{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:46:36Z","timestamp":1792003596440,"version":"4.4.0"},"reference-count":65,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"871","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2026,10,14]]},"abstract":"<jats:p>\n                    Microglial dysfunction is increasingly implicated in Alzheimer\u2019s disease (AD) pathogenesis, with loss-of-function variants in the microglial receptor TREM2 as major risk factors for late-onset AD. We report VG-3927, an oral, CNS-penetrant small-molecule TREM2 agonist that engages the transmembrane domains of TREM2 and its adaptor DAP12 to promote higher-order receptor complex formation and downstream signaling. VG-3927 and tool compound VG-3909 exhibited (sub)nanomolar potency, cooperated with endogenous ligands including amyloid-\u03b2 (A\u03b2), and restored signaling in disease-associated TREM2 variants. In human iPSC-derived neuron-microglia-astrocyte cultures, VG-3927 reduced inflammatory cytokines and markers of neuronal damage. In 5xFAD amyloidosis mice expressing the common variant of hTREM2 (5xFAD;hTREM2\n                    <jats:sup>CV<\/jats:sup>\n                    ), VG-3909 induced neuroprotective transcriptional reprogramming of microglia, particularly in the plaque niche; enhanced A\u03b2 phagocytosis; and boosted brain glucose metabolism. By contrast, a TREM2 agonist antibody, which may be sequestered by soluble TREM2 (sTREM2), failed to engage plaque microglia. In a first-in-human, randomized, double-blind, placebo-controlled phase 1 trial (NCT06343636,\n                    <jats:italic toggle=\"yes\">n<\/jats:italic>\n                    \u00a0=\u00a0115), VG-3927 was well tolerated across single and multiple ascending doses of up to 140\u00a0milligrams. Pharmacokinetics supported once-daily dosing with high CNS penetration (CSF-to-unbound plasma ratio of 0.91). VG-3927 induced dose-dependent reductions in CSF sTREM2, a biomarker of target engagement, consistent across healthy and elderly participants and participants with AD, supporting further clinical development in AD under the new designation SAR448851.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.aec5740","type":"journal-article","created":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:58:41Z","timestamp":1792000721000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Preclinical and first-in-human evaluation of VG-3927\/SAR448851, an oral small-molecule TREM2 agonist for Alzheimer\u2019s disease"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-6843-1418","authenticated-orcid":true,"given":"Borislav","family":"Dejanovic","sequence":"first","affiliation":[{"name":"Vigil Neuroscience, a Sanofi company, Watertown, MA 02472, 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