{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "1 Neurobiology of Aging Laboratory, Institute of Biology and Experimental Medicine (IBYME-CONICET), Buenos Aires, Argentina. 2 Department of Biological Chemistr"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 9,
  "authors": [
    {
      "name": "M. Bellotto"
    },
    {
      "name": "N. Gonzalez Perez"
    },
    {
      "name": "M. Bentivegna"
    },
    {
      "name": "M. Carrera"
    },
    {
      "name": "J. Presa"
    },
    {
      "name": "A. Vinuesa"
    },
    {
      "name": "C. Pomilio"
    },
    {
      "name": "F. Saravia"
    },
    {
      "affs": [
        0
      ],
      "name": "J. Beauquis"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2nbw3f999ad9x.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.04.749232",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.04.749232v1.full",
  "id": "2nbw3f999ad9x",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.04.749232v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ],
    [
      "openalex",
      "2737|Alzheimer's disease research and treatments"
    ]
  ],
  "openalex": "W7212224913",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.04.749232v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-04",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/2nbw3f999ad9x.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:21:29Z",
      "native_id": "10.64898/2026.09.04.749232",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.04.749232v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    }
  ],
  "title": "Differential Effects of Neutral Sphingomyelinase and Serine Palmitoyltransferase Inhibitors on Alzheimer's-Like Neuropathology.",
  "title_text": "Differential Effects of Neutral Sphingomyelinase and Serine Palmitoyltransferase Inhibitors on Alzheimer's-Like Neuropathology.",
  "type": "preprint",
  "updated_at": "2026-10-30T12:21:29Z",
  "url": "https://research.draconitic.com/paper/2nbw3f999ad9x",
  "venue": "bioRxiv",
  "versions": []
}