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Pharmocologic treatment with histone deacetylase 6 inhibitor (ACY-738) recovers Alzheimer's disease phenotype in amyloid precursor protein/presenilin 1 (APP/PS1) mice

INTRODUCTION: Current therapy for Alzheimer's disease (AD) focuses on delaying progression, illustrating the need for more effective therapeutic targets. Histone deacetylase 6 (HDAC6) modulates tubulin acetylation and has been implicated as an attractive target. HDAC6 is also elevated in postmo...

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Autores principales: Majid, Tabassum, Griffin, Deric, Criss, Zachary, Jarpe, Matthew, Pautler, Robia G.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975056/
https://www.ncbi.nlm.nih.gov/pubmed/29854936
http://dx.doi.org/10.1016/j.trci.2015.08.001
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author Majid, Tabassum
Griffin, Deric
Criss, Zachary
Jarpe, Matthew
Pautler, Robia G.
author_facet Majid, Tabassum
Griffin, Deric
Criss, Zachary
Jarpe, Matthew
Pautler, Robia G.
author_sort Majid, Tabassum
collection PubMed
description INTRODUCTION: Current therapy for Alzheimer's disease (AD) focuses on delaying progression, illustrating the need for more effective therapeutic targets. Histone deacetylase 6 (HDAC6) modulates tubulin acetylation and has been implicated as an attractive target. HDAC6 is also elevated in postmortem tissue samples from patients. However, HDAC6 inhibitors have had limited success preclinically due to low blood-brain barrier penetration. METHOD: We investigated a specific, potent HDAC6 inhibitor (ACY-738) in a mouse model of AD. We determined the effects of ACY-738 treatment on axonal transport, behavior, and pathology in amyloid precursor protein/presenilin 1 mice. RESULTS: We demonstrated improvements in in vivo axonal transport in two treatment groups as a result of ACY-738 brain levels. We also demonstrated recovery of short-term learning and memory deficits, hyperactivity, and modifications of tau and tubulin. DISCUSSION: Our findings implicate specific, targeted HDAC6 inhibitors as potential therapeutics and demonstrate that further investigations are warranted into effects of HDAC6 inhibitors in AD.
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spelling pubmed-59750562018-05-31 Pharmocologic treatment with histone deacetylase 6 inhibitor (ACY-738) recovers Alzheimer's disease phenotype in amyloid precursor protein/presenilin 1 (APP/PS1) mice Majid, Tabassum Griffin, Deric Criss, Zachary Jarpe, Matthew Pautler, Robia G. Alzheimers Dement (N Y) Featured Article INTRODUCTION: Current therapy for Alzheimer's disease (AD) focuses on delaying progression, illustrating the need for more effective therapeutic targets. Histone deacetylase 6 (HDAC6) modulates tubulin acetylation and has been implicated as an attractive target. HDAC6 is also elevated in postmortem tissue samples from patients. However, HDAC6 inhibitors have had limited success preclinically due to low blood-brain barrier penetration. METHOD: We investigated a specific, potent HDAC6 inhibitor (ACY-738) in a mouse model of AD. We determined the effects of ACY-738 treatment on axonal transport, behavior, and pathology in amyloid precursor protein/presenilin 1 mice. RESULTS: We demonstrated improvements in in vivo axonal transport in two treatment groups as a result of ACY-738 brain levels. We also demonstrated recovery of short-term learning and memory deficits, hyperactivity, and modifications of tau and tubulin. DISCUSSION: Our findings implicate specific, targeted HDAC6 inhibitors as potential therapeutics and demonstrate that further investigations are warranted into effects of HDAC6 inhibitors in AD. Elsevier 2015-10-11 /pmc/articles/PMC5975056/ /pubmed/29854936 http://dx.doi.org/10.1016/j.trci.2015.08.001 Text en © 2015 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Featured Article
Majid, Tabassum
Griffin, Deric
Criss, Zachary
Jarpe, Matthew
Pautler, Robia G.
Pharmocologic treatment with histone deacetylase 6 inhibitor (ACY-738) recovers Alzheimer's disease phenotype in amyloid precursor protein/presenilin 1 (APP/PS1) mice
title Pharmocologic treatment with histone deacetylase 6 inhibitor (ACY-738) recovers Alzheimer's disease phenotype in amyloid precursor protein/presenilin 1 (APP/PS1) mice
title_full Pharmocologic treatment with histone deacetylase 6 inhibitor (ACY-738) recovers Alzheimer's disease phenotype in amyloid precursor protein/presenilin 1 (APP/PS1) mice
title_fullStr Pharmocologic treatment with histone deacetylase 6 inhibitor (ACY-738) recovers Alzheimer's disease phenotype in amyloid precursor protein/presenilin 1 (APP/PS1) mice
title_full_unstemmed Pharmocologic treatment with histone deacetylase 6 inhibitor (ACY-738) recovers Alzheimer's disease phenotype in amyloid precursor protein/presenilin 1 (APP/PS1) mice
title_short Pharmocologic treatment with histone deacetylase 6 inhibitor (ACY-738) recovers Alzheimer's disease phenotype in amyloid precursor protein/presenilin 1 (APP/PS1) mice
title_sort pharmocologic treatment with histone deacetylase 6 inhibitor (acy-738) recovers alzheimer's disease phenotype in amyloid precursor protein/presenilin 1 (app/ps1) mice
topic Featured Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975056/
https://www.ncbi.nlm.nih.gov/pubmed/29854936
http://dx.doi.org/10.1016/j.trci.2015.08.001
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