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

Anne Leiteritz, Benjamin Dilberger, Uwe Wenzel, Elena Fitzenberger

The 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. Betaine 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. Our 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.