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Combined targeting of pathways regulating synaptic formation and autophagy attenuates Alzheimer’s disease pathology in mice

All drug trials completed to date have fallen short of meeting the clinical endpoint of significantly slowing cognitive decline in Alzheimer’s disease (AD) patients. In this study, we repurposed two FDA-approved drugs, Fasudil and Lonafarnib, targeting synaptic formation (i.e., Wnt signaling) and ce...

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Autores principales: Bjorkli, Christiana, Hemler, Mary, Julian, Joshua B., Sandvig, Axel, Sandvig, Ioanna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9426773/
https://www.ncbi.nlm.nih.gov/pubmed/36052130
http://dx.doi.org/10.3389/fphar.2022.913971
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author Bjorkli, Christiana
Hemler, Mary
Julian, Joshua B.
Sandvig, Axel
Sandvig, Ioanna
author_facet Bjorkli, Christiana
Hemler, Mary
Julian, Joshua B.
Sandvig, Axel
Sandvig, Ioanna
author_sort Bjorkli, Christiana
collection PubMed
description All drug trials completed to date have fallen short of meeting the clinical endpoint of significantly slowing cognitive decline in Alzheimer’s disease (AD) patients. In this study, we repurposed two FDA-approved drugs, Fasudil and Lonafarnib, targeting synaptic formation (i.e., Wnt signaling) and cellular clearance (i.e., autophagic) pathways respectively, to test their therapeutic potential for attenuating AD-related pathology. We characterized our 3xTg AD mouse colony to select timepoints for separate and combinatorial treatment of both drugs while collecting cerebrospinal fluid (CSF) using an optimized microdialysis method. We found that treatment with Fasudil reduced Aβ at early and later stages of AD, whereas administration of Lonafarnib had no effect on Aβ, but did reduce tau, at early stages of the disease. Induction of autophagy led to increased size of amyloid plaques when administered at late phases of the disease. We show that combinatorial treatment with both drugs was effective at reducing intraneuronal Aβ and led to improved cognitive performance in mice. These findings lend support to regulating Wnt and autophagic pathways in order to attenuate AD-related pathology.
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spelling pubmed-94267732022-08-31 Combined targeting of pathways regulating synaptic formation and autophagy attenuates Alzheimer’s disease pathology in mice Bjorkli, Christiana Hemler, Mary Julian, Joshua B. Sandvig, Axel Sandvig, Ioanna Front Pharmacol Pharmacology All drug trials completed to date have fallen short of meeting the clinical endpoint of significantly slowing cognitive decline in Alzheimer’s disease (AD) patients. In this study, we repurposed two FDA-approved drugs, Fasudil and Lonafarnib, targeting synaptic formation (i.e., Wnt signaling) and cellular clearance (i.e., autophagic) pathways respectively, to test their therapeutic potential for attenuating AD-related pathology. We characterized our 3xTg AD mouse colony to select timepoints for separate and combinatorial treatment of both drugs while collecting cerebrospinal fluid (CSF) using an optimized microdialysis method. We found that treatment with Fasudil reduced Aβ at early and later stages of AD, whereas administration of Lonafarnib had no effect on Aβ, but did reduce tau, at early stages of the disease. Induction of autophagy led to increased size of amyloid plaques when administered at late phases of the disease. We show that combinatorial treatment with both drugs was effective at reducing intraneuronal Aβ and led to improved cognitive performance in mice. These findings lend support to regulating Wnt and autophagic pathways in order to attenuate AD-related pathology. Frontiers Media S.A. 2022-08-16 /pmc/articles/PMC9426773/ /pubmed/36052130 http://dx.doi.org/10.3389/fphar.2022.913971 Text en Copyright © 2022 Bjorkli, Hemler, Julian, Sandvig and Sandvig. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Bjorkli, Christiana
Hemler, Mary
Julian, Joshua B.
Sandvig, Axel
Sandvig, Ioanna
Combined targeting of pathways regulating synaptic formation and autophagy attenuates Alzheimer’s disease pathology in mice
title Combined targeting of pathways regulating synaptic formation and autophagy attenuates Alzheimer’s disease pathology in mice
title_full Combined targeting of pathways regulating synaptic formation and autophagy attenuates Alzheimer’s disease pathology in mice
title_fullStr Combined targeting of pathways regulating synaptic formation and autophagy attenuates Alzheimer’s disease pathology in mice
title_full_unstemmed Combined targeting of pathways regulating synaptic formation and autophagy attenuates Alzheimer’s disease pathology in mice
title_short Combined targeting of pathways regulating synaptic formation and autophagy attenuates Alzheimer’s disease pathology in mice
title_sort combined targeting of pathways regulating synaptic formation and autophagy attenuates alzheimer’s disease pathology in mice
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9426773/
https://www.ncbi.nlm.nih.gov/pubmed/36052130
http://dx.doi.org/10.3389/fphar.2022.913971
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