Sullivan A Campbell, Zuniga Gabrielle, Ramirez Paulino, Fernandez Roman, Wang Chen-Pin, Li Ji, Davila Lisa, Pelton Kristine, Gomez Sandra, Sohn Claira, Gonzalez Elias, Lopez-Cruzan Marisa, Gonzalez David A, Parker Alicia, Zilli Eduardo, de Erausquin Gabriel A, Seshadri Sudha, Espinoza Sara, Musi Nicolas, Frost Bess
Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health San Antonio, San Antonio, TX USA.
Department of Neurology, University of Texas Health San Antonio, San Antonio, TX USA.
NPJ Dement. 2025;1(1):2. doi: 10.1038/s44400-024-00001-z. Epub 2025 Mar 12.
Retrotransposons constitute over 40% of the human genome. Studies in , mice, cultured cells, and human brain show that retrotransposons are activated in tauopathies, including Alzheimer's disease, and causally drive neurodegeneration. The reverse transcriptase inhibitor 3TC (lamivudine) reduces retrotransposon activation and suppresses tau neurotoxicity among model systems. This phase 2a open-label trial (Pilot Study to Investigate the Safety and Feasibility of Anti-Retroviral Therapy for Alzheimer's Disease, NCT04552795, registered 09/10/2020) followed 12 participants with early Alzheimer's disease (MMSE > 24, CDR = 0.5) over 24 weeks to assess safety, tolerability, and feasibility of daily 300 mg 3TC treatment. The sample was well-educated (12-20 years) and culturally diverse (25% from underrepresented groups). In addition to a favorable safety profile and stable cognitive measures, notable significant changes in fluid-based biomarkers include reduction of glial fibrillary acidic protein (GFAP) ( = 0.03) in CSF, suggestive of reduced neuroinflammation, and elevation of Aβ42/40 ( = 0.009) in plasma, suggestive of reduced plaque load in the brain. These results warrant further exploration in a larger, placebo-controlled trial.
逆转录转座子占人类基因组的40%以上。对小鼠、培养细胞和人类大脑的研究表明，逆转录转座子在包括阿尔茨海默病在内的tau蛋白病中被激活，并因果性地驱动神经退行性变。逆转录酶抑制剂3TC（拉米夫定）可减少逆转录转座子的激活，并在模型系统中抑制tau蛋白的神经毒性。这项2a期开放标签试验（阿尔茨海默病抗逆转录病毒治疗安全性和可行性的初步研究，NCT04552795，于2020年10月9日注册）对12名早期阿尔茨海默病患者（MMSE > 24，CDR = 0.5）进行了为期24周的随访，以评估每日300 mg 3TC治疗的安全性、耐受性和可行性。样本接受过良好教育（12 - 20年），且文化背景多样（25%来自代表性不足的群体）。除了良好的安全性和稳定的认知指标外，基于液体的生物标志物的显著变化包括脑脊液中胶质纤维酸性蛋白（GFAP）降低（P = 0.03），提示神经炎症减轻，血浆中Aβ42/40升高（P = 0.009），提示脑内斑块负荷降低。这些结果值得在更大规模的安慰剂对照试验中进一步探索。
