Betaine reduces β-amyloid-induced paralysis through activation of cystathionine-β-synthase in an Alzheimer model of Caenorhabditis elegans

Abstract

BackgroundThe neurodegenerative disorder Alzheimer’s disease is caused by the accumulation of toxic aggregates of β-amyloid in the human brain. On the one hand, hyperhomocysteinemia has been shown to be a risk factor for cognitive decline in Alzheimer’s disease. On the other hand, betaine has been demonstrated to attenuate Alzheimer-like pathological changes induced by homocysteine. It is reasonable to conclude that this is due to triggering the remethylation pathway mediated by betaine-homocysteine-methyltransferase. In the present study, we used the transgenic Caenorhabditis elegans strain CL2006, to test whether betaine is able to reduce β-amyloid-induced paralysis in C. elegans. This model expresses human β-amyloid 1–42 under control of a muscle-specific promoter that leads to progressive, age-dependent paralysis in the nematodes.ResultsBetaine at a concentration of 100 μM was able to reduce homocysteine levels in the presence and absence of 1 mM homocysteine. Simultaneously, betaine both reduced normal paralysis rates in the absence of homocysteine and increased paralysis rates triggered by addition of homocysteine. Knockdown of cystathionine-β-synthase using RNA interference both increased homocysteine levels and paralysis. Additionally, it prevented the reducing effects of betaine on homocysteine levels and paralysis.ConclusionOur studies show that betaine is able to reduce homocysteine levels and β-amyloid-induced toxicity in a C. elegans model for Alzheimer’s disease. This effect is independent of the remethylation pathway but requires the transsulfuration pathway mediated by cystathionine-β-synthase.

Effects of Combining Biofactors on Bioenergetic Parameters, Aβ Levels and Survival in Alzheimer Model Organisms

“…Both combinations were able to reduce the paralyzes, indicating the significantly reduced toxicity of Aβ. Similar effects have been shown with other substances, which reduced the paralysis and thus the toxicity of Aβ [ 73 , 79 , 80 , 81 ]. The reduced toxicity could be a consequence of the reduction of Aβ levels in C. elegans .…”

“…In contrast, all tested combinations and single substances, have a significantly increased effect on mean survival ( Figure 7 C). CL2006 continuously produces Aβ, which has a toxic effect on the lifespan [ 70 , 73 ]. In particular, it has effects on DAF-16, which is expressed in the nucleus during stress and has an effect on life span extension [ 74 ].…”

Modeling Alzheimer’s Disease in Caenorhabditis elegans

“…B12 supplementation reduced homocysteine levels, suggesting that oxidative stress caused by elevated homocysteine levels may be an important factor in Aβ toxicity [ 160 ]. Consistently, betaine reduced Aβ-induced degeneration in an AD model in C. elegans through an activation of cystathionine-β-synthase and a reduction in homocysteine levels [ 161 ].…”

A Lactobacilli diet that confers MRSA resistance causes amino acid depletion and increased antioxidant levels in the C. elegans host

“…The increased level of betaine found in worms fed Lb21 could play a role in the protective effect against stress as supplementation with betaine reduces protein aggregation induced paralysis in an Alzheimer's disease C. elegans model (Leiteritz et al, 2018 ). The paralysis-reducing effect of betaine was found to be dependent on the enzyme cystathionin-β-synthase ( cbs-1 ).…”