Pharmacologic reversal of advanced Alzheimer’s disease in mice and identification of potential therapeutic nodes in human brain
Alzheimer's disease (AD) is traditionally considered irreversible. Here, however, we provide proof of principle for therapeutic reversibility of advanced AD. In advanced disease amyloid-driven 5xFAD mice, treatment with P7C3-A20, which restores nicotinamide adenine dinucleotide (NAD<sup>+</sup>) homeostasis, reverses tau phosphorylation, blood-brain barrier deterioration, oxidative stress, DNA damage, and neuroinflammation and enhances hippocampal neurogenesis and synaptic plasticity, resulting in full cognitive recovery and reduction of plasma levels of the clinical AD biomarker p-tau217. P7C3-A20 also reverses advanced disease in tau-driven PS19 mice and protects human brain microvascular endothelial cells from oxidative stress. In humans and mice, pathology severity correlates with disruption of brain NAD<sup>+</sup> homeostasis, and the brains of nondemented people with Alzheimer's neuropathology exhibit gene expression patterns suggestive of preserved NAD<sup>+</sup> homeostasis. Forty-six proteins aberrantly expressed in advanced 5xFAD mouse brain and normalized by P7C3-A20 show similar alterations in human AD brain, revealing targets with potential for optimizing translation to patient care.
Authors
- Hua Fang (ORCID: https://orcid.org/0000-0003-1669-4898)
- Kathryn Franke (ORCID: https://orcid.org/0000-0002-3038-2826)
- Bindu D. Paul (ORCID: https://orcid.org/0000-0002-1862-6103)
- Sophia Miryam Schüssler‐Fiorenza Rose (ORCID: https://orcid.org/0000-0002-6311-6671)
- Kalyani Chaubey (ORCID: https://orcid.org/0000-0002-6378-6739)
- Salvatore G. Caradonna (ORCID: https://orcid.org/0000-0001-9192-2630)
- Tamar Gefen (ORCID: https://orcid.org/0000-0002-2380-3100)
- Zea Bud
- Youngmin Yu
- Xinming Wang (ORCID: https://orcid.org/0000-0001-5290-8254)
- Preethy S. Sridharan (ORCID: https://orcid.org/0000-0001-7692-6342)
- Mai Yamakawa (ORCID: https://orcid.org/0000-0002-6474-8910)
- Yeojung Koh (ORCID: https://orcid.org/0000-0002-4294-7871)
- Sunil Jamuna Tripathi (ORCID: https://orcid.org/0000-0001-9107-2437)
- Hisashi Fujioka (ORCID: https://orcid.org/0000-0001-8511-7141)
- Jessica E. Rexach (ORCID: https://orcid.org/0000-0002-4462-7249)
- Suwarna Chakraborty (ORCID: https://orcid.org/0000-0001-9456-4322)
- Brigid Wilson (ORCID: https://orcid.org/0000-0003-2966-2940)
- David E. Kang (ORCID: https://orcid.org/0000-0002-7132-821X)
- Coral J. Cintrón-Pérez (ORCID: https://orcid.org/0000-0003-2160-4244)
- Noelle Sevilir Williams (ORCID: https://orcid.org/0000-0003-1894-5742)
- Sofia Corella
- Min-Kyoo Shin (ORCID: https://orcid.org/0000-0001-6697-3639)
- Lawrence Chen (ORCID: https://orcid.org/0000-0003-1721-2483)
- Taylor Tomco
- Jung-A Woo
- Andrew A. Pieper
- Xiongwei Zhu
- Emiko Miller
- Margaret E. Flanagan
- Matasha Dhar
- Edwin Vázquez-Rosa
- Adrian A. Cintrón-Pérez
- Sarah Barker
- Feixiong Cheng
- Lijun Dou
Institutions
- Northwestern University (US)
- Cleveland Clinic (US)
- Johns Hopkins University (US)
- University of California, Los Angeles (US)
- The University of Texas at San Antonio Health Science Center (US)
- University Hospitals of Cleveland (US)
- Johns Hopkins Medicine (US)
- Cleveland Clinic Lerner College of Medicine (US)
- Alzheimer’s Disease Neuroimaging Initiative (US)
- Louis Stokes Cleveland VA Medical Center (US)
- Lieber Institute for Brain Development (US)
- University School (US)
- Case Western Reserve University (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-12-22
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102535
- Citations
- 1
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 1.16