Differential Effects of Neutral Sphingomyelinase and Serine Palmitoyltransferase Inhibitors on Alzheimer's-Like Neuropathology.
- 11 Neurobiology of Aging Laboratory, Institute of Biology and Experimental Medicine (IBYME-CONICET), Buenos Aires, Argentina. 2 Department of Biological Chemistr
Abstract
Alzheimer's disease (AD) involves progressive neurodegeneration, amyloid-{beta} (A{beta}) pathology and chronic neuroinflammation. Elevated ceramides, generated via neutral sphingomyelinase (nSMase)-mediated sphingomyelin hydrolysis or serine palmitoyltransferase (SPT)-driven de novo synthesis, amplify these processes. Here, we performed a direct comparison of pharmacological inhibition of these pathways in the PDAPP-J20 transgenic mouse model and in fibrillized A{beta}1-42-challenged BV-2 murine microglial cell line. Eight-month-old PDAPP-J20 female mice received intraperitoneal GW4869 (nSMase inhibitor, 1.25 mg/kg) or myriocin (SPT inhibitor, 0.3 mg/kg) three times weekly for 3 weeks. Neutral SMase inhibition restored spatial learning in the Barnes maze, reduced hippocampal neuronal loss and layer atrophy, decreased amyloid plaque burden, and attenuated microglial activation (Iba1 morphology and peri-plaque reactivity). In contrast, SPT inhibition worsened thigmotaxis, failed to improve cognition, and increased plaque load. In vitro, nSMase blockade (GW4869 and cambinol) suppressed A{beta}-induced NF{kappa}B p65 nuclear translocation, blunted TNF- expression, and reduced intracellular A{beta} accumulation in microglia, suggesting enhanced endolysosomal degradation. SPT inhibition lacked these anti-inflammatory and clearance-promoting effects. These results identify nSMase as a critical node linking ceramide metabolism, microglial dysfunction, and amyloid progression in AD. Targeted nSMase inhibition offers a promising molecular strategy to interrupt neuroinflammation and restore neuronal homeostasis, while broad SPT blockade appears counterproductive. Pathway-selective modulation of ceramide signaling may open new therapeutic avenues for AD.
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BibTeX
@misc{bellotto2026differential,
title = {{Differential Effects of Neutral Sphingomyelinase and Serine Palmitoyltransferase Inhibitors on Alzheimer's-Like Neuropathology.}},
author = {M. Bellotto and N. Gonzalez Perez and M. Bentivegna and M. Carrera and J. Presa and A. Vinuesa and C. Pomilio and F. Saravia and J. Beauquis},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.04.749232},
url = {https://www.biorxiv.org/content/10.64898/2026.09.04.749232v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Differential Effects of Neutral Sphingomyelinase and Serine Palmitoyltransferase Inhibitors on Alzheimer's-Like Neuropathology.
AU - M. Bellotto
AU - N. Gonzalez Perez
AU - M. Bentivegna
AU - M. Carrera
AU - J. Presa
AU - A. Vinuesa
AU - C. Pomilio
AU - F. Saravia
AU - J. Beauquis
PY - 2026
DA - 2026/09/04
PB - bioRxiv
DO - 10.64898/2026.09.04.749232
UR - https://www.biorxiv.org/content/10.64898/2026.09.04.749232v1
AB - Alzheimer's disease (AD) involves progressive neurodegeneration, amyloid-{beta} (A{beta}) pathology and chronic neuroinflammation. Elevated ceramides, generated via neutral sphingomyelinase (nSMase)-mediated sphingomyelin hydrolysis or serine palmitoyltransferase (SPT)-driven de novo synthesis, amplify these processes. Here, we performed a direct comparison of pharmacological inhibition of these pathways in the PDAPP-J20 transgenic mouse model and in fibrillized A{beta}1-42-challenged BV-2 murine microglial cell line. Eight-month-old PDAPP-J20 female mice received intraperitoneal GW4869 (nSMase inhibitor, 1.25 mg/kg) or myriocin (SPT inhibitor, 0.3 mg/kg) three times weekly for 3 weeks. Neutral SMase inhibition restored spatial learning in the Barnes maze, reduced hippocampal neuronal loss and layer atrophy, decreased amyloid plaque burden, and attenuated microglial activation (Iba1 morphology and peri-plaque reactivity). In contrast, SPT inhibition worsened thigmotaxis, failed to improve cognition, and increased plaque load. In vitro, nSMase blockade (GW4869 and cambinol) suppressed A{beta}-induced NF{kappa}B p65 nuclear translocation, blunted TNF- expression, and reduced intracellular A{beta} accumulation in microglia, suggesting enhanced endolysosomal degradation. SPT inhibition lacked these anti-inflammatory and clearance-promoting effects. These results identify nSMase as a critical node linking ceramide metabolism, microglial dysfunction, and amyloid progression in AD. Targeted nSMase inhibition offers a promising molecular strategy to interrupt neuroinflammation and restore neuronal homeostasis, while broad SPT blockade appears counterproductive. Pathway-selective modulation of ceramide signaling may open new therapeutic avenues for AD.
ER -