Abstract
Abstract Objectives Alzheimer’s disease is complex and involves several proteins. Most affected are Tau protein and amyloid precursor protein (APP) which, when cleaved by the enzymes β-secretase (BACE1) and γ-secretase (Nicastrin), yield the amyloid peptide. Although these processes take place mainly in neurons, it is not exclusive of them, as glia cells also contribute to these processes. The objective of this study was to evaluate the effect of nimesulide, resveratrol and citalopram on C6 (glioma) cells when exposed to Lipopolysaccharide (LPS). Methods Expression levels of the proteins APP, BACE1, COX-2, Nicastrin and Tau-p were evaluated by Western-blot and ELISA in C6 cells by effect of LPS, and the drugs citalopram, nimesulide and resveratrol. Results It was found that LPS is able to hyperphosphorylate Tau in this cell model and the drugs decrease hyperphosphorylation. We also found that the drugs increase the expression of APP, decrease BACE1 and promote the expression of Nicastrin. COX-2 decreases its expression when nimesulide is used. Conclusions Our results suggest that C6 cell line is useful to analyze the effect of pro-inflammatory molecules on tau phosphorylation and APP expression in vitro. The beneficial effect on the reduction of tau hyperphosphorylation shown by citalopram, nimesulide and resveratrol should be taken with caution due to the limitations of the present study and further research on these compounds is needed to determine their therapeutic use in neurodegenerative diseases such as Alzheimer’s disease. Amaç Alzheimer hastalığı karmaşıktır ve birkaç protein içerir. En çok etkilenenler, u-sekretaz (BACE1) ve γ-sekretaz (Nicastrin) enzimleri tarafından parçalandığında amiloid peptidi veren Tau proteini ve amiloid öncü proteinidir (APP). Bu süreçler esas olarak nöronlarda gerçekleşmesine rağmen, glia hücreleri de bu süreçlere katkıda bulunduğundan, bunlardan ayrı değildir. Amaç: Bu çalışmanın amacı, LPS’ye maruz kaldığında nimesulid, resveratrol ve sitalopramın C6 (glioma) hücreleri üzerindeki etkisini değerlendirmektir. Gereç ve Yöntem APP, BACE1, COX-2, Nicastrin ve Tau-p proteinlerinin ekspresyon seviyeleri, LPS’nin etkisi ile C6 hücrelerinde Western-blot ve ELISA ve sitalopram, nimesulid ve resveratrol ilaçları ile değerlendirildi. Bulgular Bu hücre modelinde LPS’nin Tau’yu hiperfosforilat edebildiği ve ilaçların hiperfosforilasyonu azalttığı bulundu. Ayrıca ilaçların APP ekspresyonunu arttırdığını, BACE1’i azalttığını ve Nicastrin ekspresyonunu teşvik ettiğini bulduk. Nimesulid kullanıldığında COX-2 ekspresyonunu azaltır. Sonuçlar Sonuçlarımız, pro-enflamatuar moleküllerin tau fosforilasyonu ve in vitro APP ekspresyonu üzerindeki etkisini analiz etmek için C6 hücre hattının yararlı olduğunu göstermektedir. Sitalopram, nimesulid ve resveratrol tarafından gösterilen tau hiperfosforilasyonunun azaltılması üzerindeki yararlı etki, mevcut çalışmanın sınırlamaları nedeniyle dikkatle alınmalı ve bu bileşikler üzerinde, Alzheimer hastalığı gibi nörodejeneratif hastalıklarda terapötik kullanımlarının belirlenmesi için daha fazla araştırmaya ihtiyaç vardır.
Highlights
Worldwide, approximately 50 million people are affected by dementia, with Alzheimer’s disease (AD) being the most common, according to the World Alzheimer’s Report 2018 [1]
We found that the drugs increase the expression of amyloid precursor protein (APP), decrease BACE1 and promote the expression of Nicastrin
The beneficial effect on the reduction of tau hyperphosphorylation shown by citalopram, nimesulide and resveratrol should be taken with caution due to the limitations of the present study and further research on these compounds is needed to determine their therapeutic use in neurodegenerative diseases such as Alzheimer’s disease
Summary
Approximately 50 million people are affected by dementia, with Alzheimer’s disease (AD) being the most common, according to the World Alzheimer’s Report 2018 [1] It is characterized by two typical lesions: the formation of amyloid plaques in the extracellular space and intracellular neurofibrillary tangles. Another key process during the development of AD is neuroinflammation, in which pro-inflammatory molecules such as COX-2, interleukin-1, TNF-α, NF-κβ, among others, have a very relevant effect on the development of the disease and are associated with malfunctioning of microglia and astrocytes [2]. Evidence suggests that astrocytes dynamically modulate information processing, signal transmission, and synaptic plasticity They release trophic factors, provide metabolic support and regulate the growth of dendrites and axons [4]. When astrocytes are activated, they become hypertrophic, accumulate β-amyloid in their cytoplasm, occasionally lose their ability to express the EAAT-2 protein, all due to their exposure to amyloid plaques, and “neglect” their physiological functions which induces neuronal degeneration, loss of synapses, formation of neurofibrillary tangles and neuritic degeneration [5]
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