D-002 | Effect of ceramide synthesis pathway inhibition in murine model of Alzheimer’s disease.

Cellular and Molecular Neurobiology
Author: Melina Paula Bellotto | Email: melinabellotto@gmail.com

Melina Bellotto^1°2°, Melisa Bentivegna^1°2°, Nicolás Gonzáles Pérez^1°2°,  Jessica Presa^1°2°, Carlos Pomilio^1°2°, Flavia Saravia^1°2°, Juan Beauquis^1°2°

^1° Instituto de Biología y Medicina Experimental (IBYME-CONICET)
^2° Departamento de Química Biológica, FCEN, UBA

Alzheimer’s disease (AD) is the main cause of dementia. Among the molecular hallmarks are amyloid plaques and Tau neurofibrilary tangles. We hypotesized that ceramides, membrane lipids that mediate inflammation, have a role in the neurodegeneration and glial activation that occur in AD.

The aim of this work was to study the effects of inhibiting ceramide synthesis pathways on the pathology of PDAPPJ20 transgenic mice, model of AD. We treated mice with farmacological inhibitors of 1) the de novo pathway, mediated by serin-palmitoyl transferase (SPT), and 2) the pathway mediated by neutral sphingomyelinase 2 (nSMase2), involved in exosome synthesis.

8-month-old female PDAPPJ20 mice were treated with the inhibitors Myriocin (Myr; inh. SPT; 0,3 mg/Kg; i.p.) or GW4869 (GW; inh. NSMAse2; 1,25 mg/Kg, i.p.). Myr-treated mice exhibited an exacerbated behavioral phenotype in the Open-Field and Barnes Maze tests. We studied amyloid plaque content in brain samples and found that Myr-treated mice showed more plaques in the hilus (p<0.01) region and larger plaques in the stratum radiatum (p<0.01) compared to vehicle-treated mice. The results of Myr treatment could indicate that the inhibition of SPT mediated ceramide synthesis pathway could accelerate the progression of the disease. Results from the GW treatment and from in vitro experiments will help us understand the relevance of the nSmase2 pathway in AD.