DMSO Delays Alzheimer Disease Causing Aβ-induced Paralysis in C. elegans Through Modulation of Glutamate/Acetylcholine Neurotransmission

Abstract

Background: Alzheimer’s disease (AD), a prevalent neurodegenerative disease with progressive dementia and neurotransmission (NT)-dysfunction-related complications in older adults, is known to be caused by abnormal Amyloid-β (Aβ) peptide and associated amyloid plaques in the brain. Drugs to cure AD are not in sight. Two major excitatory neurotransmitters, glutamate (Glu) and acetylcholine (ACh), and their signaling systems are implicated in AD. Objective: To determine the effect of various NT-altering compounds including fenobam, quisqualic acid, and dimethyl sulfoxide (DMSO) in the protection against Aβ toxicity. Further, to identify the potential mechanism through which the protection happens. Methods: The well-known C. elegans AD model, CL4176, in which human Aβ expression is turned on upon a temperature shift to 25 °C that leads to paralysis, was screened for protection/delay in paralysis because of Αβ toxicity. While screening the compounds, dimethyl sulfoxide (DMSO), a universal solvent used to solubilize compounds, was identified to provide protection. Aldicarb and levamisole assays were performed to identify the contribution of ACh neurotransmission in Αβ toxicity protection by DMSO. Results: One percent and two percent DMSO delayed paralysis by 48% and 90%, respectively. DMSO was dominant over one of the Glu-NT pathway-related compounds, Fenobam-Group I mGluR antagonist. But DMSO provided only 30% to 50% protection against Quisqualic acid, the Glu-agonist. DMSO (2%) delayed ACh-NT, both presynaptic acetylcholine esterase inhibitor (AchEi)-aldicarb and postsynaptic-iAChR-agonst-levamisole induced paralysis, by ∼70% in CL4176. DMSO seems to be altering Ca2+ ion permeability essential for NT as EthyleneDiamine Tetra-Acetic acid (EDTA) and DMSO provided similar aldicarb resistance either combined or alone in wildtype worms. But postsynaptic Ca2+ depletion by EDTA could reverse DMSO-induced levamisole hypersensitivity. Surprisingly, the absence of FOrkhead boXO (FOXO) transcription factor homolog, daf-16 (loss-of-function mutant), a critical transcription factor in the reduced IIS-mediated longevity in C. elegans, abolished DMSO-mediated AldR. Conclusion: DMSO and Fenobam protect against Aβ toxicity through modulation of NT.

Light‐controlled molecular tweezers capture specific amyloid oligomers

“…For the same conditions as that in LMT1 groups, Dimethyl sulfoxide (DMSO) (1%, v/v) was used in the vehicle group, which would lead to the delayed onset of worm paralysis. [ 42 ] Compared to the vehicle group, treatment with cis‐LMT1 and irradiation at 365 nm obviously postponed the paralysis (Figure 7B), suggesting that cis‐LMT1 could alleviate the neurotoxicity of Aβ aggregation in C. elegans by blocking the aggregation via freezing Aβ42 dimers. In the dark, almost no delay in paralysis was observed in worms treated with trans‐LMT1, confirming that trans‐LMT1 cannot intervene Aβ aggregation in vivo.…”

Abl depletion via autophagy mediates the beneficial effects of quercetin against Alzheimer pathology across species

“…Some studies also indicated lutein and EGCG preferentially display beneficial effects in compromised C. elegans backgrounds [45,46], while others have shown the compounds increase stress resistance and extend lifespan also in wild-type animals [47,48]. These seemingly conflicting results can be explained by different exposure scenarios: bimodal dose-dependent effects have been often reported with dietary interventions [47,49]; different bacterial types used as food source (e.g., HT115 vs OP50; dead vs alive bacteria) can influence animals phenotypes and behaviors in basal conditions, as well as compounds metabolism and therefore their biological effects on lifespan and age-associated features [50][51][52]; vehicles, methods and age of administration may add further variability [53][54][55]. For instance, we here observed that different experimental paradigms (e.g., ±solvent) slightly affect resistance to stress and attraction to food in the nAD strain compared to wild-type animals.…”

Abl depletion via autophagy mediates the beneficial effects of quercetin against Alzheimer pathology across species

“…Moreover, differently from the original study [30], the nAD strain, which we fed here HT115 plus vehicle, was not short lived compared to wild-type animals. Interestingly, DMSO, the most commonly used solvent used for compound feeding, has been shown to have repercussion on a broad spectrum of animals' phenotypes including lifespan [50][51][52].…”