Pharmacologic reversal of advanced Alzheimer’s disease in mice and identification of potential therapeutic nodes in human brain
Kalyani Chaubey, Edwin Vázquez-Rosa, Sunil Jamuna Tripathi, Min-Kyoo Shin, Youngmin Yu, Matasha Dhar, Suwarna Chakraborty, Mai Yamakawa, Xinming Wang, Preethy Sridharan, Emiko Miller, Zea Bud, Sofia Corella, Sarah Barker, Salvatore G. Caradonna, Yeojung Koh, Kathryn Franke, Coral J. Cintrón-Pérez, Sophia Miryam Schüssler‐Fiorenza Rose, Hua Fang, Adrian A. Cintrón-Pérez, Taylor Tomco, Xiongwei Zhu, Hisashi Fujioka, Tamar Gefen, Margaret E. Flanagan, Noelle S. Williams, Brigid Wilson, Lawrence Chen, Lijun Dou, Feixiong Cheng, Jessica E. Rexach, Jung-A Woo, David E. Kang, Bindu D. Paul, Andrew A. Pieper
Abstract
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 + ) 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 + homeostasis, and the brains of nondemented people with Alzheimer's neuropathology exhibit gene expression patterns suggestive of preserved NAD + 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.