Enhancement of tripartite synapses as a potential therapeutic strategy for Alzheimer’s disease: a preclinical study in rTg4510 mice

Abstract Background The lack of effective treatment options for Alzheimer’s disease (AD) is of momentous societal concern. Synaptic loss is the hallmark of AD that correlates best with impaired memory and occurs early in the disease process, before the onset of clinical symptoms. We have developed a...

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Main Authors: Joshua B. Foster, Rashelle Lashley, Fangli Zhao, Xueqin Wang, Nydia Kung, Candice C. Askwith, Lin Lin, Michael W. Shultis, Kevin J. Hodgetts, Chien-Liang Glenn Lin
Format: Article
Language:English
Published: BMC 2019-08-01
Series:Alzheimer’s Research & Therapy
Subjects:
Online Access:http://link.springer.com/article/10.1186/s13195-019-0530-z
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author Joshua B. Foster
Rashelle Lashley
Fangli Zhao
Xueqin Wang
Nydia Kung
Candice C. Askwith
Lin Lin
Michael W. Shultis
Kevin J. Hodgetts
Chien-Liang Glenn Lin
author_facet Joshua B. Foster
Rashelle Lashley
Fangli Zhao
Xueqin Wang
Nydia Kung
Candice C. Askwith
Lin Lin
Michael W. Shultis
Kevin J. Hodgetts
Chien-Liang Glenn Lin
author_sort Joshua B. Foster
collection DOAJ
description Abstract Background The lack of effective treatment options for Alzheimer’s disease (AD) is of momentous societal concern. Synaptic loss is the hallmark of AD that correlates best with impaired memory and occurs early in the disease process, before the onset of clinical symptoms. We have developed a small-molecule, pyridazine-based series that enhances the structure and function of both the glial processes and the synaptic boutons that form the tripartite synapse. Previously, we have shown that these pyridazine derivatives exhibit profound efficacy in an amyloid precursor protein AD model. Here, we evaluated the efficacy of an advanced compound, LDN/OSU-0215111, in rTg4510 mice—an aggressive tauopathy model. Methods rTg4510 mice were treated orally with vehicle or LDN/OSU-0215111 (10 mg/kg) daily from the early symptomatic stage (2 months old) to moderate (4 months old) and severe (8 months old) disease stages. At each time point, mice were subjected to a battery of behavioral tests to assess the activity levels and cognition. Also, tissue collections were performed on a subset of mice to analyze the tripartite synaptic changes, neurodegeneration, gliosis, and tau phosphorylation as assessed by immunohistochemistry and Western blotting. At 8 months of age, a subset of rTg4510 mice treated with compound was switched to vehicle treatment and analyzed behaviorally and biochemically 30 days after treatment cessation. Results At both the moderate and severe disease stages, compound treatment normalized cognition and behavior as well as reduced synaptic loss, neurodegeneration, tau hyperphosporylation, and neuroinflammation. Importantly, after 30 days of treatment cessation, the benefits of compound treatment were sustained, indicating disease modification. We also found that compound treatment rapidly and robustly reduced tau hyperphosphorylation/deposition possibly via the inhibition of GSK3β. Conclusions The results show that LDN/OSU-0215111 provides benefits for multiple aspects of tauopathy-dependent pathology found in Alzheimer’s disease including tripartite synapse normalization and reduction of toxic tau burden, which, in turn, likely accounted for normalized cognition and activity levels in compound-treated rTg4510 mice. This study, in combination with our previous work regarding the benefit of pyridazine derivatives against amyloid-dependent pathology, strongly supports pyridazine derivatives as a viable, clinically relevant, and disease-modifying treatment for many of the facets of Alzheimer’s disease.
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spelling doaj.art-8667be5d6cb241dcb817f7bf96dab56b2022-12-21T18:52:12ZengBMCAlzheimer’s Research & Therapy1758-91932019-08-0111111910.1186/s13195-019-0530-zEnhancement of tripartite synapses as a potential therapeutic strategy for Alzheimer’s disease: a preclinical study in rTg4510 miceJoshua B. Foster0Rashelle Lashley1Fangli Zhao2Xueqin Wang3Nydia Kung4Candice C. Askwith5Lin Lin6Michael W. Shultis7Kevin J. Hodgetts8Chien-Liang Glenn Lin9Department of Neuroscience, College of Medicine, The Ohio State UniversityDepartment of Neuroscience, College of Medicine, The Ohio State UniversityDepartment of Neuroscience, College of Medicine, The Ohio State UniversityDepartment of Neuroscience, College of Medicine, The Ohio State UniversityDepartment of Neuroscience, College of Medicine, The Ohio State UniversityDepartment of Neuroscience, College of Medicine, The Ohio State UniversityDepartment of Neurology, Brigham and Women’s Hospital, Harvard Medical SchoolDepartment of Neurology, Brigham and Women’s Hospital, Harvard Medical SchoolDepartment of Neurology, Brigham and Women’s Hospital, Harvard Medical SchoolDepartment of Neuroscience, College of Medicine, The Ohio State UniversityAbstract Background The lack of effective treatment options for Alzheimer’s disease (AD) is of momentous societal concern. Synaptic loss is the hallmark of AD that correlates best with impaired memory and occurs early in the disease process, before the onset of clinical symptoms. We have developed a small-molecule, pyridazine-based series that enhances the structure and function of both the glial processes and the synaptic boutons that form the tripartite synapse. Previously, we have shown that these pyridazine derivatives exhibit profound efficacy in an amyloid precursor protein AD model. Here, we evaluated the efficacy of an advanced compound, LDN/OSU-0215111, in rTg4510 mice—an aggressive tauopathy model. Methods rTg4510 mice were treated orally with vehicle or LDN/OSU-0215111 (10 mg/kg) daily from the early symptomatic stage (2 months old) to moderate (4 months old) and severe (8 months old) disease stages. At each time point, mice were subjected to a battery of behavioral tests to assess the activity levels and cognition. Also, tissue collections were performed on a subset of mice to analyze the tripartite synaptic changes, neurodegeneration, gliosis, and tau phosphorylation as assessed by immunohistochemistry and Western blotting. At 8 months of age, a subset of rTg4510 mice treated with compound was switched to vehicle treatment and analyzed behaviorally and biochemically 30 days after treatment cessation. Results At both the moderate and severe disease stages, compound treatment normalized cognition and behavior as well as reduced synaptic loss, neurodegeneration, tau hyperphosporylation, and neuroinflammation. Importantly, after 30 days of treatment cessation, the benefits of compound treatment were sustained, indicating disease modification. We also found that compound treatment rapidly and robustly reduced tau hyperphosphorylation/deposition possibly via the inhibition of GSK3β. Conclusions The results show that LDN/OSU-0215111 provides benefits for multiple aspects of tauopathy-dependent pathology found in Alzheimer’s disease including tripartite synapse normalization and reduction of toxic tau burden, which, in turn, likely accounted for normalized cognition and activity levels in compound-treated rTg4510 mice. This study, in combination with our previous work regarding the benefit of pyridazine derivatives against amyloid-dependent pathology, strongly supports pyridazine derivatives as a viable, clinically relevant, and disease-modifying treatment for many of the facets of Alzheimer’s disease.http://link.springer.com/article/10.1186/s13195-019-0530-zAlzheimer’s diseaseGlutamate transporter EAAT2TauopathySmall-moleculerTg4510
spellingShingle Joshua B. Foster
Rashelle Lashley
Fangli Zhao
Xueqin Wang
Nydia Kung
Candice C. Askwith
Lin Lin
Michael W. Shultis
Kevin J. Hodgetts
Chien-Liang Glenn Lin
Enhancement of tripartite synapses as a potential therapeutic strategy for Alzheimer’s disease: a preclinical study in rTg4510 mice
Alzheimer’s Research & Therapy
Alzheimer’s disease
Glutamate transporter EAAT2
Tauopathy
Small-molecule
rTg4510
title Enhancement of tripartite synapses as a potential therapeutic strategy for Alzheimer’s disease: a preclinical study in rTg4510 mice
title_full Enhancement of tripartite synapses as a potential therapeutic strategy for Alzheimer’s disease: a preclinical study in rTg4510 mice
title_fullStr Enhancement of tripartite synapses as a potential therapeutic strategy for Alzheimer’s disease: a preclinical study in rTg4510 mice
title_full_unstemmed Enhancement of tripartite synapses as a potential therapeutic strategy for Alzheimer’s disease: a preclinical study in rTg4510 mice
title_short Enhancement of tripartite synapses as a potential therapeutic strategy for Alzheimer’s disease: a preclinical study in rTg4510 mice
title_sort enhancement of tripartite synapses as a potential therapeutic strategy for alzheimer s disease a preclinical study in rtg4510 mice
topic Alzheimer’s disease
Glutamate transporter EAAT2
Tauopathy
Small-molecule
rTg4510
url http://link.springer.com/article/10.1186/s13195-019-0530-z
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