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Neuropharmacology. 2018 Mar 1;130:54-61. doi: 10.1016/j.neuropharm.2017.11.042. Epub 2017 Nov 27.

Disease-modifying benefit of Fyn blockade persists after washout in mouse Alzheimer's model.

Author information

1
Cellular Neuroscience, Neurodegeneration and Repair Program, Yale University School of Medicine, New Haven, CT 06510, USA; Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06510, USA.
2
Cellular Neuroscience, Neurodegeneration and Repair Program, Yale University School of Medicine, New Haven, CT 06510, USA.
3
Cellular Neuroscience, Neurodegeneration and Repair Program, Yale University School of Medicine, New Haven, CT 06510, USA; Departments of Neurology and of Neuroscience, Yale University School of Medicine, New Haven, CT 06510, USA. Electronic address: stephen.strittmatter@yale.edu.

Abstract

Alzheimer's disease remains without a disease-modifying therapy that improves symptoms after therapy withdrawal. Because no investigational agents have demonstrated disease-modifying effects clinically, we tested whether the Fyn inhibitor, saracatinib, provides persistent improvement in a transgenic model. Aged APPswe/PS1ΔE9 mice were treated with saracatinib or memantine for 4 weeks and spatial memory improved to control levels. After drug washout, there was sustained rescue of both memory function and synapse density by saracatinib, but a loss of benefit from memantine. These data demonstrate a disease-modifying persistent benefit for saracatinib in a preclinincal Alzheimer's model, and distinguish its action from that of memantine.

KEYWORDS:

APPswe/PS1ΔE9 mice; AZD0530; Alzheimer's disease; Fyn kinase; Memantine; Namenda; Saracatinib

PMID:
29191754
PMCID:
PMC5743608
[Available on 2019-03-01]
DOI:
10.1016/j.neuropharm.2017.11.042

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