scholarly journals Targeting the miRNA-155/TNFSF10 network restrains inflammatory response in the retina in a mouse model of Alzheimer’s disease

2021 ◽  
Vol 12 (10) ◽  
Author(s):  
Chiara Burgaletto ◽  
Chiara Bianca Maria Platania ◽  
Giulia Di Benedetto ◽  
Antonio Munafò ◽  
Giovanni Giurdanella ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Mirna Gene ◽  
Death Receptor ◽  
Amyloid Β ◽  
Age Related Macular Degeneration ◽  
Protein Accumulation ◽  
Model Of Alzheimer’S Disease ◽  
Age Related

AbstractAge-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.

scholarly journals Tetrahydrobiopterin Improves Recognition Memory in the Triple-Transgenic Mouse Model of Alzheimer’s Disease, Without Altering Amyloid-β and Tau Pathologies

2020 ◽  
pp. 1-19
Author(s):  
Hortense Fanet ◽  
Marine Tournissac ◽  
Manon Leclerc ◽  
Vicky Caron ◽  
Cyntia Tremblay ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Metabolic Disorders ◽  
Amyloid Β ◽  
Transgenic Mouse Model ◽  
Model Of Alzheimer’S Disease ◽  
Age Related ◽  
Triple Transgenic Mouse

Background: Alzheimer’s disease (AD) is a multifactorial disease, implying that multi-target treatments may be necessary to effectively cure AD. Tetrahydrobiopterin (BH4) is an enzymatic cofactor required for the synthesis of monoamines and nitric oxide that also exerts antioxidant and anti-inflammatory effects. Despite its crucial role in the CNS, the potential of BH4 as a treatment in AD has never been scrutinized. Objective: Here, we investigated whether BH4 peripheral administration improves cognitive symptoms and AD neuropathology in triple-transgenic mouse model of AD (3xTg-AD) mice, a model of age-related tau and amyloid-β (Aβ) neuropathologies associated with behavior impairment. Methods: Non-transgenic (NonTg) and 3xTg-AD mice were subjected to a control diet (5% fat – CD) or to a high-fat diet (35% fat - HFD) from 6 to 13 months to exacerbate metabolic disorders. Then, mice received either BH4 (15 mg/kg/day, i.p.) or vehicle for ten consecutive days. Results: This sub-chronic administration of BH4 rescued memory impairment in 13-month-old 3xTg-AD mice, as determined using the novel object recognition test. Moreover, the HFD-induced glucose intolerance was completely reversed by the BH4 treatment in 3xTg-AD mice. However, the HFD or BH4 treatment had no significant impact on Aβ and tau neuropathologies. Conclusion: Overall, our data suggest a potential benefit from BH4 administration against AD cognitive and metabolic symptoms accentuated by HFD consumption in 3xTg-AD mice, without altering classical neuropathology. Therefore, BH4 should be considered as a candidate for drug repurposing, at least in subtypes of cognitively impaired patients experiencing metabolic disorders.

scholarly journals Effects of γ-Secretase Inhibition on the Amyloid β Isoform Pattern in a Mouse Model of Alzheimer’s Disease

2009 ◽  
Vol 6 (5-6) ◽  
pp. 258-262 ◽  
Author(s):  
Erik Portelius ◽  
Bin Zhang ◽  
Mikael K. Gustavsson ◽  
Gunnar Brinkmalm ◽  
Ann Westman-Brinkmalm ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Amyloid Β ◽  
Model Of Alzheimer’S Disease

scholarly journals Neurogenesis, Neurodegeneration, Interneuron Vulnerability, and Amyloid-β in the Olfactory Bulb of APP/PS1 Mouse Model of Alzheimer's Disease

2016 ◽  
Vol 10 ◽  
Author(s):  
Carlos De la Rosa-Prieto ◽  
Daniel Saiz-Sanchez ◽  
Isabel Ubeda-Banon ◽  
Alicia Flores-Cuadrado ◽  
Alino Martinez-Marcos
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Olfactory Bulb ◽  
Amyloid Β ◽  
Model Of Alzheimer’S Disease

scholarly journals Impact of CRFR1 Ablation on Amyloid-β Production and Accumulation in a Mouse Model of Alzheimer's Disease

2015 ◽  
Vol 45 (4) ◽  
pp. 1175-1184 ◽  
Author(s):  
Shannon N. Campbell ◽  
Cheng Zhang ◽  
Allyson D. Roe ◽  
Nickey Lee ◽  
Kathleen U. Lao ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Amyloid Β ◽  
Model Of Alzheimer’S Disease

scholarly journals Suppression of AMD-Like Pathology by Mitochondria-Targeted Antioxidant SkQ1 Is Associated with a Decrease in the Accumulation of Amyloid β and in mTOR Activity

Antioxidants ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 177 ◽  
Author(s):  
Natalia A. Muraleva ◽  
Oyuna S. Kozhevnikova ◽  
Anzhela Z. Fursova ◽  
Nataliya G. Kolosova
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Developed Countries ◽  
Term Treatment ◽  
Age Related Macular Degeneration ◽  
Eye Health ◽  
Age Related ◽  
Long Term Treatment

Age-related macular degeneration (AMD) is a major cause of irreversible visual impairment and blindness in developed countries, and the molecular pathogenesis of AMD is poorly understood. Recent studies strongly indicate that amyloid β (Aβ) accumulation —found in the brain and a defining feature of Alzheimer’s disease—also forms in the retina in both Alzheimer’s disease and AMD. The reason why highly neurotoxic proteins of consistently aggregate in the aging retina, and to what extent they contribute to AMD, remains to be fully addressed. Nonetheless, the hypothesis that Aβ is a therapeutic target in AMD is debated. Here, we showed that long-term treatment with SkQ1 (250 nmol/[kg body weight] daily from the age of 1.5 to 22 months) suppressed the development of AMD-like pathology in senescence-accelerated OXYS rats by reducing the level of Aβ and suppressing the activity of mTOR in the retina. Inhibition of mTOR signaling activity, which plays key roles in aging and age-related diseases, can be considered a new mechanism of the prophylactic effect of SkQ1. It seems probable that dietary supplementation with mitochondria-targeted antioxidant SkQ1 can be a good prevention strategy to maintain eye health and possibly a treatment of AMD.

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