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

Tabassum Majid; Deric Griffin; Zachary Criss 2nd; Matthew Jarpe; Robia G Pautler

doi:10.1016/j.trci.2015.08.001

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

Alzheimers Dement (N Y). 2015 Oct 11;1(3):170-181. doi: 10.1016/j.trci.2015.08.001. eCollection 2015 Nov.

Authors

Tabassum Majid¹, Deric Griffin¹, Zachary Criss 2nd¹, Matthew Jarpe², Robia G Pautler^{1

3

4}

Affiliations

¹ Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.
² Acetylon Pharmaceuticals, Boston, MA, USA.
³ Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
⁴ Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.

Abstract

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.

Keywords: ACY-738; Acetylated tubulin; Alzheimer's disease; Axonal transport; HDAC6; Microtubule; Preclinical; Therapeutic.