Cellulose ethers reduce amyloid‐beta pathology in in vitro and in vivo Alzheimer's disease model: Preclinical small‐molecule drug discovery. (7th December 2020)

• Record Type: Journal Article
• Authors: Ali, Tahir; Klein, Antonia N.; Vu, Alex; Gilch, Sabine
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 9
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.043995
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most prevalent cause of dementia. Neuropathologically, AD is characterized by amyloid‐beta (Aβ) aggregation. This is thought to be a primary pathological event impairing cellular homeostasis, neurotransmitters, inflammatory response, induces misfolding of other proteins and consequently leads to synaptic/neuronal loss. To date, no therapeutics are available to cure AD. Hence, we aimed to determine the therapeutic effects of cellulose ether (CE)‐based compounds for the treatment of AD. Method: We tested different concentrations of the CE TC‐5RW in vitro for its effect on Aβ aggregation by Thioflavin T assay. Similarly, we performed MTT assays to determine cell viability of human neuroblastoma (SH‐SY5Y) cells treated with Aβ aggregates formed in the presence or absence of TC‐5RW. In vivo, transgenic 5xFAD (expressing human APP and PSEN1 transgenes harboring in total 5 mutations associated with familial AD) mice were treated at the age of 6 weeks with a single subcutaneous injection of TC‐5RW at a dosage of 4g/kg. Following this treatment, the mice were euthanized at the age of 10 months and brains were harvested for further biochemical (Western blotting) and immunohistochemical analyses. Result: Our in vitro Thioflavin T assay results indicated that TC‐5RW had beneficial effects and at 0.25 % and 1 % TC‐5RW concentrations inhibited Aβ aggregation and accumulation. The MTT results showed that TC‐5RW increased cell viability of Aβ exposed SH‐SY5Y cells. Likewise, in vivo, the treatment with TC‐5RW significantly reduced the amount of oligomeric and monomeric forms of Aβ in the brains of 5xFAD+TC‐5RW mice compared to control 5xFAD mice. We performed Aβ6E10 immunofluorescence staining to analyse the number of Aβ plaques, and Aβ immunoreactivity in the hippocampus and cortex of the mice. The treatment with TC‐5RW significantly alleviated the number of Aβ plaques and immunofluorescence reactivity in the hippocampus and cortex of 5xFAD+TC‐5RW mice compared to control 5xFAD mice. These in vitro and in vivo results indicate that TC‐5RW reduces Aβ pathology. Conclusion: Taken together, our results and the safety profile (FDA approved) of CEs, suggest that these compounds have promising potential for the development of therapeutics against AD.