TY - JOUR
T1 - Pharmacologic reversal of advanced Alzheimer’s disease in mice and identification of potential therapeutic nodes in human brain
AU - Chaubey, Kalyani
AU - Vázquez-Rosa, Edwin
AU - Tripathi, Sunil Jamuna
AU - Shin, Min Kyoo
AU - Yu, Youngmin
AU - Dhar, Matasha
AU - Chakraborty, Suwarna
AU - Yamakawa, Mai
AU - Wang, Xinming
AU - Sridharan, Preethy S.
AU - Miller, Emiko
AU - Bud, Zea
AU - Corella, Sofia G.
AU - Barker, Sarah
AU - Caradonna, Salvatore G.
AU - Koh, Yeojung
AU - Franke, Kathryn
AU - Cintrón-Pérez, Coral J.
AU - Rose, Sophia
AU - Fang, Hua
AU - Cintrón-Pérez, Adrian A.
AU - Tomco, Taylor
AU - Zhu, Xiongwei
AU - Fujioka, Hisashi
AU - Gefen, Tamar
AU - Flanagan, Margaret E.
AU - Williams, Noelle S.
AU - Wilson, Brigid M.
AU - Chen, Lawrence
AU - Dou, Lijun
AU - Cheng, Feixiong
AU - Rexach, Jessica E.
AU - Woo, Jung A.
AU - Kang, David E.
AU - Paul, Bindu D.
AU - Pieper, Andrew A.
N1 - Publisher Copyright:
Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license. http://creativecommons.org/licenses/by-nc-nd/4.0/
PY - 2026/1/20
Y1 - 2026/1/20
N2 - 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.
AB - 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.
KW - 5XFAD
KW - Alzheimer's disease
KW - NAD
KW - P7C3
KW - P7C3-A20
KW - PS19
KW - neurodegeneration
KW - neuroprotection
KW - prevention
KW - reversal
UR - https://www.scopus.com/pages/publications/105028313403
UR - https://www.scopus.com/pages/publications/105028313403#tab=citedBy
U2 - 10.1016/j.xcrm.2025.102535
DO - 10.1016/j.xcrm.2025.102535
M3 - Article
C2 - 41435831
AN - SCOPUS:105028313403
SN - 2666-3791
VL - 7
JO - Cell Reports Medicine
JF - Cell Reports Medicine
IS - 1
M1 - 102535
ER -