linked to modulation of TNFSF10 itself and its death receptor TNFRSF10B, along with cytokine production by microglia, reactive gliosis, and specific AD-related neuropathological hallmarks (i.e., Aβ deposition and Tau phosphorylation) in the retina of 3xTg-AD mice. In conclusion, immunoneutralization of TNFSF10 significantly preserved the retinal tissue in 3xTg-AD mice, suggesting its potential therapeutic application in retinal degenerative disorders.
Identifiants
pubmed: 34611142
doi: 10.1038/s41419-021-04165-x
pii: 10.1038/s41419-021-04165-x
pmc: PMC8492692
doi:
Substances chimiques
Aif1 protein, mouse
0
Amyloid beta-Peptides
0
Antibodies, Neutralizing
0
Calcium-Binding Proteins
0
Glial Fibrillary Acidic Protein
0
MicroRNAs
0
Microfilament Proteins
0
Mirn155 microRNA, mouse
0
Receptors, TNF-Related Apoptosis-Inducing Ligand
0
Socs1 protein, mouse
0
Suppressor of Cytokine Signaling 1 Protein
0
TNF-Related Apoptosis-Inducing Ligand
0
TNFRSF10B protein, human
0
Tumor Necrosis Factor-alpha
0
tau Proteins
0
Interleukin-10
130068-27-8
Cyclooxygenase 2
EC 1.14.99.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
905Informations de copyright
© 2021. The Author(s).
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