ABSTRACT
Alzheimer's disease (AD) is a multifactorial health problem widespread over the world. Regarding the historical importance of the alkaloids in the central nervous system pharmacology they remain as promising drug candidates against AD. Seven alkaloids from Amaryllidaceae and Fabaceae were evaluated in vivo, in vitro and in silico targets related to the AD pathophysiology. Erythraline and erysodine showed the greatest potential compared to Memantine, a drug currently used in AD therapy, by delaying the Aß1-42-induced paralysis in the transgenic strain CL2006 Caenorhabditis elegans, an alternative model to assess the impairment of beta-amyloid peptide deposition. The in vitro inhibition of the acetylcholinesterase was observed for the first time for Erythrina alkaloids; however Lycorine was the most active. Docking simulation contributed to comprehend this potential by showing a hydrophobic interaction between acetylcholinesterase and Lycorine in the amino acid residue TRP 84 as well as hydrogen bonds with TRY 121 and ASP 72.
Subject(s)
Alkaloids , Alzheimer Disease , Acetylcholinesterase , Alkaloids/pharmacology , Alzheimer Disease/drug therapy , Amyloid beta-Peptides/toxicity , Animals , Caenorhabditis elegans , Isoquinolines/pharmacology , Peptide FragmentsABSTRACT
Rare coding variants in TREM2, PLCG2, and ABI3 were recently associated with the susceptibility to Alzheimer's disease (AD) in Caucasians. Frequencies and AD-associated effects of variants differ across ethnicities. To start filling the gap on AD genetics in South America and assess the impact of these variants across ethnicity, we studied these variants in Argentinian population in association with ancestry. TREM2 (rs143332484 and rs75932628), PLCG2 (rs72824905), and ABI3 (rs616338) were genotyped in 419 AD cases and 486 controls. Meta-analysis with European population was performed. Ancestry was estimated from genome-wide genotyping results. All variants show similar frequencies and odds ratios to those previously reported. Their association with AD reach statistical significance by meta-analysis. Although the Argentinian population is an admixture, variant carriers presented mainly Caucasian ancestry. Rare coding variants in TREM2, PLCG2, and ABI3 also modulate susceptibility to AD in populations from Argentina, and they may have a European heritage.
