Catechins from green tea and resveratrol show neuroprotective properties in Alzheimer's models

Catechins from green tea and resveratrol show neuroprotective properties in Alzheimer's models

In a study recently published in the journal Free radical biology and medicine Researchers searched for neuroprotective compounds against Alzheimer's disease (AD).

Alzheimer's disease, the sixth leading cause of death in the United States (US), is a progressive neurodegenerative disease and the most common cause of dementia in older adults. Increasing evidence suggests that pathogens trigger the amyloid cascade, tau protein hyperphosphorylation, and neuroinflammation in some patients. In particular, herpes simplex virus (HSV) type 1 has been implicated as an etiological agent in sporadic AD (sAD).

HSV-1 is a neurotrophic virus with a prevalence of 67% in US individuals aged 14 to 49 years. Recently, epidemiological studies have reported associations between antiherpetic treatments and a lower risk of dementia. Previously, the authors' laboratory reported the development of a three-dimensional (3D) human cortical brain tissue model of herpes-induced AD, which provided evidence for the causality of AD by HSV-1.

Learn: Screening neuroprotective compounds in cellular and 3D tissue models of herpes-induced Alzheimer's disease. Photo credit: bonchan / Shutterstock

The study and results

In the present study, researchers searched for neuroprotective compounds against AD. Human induced neural stem cells (hiNSCs) were generated by direct reprogramming using human foreskin fibroblasts. These cells were infected with HSV-1 at a multiplicity of infection (MOI) of 0.0001. 3D models of human cortical brain tissue were created. Experimental compounds were added simultaneously with viral inoculum.

2D cell cultures were maintained for 1 week and processed for immunostaining and gene expression analysis, while 3D models were maintained for 10 days and processed for calcium imaging and immunostaining. Immunofluorescence was performed on cells grown in 2D cultures or 3D models. The relative size and number of beta-amyloid (Aβ) plaque-like formations were quantified.

A library of compounds with purported neuroprotective properties was compiled from a list of Food and Drug Administration (FDA)-approved drugs for non-AD diseases, herbal/dietary supplements, and nutraceuticals. In addition, various FDA-approved medications that improve or worsen cognitive decline have been studied.

The primary 2D screen was performed using the entire library of 21 compounds to assess the formation of plaque-like Aβ formations, mRNA transcripts of AD mediators (amyloid precursor protein [APP], presenilin 1 [PSEN1], and cell morphology. The main candidates from the 2D screen were analyzed in 3D tissue models for plaque-like formations, dendritic network integrity, and calcium imaging tested.

Most compounds failed to reduce HSV-1-induced plaque formation and were not considered for further studies. Only green tea catechins, citicoline, ashwagandha extract, curcumin, resveratrol and metformin reduced plaque area induced by HSV. Notably, ashwagandha was excluded from further analysis due to significant toxicity.

Citicoline reduced Aβ plaque formation at 10 μM and 100 μM in 2D cultures. In 3D tissues, Aβ plaque formation was similarly reduced by citicoline treatment. However, there was a noticeable decrease in cell number along with a less interconnected dendritic network. Firing rate was significantly reduced in infected but untreated 3D tissues, and treatment with citicoline abolished this effect.

Curcumin treatment reduced the number and size of plaques in HSV-1-infected 2D cultures. Furthermore, curcumin treatment at 100 μM caused significant cell death. Treatment with 10 μM curcumin restored APP and PSEN1 expression levels to uninfected levels. Of note, curcumin treatment of 3D tissues caused significant cell death and was therefore not studied further.

Green tea catechins reduced plaque formation at 0.1 μg/ml and 1 μg/ml in 2D cell cultures. In 3D tissue models, green tea catechins caused a similar reduction in plaque burden as in 2D cultures, with high cell viability. Metformin also reduced plaque formation and preserved cell viability at concentrations of 10 μM and 1 mM.

Gene expression showed significantly low APP levels but increased PSEN2 expression in virus-infected cells. Metformin maintained high cell viability and plaque reductions in 3D models. However, metformin could not prevent the reduced firing rate induced by HSV infection.

Resveratrol showed a moderate reduction in plaque number at 1 μM and 10 μM, but completely suppressed plaque formation at 100 μM without affecting cell viability. 3D tissue models showed similar minimal toxicity at 100 μM with a significant reduction in plaques as in the 2D screen.

Foods rich in resveratrol. Photo credit: DIVA.photo / Shutterstock

Conclusions

In summary, the study identified green tea catechins and resveratrol as promising candidates for anti-plaque properties, functional neuroprotective properties against AD, and minimal toxicity. Although citicoline and metformin treatments demonstrated plaque suppression and low toxicity, these compounds did not protect against HSV-induced disruptions in neuronal signaling. Overall, the study established a simple platform for the rapid screening and characterization of anti-AD compounds in 2D cell cultures and 3D models of human cortical tissue.

Reference:

• Silveira IA, Mullis AS, Cairns DM, et al. Screening neuroprotektiver Verbindungen in Zell- und 3D-Gewebemodellen der Herpes-induzierten Alzheimer-Krankheit. Free Radical Biology and Medicine, 2022. DOI: 10.1016/j.freeradbiomed.2022.05.002, https://www.sciencedirect.com/science/article/pii/S0891584922001770?via%3Dihub#!

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